MANUSCRIPT CITATION: 

Tottman AC, Alsweiler JM, Bloomfield FH, Gamble G, Jiang Y, Leung M, et al. Long-Term Outcomes of Hyperglycemic Preterm Infants Randomized to Tight Glycemic Control. J Pediatr 2018; 193: 68-75.e1. DOI:10.1016/j.jpeds.2017.09.081. PMID: 29198539

REVIEWED BY

Anisha Bhatia, MD
Neonatal-Perinatal Medicine Fellow
Division of Neonatology, Department of Pediatrics
The University of Alabama at Birmingham

Ariel A. Salas, MD, MSPH
Assistant Professor
Division of Neonatology, Department of Pediatrics
The University of Alabama at Birmingham

TYPE OF INVESTIGATION 

 Treatment

QUESTION 

Does the use of insulin to achieve tight glycemic control of neonatal hypoglycemia change neurodevelopment, growth, and metabolism at school age?

METHODS

• Design: Ancillary Follow-up Study of Hyperglycemia in Neonates Trial (Randomized Controlled Trial)
• Allocation: Concealed; 1:1 ratio
• Blinding: Examiners were masked to allocation groups
• Follow-up Period: 7 years +/- 6 months corrected age
  • Outcomes assessed using:
    • Wechsler Intelligent Scale for Children Fourth Edition,
    • Movement Assessment Battery for Children 2
    • Visual and neurologic examinations
    • Growth assessments
    • Dual x-ray absorptiometry
    • IV glucose tolerance test
  • Setting:
    • All trial participants, formerly hospitalized at National Women’s Health NICU in Auckland, NZ (2005-2008), were eligible for follow-up assessment at 7 years +/- 6 months corrected age
  • Patients:
    • Included:
      • Born < 30 weeks gestational age
      • Birth weight < 1500 grams
      • Developed hyperglycemia (Blood Glucose [BG] >8.5 mmol/L [153 mg/dL] on 2 consecutive assessments 4 hours apart)
    • Excluded:
      • Hyperglycemia because of iatrogenic overdose of glucose
      • Major congenital malformation
      • Clinically judged to be dying
  • Intervention:
    • As per Hyperglycemia in Neonates Trial by Alsweiler et al., very low birth weight (VLBW) infants with hyperglycemia (as defined above) were randomized to a trial of tight glycemic control vs. standard glycemic control.
      • Tight glycemic control (n=43): BG maintained <8.6 mmol/L (<155 mg/dL) if not on insulin, or 4-6 mmol/L (72-108 mg/dL) if receiving insulin
      • Standard control (n=45): BG maintained <10 mmol/L (<180 mg/dL) if not on insulin, or 8-10 mmol/L (144-180 mg/dL) if receiving insulin
    • Tight glycemic control group started on insulin immediately at 0.05 U/kg
    • Standard practice group started on insulin (0.05 U/kg) if they met all of the following criteria:
      • BG >10 mmol/L (>180 mg/dL) or persistent glycosuria 2+
      • Tolerating <100 kcal/kg per day
      • >72 hours of age
      • Not acutely stressed
  • Outcomes:
    • Primary: Survival without neurodevelopmental impairment (NDI) at 7 years of age
      • Defined as any of the following:
        • Full-scale Intelligence Quotient (IQ) standard score > 1 SD below mean
        • Movement Assessment Battery for Children (MABC-2) total score ≤ 5^th percentile
        • Cerebral palsy
        • Visual acuity of 6/60 or worse in best eye
        • Hearing impairment requiring hearing aids
    • Secondary:
      • Individual components of primary outcome
      • Executive function
      • Growth
      • Glucose metabolism
      • Blood pressure
      • Body composition
      • Health
      • Quality of life
    • The reported primary and secondary outcomes of this follow-up study were not listed in the study protocol posted on TrialNet New Zealand (Trial registration code: ACTRN: 12606000270516)
  • Analysis and Sample Size:
    • Continuous variables were compared between groups using the 2-sample t test, or the Wilcoxon test if not normally distributed
    • Categorical data were compared using exact methods.
    • Primary and secondary outcomes were compared using unadjusted and adjusted linear regression, adjusted for sex, small-for-gestational age, birth plurality, clustering of twins
    • Randomization in Hyperglycemia in Neonates Trial was stratified by sex, weight, and average-for-gestational-age/small-for-gestational-age status
    • All analyses were adjusted for this
    • Prespecified potential confounders: gestational age, New Zealand Deprivation Index at birth, birth plurality and protein intake in first 14 postnatal days
    • These were assessed for balance between groups in the follow-up cohort
  • Patient Follow-up:
    • Of 88 patients initially included in the Hyperglycemia in Neonates Trial, 11 died and 57 patients were assessed at 7 years of age. Primary outcome information was available for 68 patients
    • Overall follow-up percentage included in analysis: 77%

