Very low birth weight (VLBW) preterm infants (birth weight < 1500 g) are at high risk of stunted postnatal growth due to the premature interruption of placental nutrient transfer at a critical time of growth and development.1 To address this problem, current guidelines recommend combining early aggressive parenteral nutrition (PN) to ensure high energy and protein intakes with breast milk.2–5

Although this strategy has proven effective in optimising postnatal nutrition and neurodevelopmental outcomes, findings from several recent studies suggest that a high amino acid intake (>3 g/kg/day) may cause electrolyte imbalances in this population, particularly involving calcium-phosphorus metabolism.4–9

As described in the literature, high energy and amino acid intakes in the first week of life would maintain cells in an anabolic state, leading to an increase in the cellular uptake of phosphorus and potassium, which are required for nucleic acid and adenosine triphosphate production, among other processes. Inadequate intake of phosphorus and potassium results in depleted plasma levels of these electrolytes and increased calcium levels largely resulting from bone resorption.6–8 This process has been referred to as “placental interrupted feeding syndrome of the preterm infant”.10–12

In a randomised controlled trial that compared two feeding protocols in VLBW infants, Moltu et al.7 found a higher prevalence of hypercalcaemia, hypophosphataemia, and hypokalaemia and a higher risk of septicaemia in infants who received 3.5 g/kg/day of amino acids compared to infants in a control group receiving approximately 2 g/kg/day. On their part, Bonsante et al.8 found a correlation between different amino acid intakes (< 1.5 g/kg/day, 1.5−2 g/kg/day, and > 2 g/kg/day) and the development of hypercalcaemia and hypophosphataemia, observing that these disturbances were more common in infants with higher intakes. More recently, Brener et al.9 reported an association between aggressive PN and hypercalcaemia and hypophosphataemia when comparing preterm infants managed with an aggressive nutrition regimen (2.3-3.7 g/kg/day) to controls managed with a standard regimen (2.5-3.1 g/kg/day).

Electrolyte imbalances frequently do not cause symptoms, as they are corrected early. Hypercalcaemia (defined as a total calcium level > 3.5 mmol/L or an ionized calcium level > 1.73 mg/dL), however, may cause vomiting, irritability and even ventricular arrhythmia, while severe hypophosphataemia (phosphate level < 0.9 mmol/L) is associated with muscle weakness, delayed weaning from ventilatory support, and nosocomial infections.12,13

The aim of our study was to evaluate the association between the amount of protein delivered through PN and the presence of electrolyte imbalances (hypercalcaemia, hypophosphataemia, and hypokalaemia) in a cohort of VLBW preterm infants.

Our secondary objectives were to analyse the timing of the onset and the duration of phosphate and calcium imbalances and to assess the appropriateness of the calcium-to-phosphorus ratio (CA:P) of the PN solution used in our hospital.

We considered 135 preterm infants managed with PN for inclusion in the study, of who we excluded 21 on account of missing data or failure to meet the inclusion criteria. This resulted in a final sample of 114 preterm infants. The analysis included a total of 306 phosphate, 503 calcium, and 464 potassium measurements.

Tables 1 and 2 present the perinatal characteristics and nutrient intakes by group. There were 60 patients in the low-intake group (amino acid intake <3 g/kg/day) and 54 in the high-intake group (≥3 g/kg/day). The groups were comparable in terms of demographic and clinical characteristics save for sepsis, which was greater in the high-intake group, although this difference was not statistically significant. When we compared PN and EN intakes in both groups, we found significant differences for all nutrients and electrolytes except the intake of magnesium through PN.

The multivariate analysis did not detect any significant associations of plasma calcium levels with perinatal variables, PN or EN intake, or Ca:P ratios. The only variables significantly associated with plasma phosphorus levels were the intake of potassium (P = .017) and calcium (P = .01) through PN. Likewise, the only significant modifiers of plasma potassium levels were the doses of calcium (P = .002) and phosphorus (P = .05) delivered through PN.

Table 3 presents the mean calcium, phosphorus, and potassium levels for each group and the absolute frequency and percentage of patients that developed hypercalcaemia, hypophosphataemia and hypokalaemia.

Fig. 1 charts the daily plasma levels of calcium and phosphate, evincing a clear trend towards hypercalcaemia and hypophosphataemia as days passed.

Figure 1.

