Elsevier

Clinical Nutrition

Volume 35, Issue 5, October 2016, Pages 1059-1065
Clinical Nutrition

Original article
Low phosphatemia in extremely low birth weight neonates: A risk factor for hyperglycemia?

https://doi.org/10.1016/j.clnu.2015.07.019Get rights and content

Summary

Background & aims

Hyperglycemia occurs in more than half of the extremely low birth weight (ELBW) neonates during the first weeks of life, and is correlated with an increased risk of morbi-mortality. Hypophosphatemia is another frequent metabolic disorder in this population. Data from animal, adult studies and clinical observation suggest that hypophosphatemia could induce glucose intolerance. Our aim was to determine whether a low phosphatemia is associated with hyperglycemia in ELBW neonates.

Methods

This observational study included ELBW infants admitted in a tertiary neonatal care center (2010–2011). According to the center's policy, they received parenteral nutrition from birth and human milk from day 1. Phosphatemia and glycemia were measured routinely during parenteral nutrition. Hyperglycemia was defined by two consecutives values >8.3 mmol/L (150 mg/dL). Statistical analysis used a joint model combining a mixed-effects and a survival submodels to measure the association between phosphate and hyperglycemia.

Results

The study included 148 patients. Mean gestational (Standard Deviation) age was 27.3 (1.6) weeks; mean birth weight was 803 (124) grams; 57% presented hyperglycemia.

The multivariate joint model showed that the hazard of hyperglycemia at a given time was multiplied by 3 for each 0.41 mmol/L decrease of phosphate level at this time (p = 0.002) and by 3.85 for the same decreased of phosphate the day before (p = 0.0015).

Conclusion

To our knowledge, this is the first study suggesting that low phosphatemia can be associated with hyperglycemia in ELBW neonates. Further studies will have to demonstrate whether better control of phosphatemia could help in preventing hyperglycemia.

Introduction

Hyperglycemia is a frequent metabolic complication in critically ill neonates and was found to occur in more than a half of extremely low birth weight (ELBW) infants [1]. The frequency of this complication is inversely related to gestational age (GA) and birth weight (BW) [2]. Beside to induce an osmotic diuresis, dehydration, hyponatremia, hypokalemia and acidosis, studies suggest that hyperglycemia increases mortality [1], [2], [3], [4] and several serious morbidities as sepsis, intraventricular hemorrhage [5] or retinopathy of prematurity [6], [7]. Both insulin resistance and failure in pancreatic islet β-cell processing of pro-insulin could contribute to hyperglycemia in extremely preterm infants [8], but the pathogenesis remains to be elucidated. The identification of risk factors and mechanisms associated to glucose intolerance is thus especially important in the context of neonatal care [1], [2], [3], [9]. There is so far no consensus on safe and efficient management of glucose intolerance, as both insulin treatment and reduction in glucose intakes can be deleterious [10], [11], [12], [13].

Hypophosphatemia is another frequent metabolic disorder in premature newborns, especially in very low birth-weight infants (VLBW) and in small for gestational age (SGA) neonates, although normal values at this age remain uncertain [14], [15], [16], [17]. In the critically ill children, it has been associated with a longer duration of mechanical ventilation and with a longer duration of stay in the pediatric intensive care unit [18]. In the preterm newborn, hypophosphatemia is frequently associated to postnatal growth deficiency and osteopenia of the preterm [19], [20] and has been recently incriminated in susceptibility for septicaemia in VLBW [21]. Various mechanisms have been raised, like limited storage, insufficient intakes in the first days or a re-feeding like syndrome in VLBW undergoing enhanced nutrition [22].

Due to our common clinical observation of hypophosphatemia preceding severe and persistent hyperglycemia, we drafted the hypothesis that hypophosphatemia could play a role in glucose intolerance in the preterm neonate. This hypothesis was sustained by some experimental studies and adult data, where hypophosphatemia could be involved in insulin resistance found in metabolic syndrome [23], [24]. Two mechanisms have been involved; first, hypophosphatemia leads to a low adenosine triphosphate (ATP) intracellular rates; in the beta cells of the pancreas, the consequent dysfunction in ATP-ase activity may lead to a reduction in the insulin production [8], [25]. Secondly, phosphorus is involved in phosphorylation of the insulin cell-receptor, which could thus be less efficient in case of low phosphatemia [25]. Whether hypophosphatemia is a risk factor for hyperglycemia in preterm neonates remains to be elucidated [26].

The aim of our study was to further investigate the association of low phosphate and the risk of glucose intolerance, defined as persistent hyperglycemia >8.3 mmol/L (>150 mg/dL) during the two first weeks of life in an ELBW cohort.

Section snippets

Patients

This study was conducted in a tertiary level Neonatal Intensive Care Unit (NICU) between January 2010 and December 2011 at the University Hospital “Femme Mère Enfant”, Lyon, France. The study population was a subset of a retrospective cohort study that was implemented in the NICU in order to monitor and assess several nutritional and growth issues in extremely low birth-weight infants [27]. It was approved by the Institutional Review Boards.

We included neonates without major congenital

Population characteristics

In all, 156 ELBW patients were admitted on their first day of life during the study period; 8 of them were excluded (no available phosphatemia in 7 cases, and 1 major congenital malformation). The main characteristics of the 148 included patients are described in Table 1.

The longitudinal submodel

In all, 469 phosphate measurements were available from the 148 patients; that is, 3.2 measurements per patient on average. Figure 1 shows these measurements over time as well as the mean curve based only on the fixed-effect

Discussion

Our study reveals that a low phosphate during the first two weeks of life is a risk factor of hyperglycemia in ELBW infants. According to our results, the risk of persistent hyperglycemia >8.3 mmol/L (>150 mg/dL) is multiplied by 3 for a decrease of 0.41 mmol/L of phosphate and by 3.85 for the same decreased of phosphate the day before. These results were statistically significant and controlled for several nutritional and clinical features, as phosphate intakes, GA, BW and SGA. To our

Authors' contributions

LD and CJFF designed the study and the data collection methods, participated in data collection and analysis, and prepared the manuscript.

DMB and LR were responsible for the statistical analyses and were involved in the manuscript preparation and revisions.

MCEMMO participated in the study development, the data collection and the manuscript revision.

SL was involved in the study drafting and critically reviewed the manuscript.

OC supervised the entire study, was involved in its design, conduct,

Conflict of interest

On behalf of all authors, the corresponding author states that there is no conflict of interest.

Acknowledgment

The authors are grateful to Mr. Jean IWAZ (Hospices Civils de Lyon, Department of Biostatistics) for the editorial revision of the manuscript, and to Mrs. Anne BLESS (Scientific Communication, Corseaux, Switzerland) for her assistance in English writing.

CF is grateful to the non-commercial foundations SICPA, SA, Switzerland and Société Académique Vaudoise, Switzerland, for their research grants obtained during the study period.

References (29)

  • E. Kermorvant-Duchemin et al.

    Neonatal hyperglycemia inhibits angiogenesis and induces inflammation and neuronal degeneration in the retina

    PLoS One

    (2013)
  • J.W. Kaempf et al.

    Hyperglycemia, insulin and slower growth velocity may increase the risk of retinopathy of prematurity

    J Perinatol

    (2011)
  • D. Mitanchez-Mokhtari et al.

    Both relative insulin resistance and defective islet beta-cell processing of proinsulin are responsible for transient hyperglycemia in extremely preterm infants

    Pediatrics

    (2004)
  • G. Alexandrou et al.

    Early hyperglycemia is a risk factor for death and white matter reduction in preterm infants

    Pediatrics

    (2010)
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