MAIN RESULTS

Of the 68 infants randomized:
Children in the tight control group were:

• Shorter than those in the standard group (121.3 [6.3] cm vs 125.1 [5.4] cm; P < .05)
• , but had similar weight and head circumference
• Greater height-adjusted lean mass (18.7 [0.3] vs 17.6 [0.2] kg; P < .01)
• Lower fasting glucose concentrations (84.6 [6.30] vs 90.0 [5.6] mg/dL; P < .05)
• No other differences were seen in measures of body composition or insulin-glucose metabolism
• Survival without neurodevelopmental impairment occurred in 25 of 68 children (37%), with no significant difference between tight (14/35; 40%) and standard (11/33; 33%) glycemic control groups (P = .60).

CONCLUSIONS

The authors conclude that tight glycemic control for neonatal hyperglycemia does not change survival without neurodevelopmental impairment, but reduces height, increases height-adjusted lean mass, and reduces fasting blood glucose concentrations at school age.

COMMENTARY

Neonatal hyperglycemia, defined as BG 180-200 mg/dL, is associated with increased morbidity and mortality in very low birth weight infants (1, 2). While this follow-up study assesses long-term effects of insulin as first line therapy for neonatal hyperglycemia, other studies suggest that – despite unsubstantiated concerns that lowering dextrose infusion rates could limit caloric intake and growth – preventing neonatal hyperglycemia in ELBW infants in the first week of life through strictly controlled glucose infusion rates could be more beneficial than insulin in improving outcomes and reducing mortality (1, 3). Furthermore, treatment of neonatal hyperglycemia with continuous insulin infusions can increase the risk of hypoglycemia and adverse neurodevelopmental outcome. A consensus on management of neonatal hyperglycemia has not yet been established, with many institutions adopting individualized approaches (4).

Two Cochrane systematic reviews have concluded that current evidence does not support routine use of insulin to prevent hyperglycemia in VLBW neonates (5, 6). They also conclude that insufficient evidence exists to inform the practice of manipulating glucose infusion rates to reduce neonatal hyperglycemia (5, 6). In Beardsall et al.’s Neonatal Insulin Replacement Therapy in Europe (NIRTURE) trial, prophylactic early insulin therapy initiated in VLBW infants resulted in lower BG levels, increased incidence of hypoglycemia, and greater risk of death before 28 days (7). In the parent study of Tottman et al.’s ancillary study, Alsweiler et al. examined the effects of tight glycemic control on linear growth rate at 36 weeks in hyperglycemic preterm infants and concluded that insulin therapy increased weight gain and head growth at the expense of reduced linear growth and greater risk of hypoglycemia (8). However, this analysis was prone to ascertainment and observational biases due to more frequent glucose checks in the intervention group and lack of blinding of practitioners who titrated insulin doses. These biases persist into the current study by Tottman and colleagues (8). Furthermore, while Alsweiler et al.’s study protocol excluded infants with hyperglycemia due to iatrogenic overdose, it remains unknown whether initial dextrose infusions delivered were higher than needed to sustain basal metabolic rates (8). Similarly, it is unclear whether the duration of hyperglycemia was sufficient to warrant insulin treatment. While authors assessed neonatal cortisol levels at time of initial randomization, acute changes in stress reactive hormones may have exacerbated hyperglycemia, resulting in escalation of continuous insulin infusions in both tight and standard glycemic control arms (8).

