In Response to: Stalter EJ, et al. Somatic Growth Outcomes in Response to an Individualized Neonatal Sodium Supplemental Protocol.

Sodium is an essential nutrient involved in maintenance of cellular homeostasis, regulation of fluid and electrolyte balance, as well as control of blood volume, blood pressure, and muscle and nerve conduction [1]. However, the role of sodium homeostasis in somatic growth has been underappreciated. Studies including Stalter et al.’s newly published cohort in this issue of the Journal, suggest sodium supplementation to maintain homeostasis likely plays a critical role in optimizing growth in preterm infants [2].

Sodium handling primarily occurs in the kidney. As blood passes through the glomerulus, sodium is freely filtered then reabsorbed at several sites [3]. Sodium reabsorption occurs via specific transporters at each site and is mediated, in part, by neurohumoral factors including atrial natriuretic peptide, aldosterone, and the renin-angiotensin system [4]. In preterm neonates, decreased glomerular filtration rates, glomerular tubular imbalance, and diminished transporter responsiveness to neurohumoral factors result in significant renal sodium losses that can persist for weeks after birth (Fig. 1) [3, 4].

Inadequate intake (especially in those with predominantly enteral nutrition), high renal and gastrointestinal losses contribute to low body sodium content. Inadequate sodium supplementation decreases absorption of glucose through the sodium-glucose cotransporter (SGLT-1) resulting in suboptimal stimulation of enteroendocrine cells resulting in low growth factor levels [5]. In addition, poor carbohydrate absorption can lead to intestinal dysbiosis and contribute to poor growth. Supplementation of sodium potentially enhances glucose absorption and stimulates neuroendocrine cells to produce growth factors. Healthy intestinal microbiome and normal sodium content may contribute to better growth in extremely preterm infants.

Without supplementation, ongoing renal losses frequently lead to significant sodium depletion in preterm infants, and somatic growth may subsequently suffer. Though the exact mechanisms by which sodium depletion impairs somatic growth are unknown, one potential mechanism implicates enteroendocrine intestinal cells. Intestinal glucose absorption is mediated predominately by a sodium-glucose transporter (e.g., SGLT-1). Inadequate sodium supplementation decreases absorption of glucose through SGLT-1 resulting in suboptimal stimulation of enteroendocrine cells and subsequently low growth factor levels. Additionally, poor carbohydrate absorption can lead to intestinal dysbiosis and contribute to poor growth. These mechanisms underline the critical role sodium plays in nutrient absorption and energy homeostasis (Fig. 1) [5].

Adequate supplementation of sodium may improve growth in preterm neonates. In prior work, Segar et al. utilized a clinical algorithm to identify preterm infants with sodium deficiency and guide supplementation, resulting in improved weight Z-scores [6]. In a randomized trial of sodium supplementation versus placebo in preterm infants, supplemented infants had less hyponatremia and greater growth velocity. The strongest findings were noted in those <28 weeks’ who experienced greater percent weight change from birth and maintained fetal reference birth percentile for body weight more often [7]. A recent metanalysis comparing higher to lower sodium supplementation before one week of age in preterm infants suggests higher supplementation may result in increased hypernatremia, similar incidence of hyponatremia, and unknown effect on growth, yet supplementation after one week may reduce hyponatremia and growth failure [8].

In this issue, Stalter et al. report on postnatal growth of 26-29 week and 30–33 week gestation infants before and after implementation of a sodium supplementation protocol. Infants with a low serum sodium or low urine sodium received sodium supplementation 4 mEq/kg/day above routine intake (Fig. 2). Post-protocol, 26–29 week gestation infants had increased gain in weight and head circumference, reduced duration of invasive mechanical ventilation, and lower incidence of culture-positive sepsis. No differences in growth were observed in the 30–33 week infants. Notably, the study did not evaluate 22–25 week infants. The physiological explanations for increased weight gain in the sodium supplemented epoch are unclear. Increased fluid retention is a likely possibility although increased head circumference suggests true somatic growth.

Supplementation was stopped when serum sodium (Na) exceeded 144 mEq/L or at a postmenstrual age (PMA) of 38 weeks. PA postnatal age, BPD bronchopulmonary dysplasia, NEC necrotizing enterocolitis.

Notably, sodium supplementation was based, in part, on urine sodium concentrations, a key factor in evaluating and treating sodium depletion in preterm neonates. Serum sodium concentrations reflect the relative relationship between salt and water, rather than total body sodium. Thus, urinary sodium concentrations help to assess sodium depletion and guide supplementation [3, 9].

Should we routinely check urine sodium in preterm infants and provide sodium supplementation if urine levels are low? If there is evidence of poor somatic growth despite adequate intake, evaluating urine sodium levels and providing sodium supplements is reasonable. Caution should be exercised, as sodium supplementation is considered in any preterm infant. Abrupt changes in serum sodium during the first month of life are associated with long-term neurologic issues [3, 10]. Potential complications of sodium supplementation include hypernatremia with resultant fluid retention and subsequent hypertension, respiratory compromise, intraventricular hemorrhage, seizures, and thrombosis [11]. However, sodium depletion may predispose to poor neurodevelopmental outcomes in addition to growth failure [12].

Before this approach can be routinely recommended as the standard of care, a randomized controlled trial evaluating sodium supplementation based on urine sodium levels in preterm infants is warranted.