Table 2.
Summary of Results
| van der Lugt, 20107 | Heald, 201227 | Ramel, 201324 | Scheurer, 201625 | Tottman, 20176 | Tottman, 201826 | Zamir, 201928 | Gonzalez Villamizar, 202023 | |
|---|---|---|---|---|---|---|---|---|
| Location | Leiden University Medical Center, The Netherlands | Australian National University Medical School, Canberra Hospital, Australia | University of MN Children’s Hospital, Minneapolis, MN, USA | University of MN Children’s Hospital, Minneapolis, MN, USA | National Women’s Hospital; Auckland, New Zealand | National Women’s Hospital; Auckland, New Zealand | Sweden (Lund, Umea, Stockholm) | University of MN Children’s Hospital, Minneapolis, MN, USA |
| Study design | Retrospective follow-up | Retrospective | Retrospective | Prospective observational | Retrospective observational cohort | Randomized control trial, follow-up | Prospective, population-based cohort | Retrospective post-hoc analysis from prospective study |
| Population | 24-32 weeks GA, Jan 2002 - Dec 2006 | 25-28 weeks GA, Jan 2006 - Dec 2008 | 22-30 weeks GA, AGA infants, Jan 2003 - July 2007 | AGA VLBW infants, April 2011 to Nov 2012 | 23-35 weeks GA, July 2005 - Oct 2008 | <1500 grams or <30 weeks GA, HINT 2005-2008 | <27 weeks GA, April 2004 - March 2007 | 22-32 weeks GA, Feb 2012 - June 2016 |
| Exposure | Hyperglycemia | Hyperglycemia treated with insulin | Hyperglycemia | Hyperglycemia | Hyperglycemia | Hyperglycemia | Hyperglycemia | Hyperglycemia |
| Definition (hyperglycemia) | ≥2 BG 180 mg/dL (≥10.0 mmol/L) during a 12-hour period | ≥2 BG of 180 mg/dL (≥10.0 mmol/L) during a 12-hour period | BG >150 mg/dL (>8.3 mmol/L) | BG >150 mg/dL (>8.3 mmol/L); Moderate (1-5) and severe (>5) hyperglycemia days | ≥ 2 measures of BG ≥155 mg/dL (≥8.6 mmol/L) >1 hour apart or any BG ≥182 mg/dL (≥10.1 mmol/L) | 2 consecutive measures of BG≥153 mg/dL (≥8.5 mmol/L) at least ≥4 hour apart | Tiers of assessment: BG >180 mg/dL (>10.0 mmol/L), >216 mg/dL (>12.0 mmol/L), 252 mg/dL (>14.0 mmol/L) | BG >150 mg/dL (>8.3 mmol/L) |
| Comparator | Age matched controls without hyperglycemia | No insulin treatment | Normoglycemia | Normoglycemia | Normoglycemia (study included 2 additional groups: hypoglycemia and unstable glycemia) | Hyperglycemic neonates randomized to tight (treated with insulin) vs. standard (+/− insulin treatment) glycemic control | Normoglycemia | 3 groups: normoglycemia; 1-4 days of hyperglycemia; >5 days of hyperglycemia |
| Sample size * | N=96(n=33 hyperglycemia; n=63 without hyperglycemia) | N=97 (n=80 no insulin, n=17 insulin) | N=80 | N=50 (n=30 normoglycemia, n=12 1-5 days of hyperglycemia, n=8 >5 days of hyperglycemia) | N=360 (n=287 normoglycemic, n=73 hyperglycemic) | N=88 (n=43 tight glycemic control, n=45 standard glycemic control) | N=171 | N=97 |
| Incidence (hyperglycemia) * | 8% (25% of ELBW infants) | 17.5% hyperglycemia + insulin drip | 77% | 45% (26% moderate, 19% severe) | 16% | All infants in cohort | 47% | 49% (27% <5 days; 22%≥5 days) |
| Assessment (glucose) | Whole blood | Not reported | Not reported | Not reported | Whole blood (blood gas analyzer) | Whole blood (glucose oxidase method) | Plasma | Not reported |