The current study represents the first randomized controlled trial to report on school-aged outcomes from a trial of managing hyperglycemia with insulin in the neonatal period (2). Authors investigated whether tight glycemic control alters neurodevelopment, growth, and metabolism at school age, and focused on the primary outcome of survival without neurodevelopmental impairment at 7 years of age. They concluded that tight glycemic reduces height, increases height-adjusted lean mass, reduces fasting blood glucose concentrations at school age, but does not change survival without neurodevelopmental impairment (2). Only 37% of hyperglycemic preterm infants randomized to tight control survived without neurodevelopmental impairment, suggesting that the authors’ conclusions on survival are correct.

With respect to growth assessment, Tottman et al. followed subject’s leg length, weight, length, and head circumference percentiles and z-scores at 7 years corrected age. The authors hypothesize shorter leg length may explain reduced linear growth in the tight control group, a consistent finding noted previously at 36 weeks post-menstrual age (2). The reassessment of leg length at time of NICU discharge and 7-year follow-up provides a level of internal consistency within the two age groups, however this must be interpreted cautiously as several studies suggest knemometry is prone to measurement error and poorly correlates with nutritional status (9-11). Additionally, the conclusion that tight glycemic control increased height-adjusted lean body mass is questionable when overall weight and head circumference were not increased, and length was shortened (8). A more appropriate interpretation could be tight glycemic control decreased fat mass, however long-term metabolic implications of early tight glycemic control and/or insulin therapy in this population remain unknown.

As with all follow-up studies of similar design, attrition rates were low, with an overall follow-up rate of 77%. The authors appropriately recognized this study was underpowered to detect differences in survival without neurodevelopmental impairment between cohorts. A retrospective power calculation revealed this study had 80% power to detect a 36% absolute difference in primary outcome, which was substantially larger than the observed 7% difference in neurodevelopmental impairment between both groups (2).

This trial underscores the importance of long-term follow-up of medical interventions implemented during the neonatal period and further supports the conclusion that early insulin therapy does not modify long-term neurodevelopmental outcomes or survival. Until further studies can delineate the role of early insulin therapy in managing hyperglycemia with a randomized, blinded study design, the routine use of early insulin therapy cannot be recommended.

REFERENCES

1. Martin RJ, Fanaroff AA, Walsh MC. Fanaroff and Martin’s Neonatal-perinatal Medicine: Diseases of the Fetus and Infant: Elsevier/Saunders, 2015.
2. Tottman AC, Alsweiler JM, Bloomfield FH, Gamble G, Jiang Y, Leung M, et al. Long-Term Outcomes of Hyperglycemic Preterm Infants Randomized to Tight Glycemic Control. J Pediatr 2018; 193:68-75 e1.
3. Stensvold HJ, Lang AM, Strommen K, Abrahamsen TG, Ogland B, Pripp AH, et al. Strictly controlled glucose infusion rates are associated with a reduced risk of hyperglycaemia in extremely low birth weight preterm infants. Acta Paediatr 2018; 107 3:442-9.
4. Lemelman MB, Letourneau L, Greeley SAW. Neonatal Diabetes Mellitus: An Update on Diagnosis and Management. Clin Perinatol 2018; 45 1:41-59.
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7. Beardsall K, Vanhaesebrouck S, Ogilvy-Stuart AL, Vanhole C, Palmer CR, van Weissenbruch M, et al. Early insulin therapy in very-low-birth-weight infants. N Engl J Med 2008; 359 18:1873-84.
8. Alsweiler JM, Harding JE, Bloomfield FH. Tight glycemic control with insulin in hyperglycemic preterm babies: a randomized controlled trial. Pediatrics 2012; 129 4:639-47.
9. Pomeroy E, Wells JC, Cole TJ, O’Callaghan M, Stock JT. Relationships of maternal and paternal anthropometry with neonatal body size, proportions and adiposity in an Australian cohort. Am J Phys Anthropol 2015; 156 4:625-36.
10. Kinra S, Sarma KV, Hards M, Smith GD, Ben-Shlomo Y. Is relative leg length a biomarker of childhood nutrition? Long-term follow-up of the Hyderabad Nutrition Trial. Int J Epidemiol 2011; 40 4:1022-9.
11. Corsi DJ, Subramanyam MA, Subramanian SV. Commentary: Measuring nutritional status of children. Int J Epidemiol 2011; 40 4:1030-6.