Plasma levels of calcium and phosphorus in 60 infants that received 3 g/kg/day of amino acids (low-intake group) and 54 infants that received 3 or more g/kg/day (high-intake group). Mean and 95% confidence interval.

(0.14MB).

When we assessed the associations between the Ca:P ratio and the doses of electrolytes delivered through PN, we found that a ratio greater than 1.05:1 protected against moderate hypophosphataemia (P = .007), while lower ratios increased its risk (P = .072). This protective effect was observed for ratios up to 1.4:1.

When we analysed the associations between the Ca:P and the overall doses of electrolytes delivered through PN, EN, and additional fluids, we found that a ration greater than 1.00:1 (to up to 1.3:1) protected against moderate hypophosphataemia (P = .043), while lower ratios increased its risk (P = .128).

In recent years, several authors have proposed that there is a link between early aggressive PN in preterm infants and serious metabolic disorders.7–9,15–18 There is evidence that nutrition in the first days of life affects calcium, phosphorus, and potassium metabolism and may cause refeeding syndrome.8,10–12

We found a similar prevalence of hypercalcaemia, hypophosphataemia, and hypokalaemia in preterm infants managed with PN that received at least 3 g/kg/day of amino acids (high-intake group) and those that received doses of less than 3 g/kg/day (low-intake group).

In the randomised controlled trial that compared two groups of VLBW infants, Moltu et al.7 found that infants who received a mean 3.7 g protein/kg/day (SD, 0.11) exhibited better postnatal growth compared to those who received a mean of 2.5 g/kg/day (SD, 0.18), but the incidence of electrolyte imbalances (hypercalcaemia, hypophosphataemia and hypokalaemia) and septicaemia was also higher in the high-protein group. Bonsante et al.8 also observed a higher incidence of hypophosphataemia and hypercalcaemia in preterm infants that received high amino acid doses (2.3 ± 0.8 g/kg/day) compared to infants receiving intermediate doses (1.49 ± 0.34 g/kg/day) or low doses (1.2 ± 0.8 g/kg/day). Brener et al.9 reported similar findings of a retrospective study that compared infants given 3.3 to 3.7 g of amino acids/kg/day versus 2.5 to 3.1 g/kg/day.

In our cohort, the mean amino acid intakes were 2.67 ± 0.3 g/kg/day in the low-intake group and 3.21 ± 0.24 g/kg/day in the high-intake group. The main reason the difference was this small that formulation of PN was dictated by the hospital guidelines.14 Besides being similar, these values were quite high, so that differences in amino acid intake may not have been large enough to have an impact on outcomes, a fact that set our sample apart from the samples analysed in the studies discussed above. This may also explain why we found no correlation between amino acid intake and electrolyte imbalances. In other words, most of the infants in our study received less than 2.6 g of protein/kg/day so that their risk of developing electrolyte imbalances was similar.7–9,15–18 On the other hand, although we found differences between groups the amount of electrolytes delivered through PN, once the contribution through EN was taken into account, there were no overall differences in the total amounts of electrolytes received by each group. In addition, as PN solutions in our hospital are customised to meet individual requirements every day, the early correction of plasma electrolyte imbalances may explain the low prevalence rates we observed. Another factor to take into account is that although the use of supplemental electrolytes was similar between groups, it could have contributed to such early correction, but we are unable to establish causality with the data available to us.

Electrolyte imbalances were considerably less frequent in our cohort compared to other studies except for ionized calcium. We classified hypophosphataemia into 3 categories based on plasma phosphorus levels. We found mild hypophosphataemia (<1.29 mmol/L) in 36.6% (22/60) of patients in the low-intake group and 38.9% (21/54) of patients in the high-intake group. Applying the same cut-off point to define hypophosphataemia as us, Moltu et al.7 and Brener et al.9 reported frequencies of 77% (36/40 patients) and 90% (17/22 patients), respectively, in the groups of infants with a high amino acid intake. The frequency of moderate hypophosphataemia (<1.1 mmol/L) in our sample was 21.7% (13/60 patients) in the low-intake group and 27.8% (15/54 patients) in the high-intake group. In yet another study that applied the same cut-off point, Brener et al.20 found that 58.3% (35/60) of patients that received 3 to 3.5 g/kg/day of amino acids developed moderate hypophosphataemia. Last of all, we found severe hypophosphataemia (<0.9 mmol/L), which can be clinically relevant, was 11.7% (7/60) of patients in the low-intake group and in 9.3% (5/54) of patients in the high-intake group.12,13 Applying a similar cut-off point (< 1 mmol/L), Bonsante et al.8 found that 18.9% (11/53) of infants in the high-intake group developed severe hypophosphataemia.