| Treatment (hyperglycemia) | Insulin (0.05 U/kg/hr) was started when hyperglycemia persisted >12 hrs despite reduction of GIR of 5-6 mg/kg/min | Insulin (0.01 u/kg/hr) was started when BG>180-216 mg/dL + glycosuria on 10% dextrose | At discretion of neonatologist, general guideline: limit GIR to 7 mg/kg/min followed by insulin bolus/infusion | At discretion of neonatologist, general guideline: limit GIR to 7 mg/kg/min followed by insulin bolus/infusion | Reducing GIR or initiation of insulin infusion to maintain BG of 72-180 mg/dL (4-10 mmol/L) | •Standard glycemic control: BG maintained <180 mg/dL (<10.0 mmol/L). Insulin treatment when BG>180 mg/dL (>10.0 mmol/L) or persistent glycosuria >2+; tolerating < 100 kcal/kg/day; >72 hours of age, and not acutely stressed. •Tight control: BG maintained <155 mg/dL (<8.6 mmol/L) with insulin treatment •Insulin treatment: Insulin (0.05 u/kg/hr) was infused to maintain BG in standard group 144-180 mg/dL (8-10 mmol/L) or in tight group 72-108 mg/dL (4-6 mmol/L) |
At the discretion of neonatologist | At discretion of neonatologist, general guideline: limit GIR to 7 mg/kg/min followed by insulin bolus/infusion |
| Age (outcome measurement) | 2 years (±3 months) CGA | 12 months CGA | Discharge, 4 months, 12 months, and 24 months CGA | Term CGA, 4 months CGA | 2 years CGA | 7 years CGA (±6 months) | 6.5 years (±3 months) | Discharge, 4 months CGA (metabolic outcomes), 12 months CGA (neurodevelopment outcomes) |
| Growth outcomes | No difference in weight, length, OFC | No difference in <10th percentile weight, length, OFC | •Decrease in weight •No difference in length or OFC •Decrease in growth velocity correlated with >5 days of hyperglycemia |
≥5 days of hyperglycemia associated with: •Increase in weight •Decrease in length and OFC |
Not reported | •Decrease in height, leg-length, and growth velocity between 36 weeks CGA to 7 years CA in tight control group •No differences in weight, sitting height, OFC, or BMI |
Not reported | Not reported |
| Metabolic outcomes | Not reported | Not reported | Not reported | ≥5 days of hyperglycemia is associated with increases in fat free mass, fat mass, and percent body fat | Not reported | •Lower fasting glucose in tight group •Lower height adjusted lean mass in tight group •No differences in abdominal circumference, blood pressure, fasting insulin concentration, glucose effectiveness, glucose disappearance constant, acute insulin response to glucose, insulin sensitivity, fat mass, height-adjusted fat mass, android/gynoid fat ratio, lean mass, bone mineral density, height-adjusted bone mineral density |
•Increased daily carbohydrate intake was associated with increased z-score for both SBP and DBP •BG>216 mg/dL (12 mmol/L) >2 days was associated with higher SBP z-scores •BG>180 mg/DL (10 mmol/L) for >3 days or >216 mg/dL (12 mmol/L) for >2 days was associated with higher DBP •Duration of BG>216 mg/dL (12 mmol/L) was positively associated with DBP z-score •BG>252 mg/dL (14 mmol/L was positively associated with both SBP and DBP z-scores |
Hyperglycemia ≥5 days was negatively associated with fat free mass z score a 4 months’ PMA |
| Neurodevelopment outcomes | •Increased abnormal neurological examination with hyperglycemia •Increased abnormal Child Behavior Checklist/2-3 with hyperglycemia •Insulin treatment did not affect outcomes |
•No differences in GQ/MDI <-2SD on either GMDS or BSID-II, CP incidence, need for walking aids, bilateral blindness, or bilateral hearing loss | •Increase in cognitive BSID-III scores •No difference in language or motor BSID-III scores |
Not reported | Decreased OR of survival without neurodevelopment impairment on BSID-II or BSID-III | •No differences in neurodevelopment impairment (WISC-IV full scale IQ<85, MABC-2 total score <5th percentile, CP, blind, deaf) between tight and standard glycemic control in hyperglycemic infants •No difference in cognitive (WISC-IV), motor (MABC-2), or executive function (BRIEF) between groups |
Not reported | Hyperglycemia for ≥5 days was negatively associated with cognition, language, and motor scores on the BSID-III |
| Sex-specific outcomes | Not reported (63% male, no differences between groups) | Not reported | Not reported (50% male) | Not reported (51% male, no differences between groups) | Not reported (55% male, no differences between groups) | Not reported (48% male, no differences between groups) | Not reported (56% male, no differences between groups) | Not reported (52% male, no differences between groups) |
| Follow-up rate | 87% | 95% | 100% at 1-year follow-up; 78% at 2-year follow-up | 95% at discharge from NICU; 89% at 4-month CGA follow-up | 65% at 2-year follow-up | 78% for primary outcome (survival without neurodevelopment impairment); 65% follow-up at 7 years | 35% of initial population-based cohort | 78% at 4 months; 68% at 12 months |
| Confounders | • Gestational age, gender, birth weight, length of stay, exposure to steroids, presence of severe RDS, sepsis, PROM, chorioamnionitis, NEC, BPD, PVL, and IVH. •Confounding was minimized by matching and using multivariable regression analysis |
• Gestational age, birth weight, illness. •No age-matching. •Confounding was minimized by multivariable regression analysis. |
• Caloric deficit and insulin use. •Confounding was minimized by linear mixed effects regression. |
• None listed. •Confounding was minimized by linear regression. |
Gestational age, birth weight z-score, socioeconomic quintile at birth, and neurodevelopment assessment type at 2 years PMA | Sex, deprivation index, SGA, multiple births, protein intake in first 14 days of life. | •Gestational age and heart rate at follow up •Results not adjusted for steroid treatment, weight, body mass index |
• Gestational age, average first week kilocalorie deficit, average first week protein deficit, SNAP-II score, IVH, OFC z score at discharge. •Confounding was minimized by linear regression analysis. Modeling used to account for nutrition and illness severity. |
Abbreviations: AGA: Average weight for gestational age, BG: Blood glucose, BMI: Body mass index, BPD: Bronchopulmonary dysplasia, BRIEF: Behavior Rating Inventory for Executive Function, BSID: Bayley Scales of Development, CGA: Corrected gestational age, CP: Cerebral palsy, DBP: diastolic blood pressure, ELBW: extremely low birthweight, GA: Gestational age, GIR: glucose infusion rate, GMDS: Griffith Mental Development Scales, GQ: Griffiths General Quotient, HINT: Hyperglycemia and Insulin in Neonates Trial, IQ: Intelligence quotient, IVH: Intraventricular hemorrhage, MABC: Movement Assessment Battery for Children, MDI: Bayley’s Mental Developmental Index, NEC: Necrotizing enterocolitis, NICU: neonatal intensive care unit, OFC: Occipital frontal circumference, OR: odds ratio; PMA: postmenstrual age, PROM: Premature rupture of membranes, PVL: Periventricular leukomalacia, RDS: Respiratory Distress Syndrome, SBP: systolic blood pressure, SGA: Small weight for gestational age, SNAP: Score for Neonatal Acute Physiology, SD: standard deviation, VLBW: Very low birthweight infant, WISC: Wechsler Intelligence Scale for Children
*
The sample size reported in this table reflects the sample size of the cohort studied at the long-term timepoint. The incidence of hyperglycemia reported in this table reflects the incidence reported by the authors in each study which in some cases reflects the incidence of hyperglycemia in the larger early neonatal cohort.6,7