We analysed total and ionized calcium plasma levels, as the former vary in relation to albumin levels, which are generally low in preterm infants. Based on the total calcium level, only 1 patient in each group had hypercalcaemia. This low prevalence contrasts sharply with the rates of 6.2% (3/48 patients) and 30.2% (16/53 patients) reported by Bonsante et al.8 for infants receiving low and high amino acid doses, respectively. The prevalence of hypercalcaemia based on plasma levels of ionized calcium, however, was much higher: 70% (42/60) in the low-intake group and 79.6% (43/54) in the high-intake group. Brener et al.9 reported a similar proportion of 87% (35/40) in patients given higher doses of amino acids.

Lastly, we found hypokalaemia in 15% (9/60) of patients in the low-intake group and 11.11% (6/54) of patients in the high-intake group. Once again, these proportions contrast sharply with the corresponding proportions of 46% (11/24 patients) and 88% (21/24 patients) reported by Moltu et al.7

Both hypophosphataemia and hypercalcaemia tended to occur towards the end of the PN period in our series, which was consistent with the findings of Moltu et al.7 and Bonsante et al.,8 although their groups reported lower phosphorus and higher calcium levels. This could be due to refeeding syndrome, which typically develops after 2 or 3 days, or to increments in enteral feeding volumes during the PN period, which reduced the opportunity to correct electrolyte imbalances.

Phosphorus is an essential mineral for cell metabolism, as it is involved in adenosine triphosphate production and correct immune cell function. Phosphorus depletion has been linked to neuromuscular weakness, insulin resistance, extubation failure, and sepsis.7,12,13,19–21 Sepsis was more common in preterm infants fed higher amounts of amino acids in the randomized controlled trials of Moltu et al.7 and Brener et al.7,20 In our study, sepsis was also more frequent in the high-intake group, although not significantly so.

According to both Senterre et al.21 and the ESPGHAN/ESPEN/ESPR/CSPEN guidelines on paediatric PN, a Ca:P ratio of 0.8 to 1.1:1 should be maintained in the first week of life in VLBW preterm infants. This ratio achieves a reduction in the incidence of hypophosphataemia and therefore hypercalcaemia in patients with optimised protein and energy intakes who do not receive nutrition high in calcium and phosphorus (0.8-2 and 1-2 mmol/kg/day, respectively). A higher ratio is recommended after the first week (1-1.3:1), as calcium and phosphorus requirements also increase during this period (to 1.6–3.5 and 1.6–3.5 mmol/kg/day, respectively).13,21

In our series, a Ca:P ratio greater than 1.05 had a protective effect against moderate hypophosphataemia (P = .007) while lower ratios increased the risk (P = .072). Thus, use of higher-than-recommended ratios (up to 1.4:1 possibly) in the first week of life might reduce the incidence of hypophosphataemia in VLWB preterm infants.

Perinatal disorders and congenital anomalies cause 76.2% of deaths in infants aged less than 1 year in our setting, and mortality in newborns under 28 days of age in 2016 was 16.5%.22 In our series, the mortality at 30 days was 3.3% in the low-intake group, and 7.4% in the high-intake group. Considering that we excluded infants with congenital anomalies, this figure is consistent with data from our setting. None of the study variables was associated with higher mortality.

There are some limitations to our study intrinsic to its retrospective and observational design. Reviews of health records are typically limited by missing information and potential bias. Daily blood test results were not available for all infants, as these tests are ordered as deemed necessary. Another important limitation was that both groups end up having high protein intakes because PN prescription is dictated by hospital guidelines. Besides, there was a difference in the protein intake on day 1 depending on whether patients were given standard PN the study protocol was applied. Another limitation is that we assumed that most of the EN administered to the infants was in the form of mature donor human milk, but we were unable to differentiate between different compositions based on the maturity of the milk. Nevertheless, data were available for a considerable number of the included patients for the period under study.

In conclusion, our analysis of a sample of VLBW preterm infants given high amino acid doses did not find an association between hypercalcaemia, hypophosphataemia, and hypokalaemia and the amino acid dose delivered through PN. However, we did find that optimising the Ca:P ratio in PN could have a protective effect against hypophosphataemia in this population, and therefore believe that this is an option worth considering.