MANUSCRIPT CITATION:

Lyu Y; Sha PS; Ye XY; Waree R; Piedboeuf B; Deshpandey A; Dunn M.; Lee SK; for the Canadian Neonatal Network. Association between admission temperature and mortality and major morbidity in preterm infants born at fewer than 33 weeks´gestation. JAMA Pediatr. 2015;169(4): e150277. PMID: 25844990

REVIEWED BY:

Julia Maletzki, MD
Stephanie Adzikah, MD
Christoph Rüegger, MD
Dirk Bassler, MD MSc

Department of Neonatology
University Hospital of Zurich
Switzerland

TYPE OF INVESTIGATION:

Prognosis

QUESTION:

In preterm infants born at fewer than 33 weeks´ gestation is there an association between admission temperature and neonatal outcome?

METHODS:

• Design: retrospective observational study
• Allocation: observational, does not apply
• Blinding: observational, does not apply
• Follow-up Period: not defined; data was extracted from the Canadian Neonatal Network (CNN), all outcomes were defined according to the CNN Abstractor´s Manual (1); follow-up period was until death or discharge from NICU.
• Setting: 29 of 30 tertiary-level NICUs participating in the Canadian Neonatal Network (CNN)
• Patients:
  • Inclusion criteria: all inborn neonates at less than 33 weeks` gestation who were admitted to one of the 29 participating tertiary-level NICUs in the CNN between January 1st, 2010 and December 31st, 2012
  • Exclusion criteria: neonates born outside a tertiary-level NICU, moribund neonates (palliative care planned at birth), neonates with major congenital anomalies, neonates with missing data on admission temperature
• Intervention: not applicable
• Outcomes:
  • Primary outcome:
    • Composite of mortality or any of the following major neonatal morbidities: grade 3 or 4 intraventricular haemorrhage or periventricular leukomalacia; retinopathy of prematurity stage 3 or higher; necrotizing enterocolitis (stage 2 or higher); bronchopulmonary dysplasia (BPD) (defined as oxygen dependency at 36 weeks´ postmenstrual age or at the time of transfer to a level 2 center); nosocomial infection (culture-positive sepsis or meningitis at older than 48 hours)
  • Secondary outcomes:
    • individual components of the primary outcome
    • duration of ventilation
• Sample size and analysis:
  • No sample size calculation was performed; all infants in the CNN that met entry criteria were included.
  • Infants were categorized according to admission temperature into 9 groups with 0.5°C increments from lower than 34.5°C to 38.0°C or higher.
  • Infant characteristics were compared in temperature groups using the X² test for categorical variables and analysis of variance (F test) for continuous variables.
  • Multiple linear regression analysis was used to determine the independent relationship between maternal and infant characteristics and admission temperature, adjusted for the characteristics associated with temperature identified in the univariate analyses using stepwise variable selection procedures.
  • The rates of neonatal morbidities were compared in the temperature groups using the X² test for categorical variables and the F test or Wilcoxon rank sum test for continuous variables.
  • Non-linear regression analyses using the quadratic model y = ax² + bx + c was used to determine if there was a U-shaped association between neonatal outcomes and admission temperature.
  • To examine the U-shaped association between binary outcomes and admission temperature multiple logistic regression with quadratic models was conducted.
  • The symmetric covariance structure was used in the models to account for the correlation owing to the clustering of participants in the hospital.
  • A birth weight z score instead of birth weight was used to reduce the collinearity between birth weight and admission temperature.
  • To examine the U-shaped association between length of ventilation and admission temperature a zero-inflated binomial regression model for the covariates was used.
  • A 2-sided P value of 0.05 was used to determine statistical significance.
• Selection of patients
  • Of 10,560 inborn neonates at less than 33 weeks’ gestation admitted to participating NICUs, 538 patients (5.1%) were excluded due to major congenital anomalies or due to being moribund on admission. Infants with missing data on admission temperature (189/1.9%) were also excluded.
  • 9,833 (93%) infants were included in this study.

RESULTS:

All outcomes were significantly associated with admission temperature, see Table. A U-shaped association between all the included outcomes and admission temperature was identified. Multivariate analyses indicated that for each outcome an admission temperature could be estimated where the rate of the outcome was at its minimum, e.g. the rate of NEC was lowest with an admission temperature of 36.5°C, the rate of nosocomial infection was lowest with an admission temperature of 37.2°C.

CONCLUSIONS:

The authors conclude that the admission temperature of preterm infants born at fewer than 33 weeks´ gestational age is related in a U-shaped association to the composite adverse outcome as defined above. They identified a temperature range of 36.5°C to 37.2°C at which the composite adverse outcome was lowest. As 40% of all preterm neonates had admission temperatures outside this range, they suggest closer monitoring of temperature in the delivery room.

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COMMENTARY:

Even though the pathophysiologic mechanisms of hypo- and hyperthermia and their impact on infants’ outcome have been known for a long time, most previous research merely covers one end of the temperature scale, namely hypothermia.

In this Canadian Neonatal Network study, Lyu et al. retrospectively investigated the effect of admission body temperature (low and high) on adverse outcomes of preterm infants. The nation-wide participation resulted in an impressive number of included infants with only very few drop outs. Nevertheless, there are a few comments to make.

The authors define the admission temperature as the temperature taken with the first vital signs within the first hour of the infant’s admission to the NICU. Information about the infant’s chronological age when admission temperature was measured is missing.

There is no standard protocol to measure the admission temperature. Not only does the location of temperature acquisition vary (rectal vs. axillary) but also the temperature detecting device. The authors cite Craig et al., who concluded that there is a pooled mean temperature difference of 0.17 °C between axillary and rectal temperature. ¹ This indicates only a small – probably not significant – difference between the two measurement locations. They forgot to mention that the range of temperature difference was wide and that the temperature measurement device (mercury vs. electronic) plays an important role. Mercury thermometers had narrower limits of agreement when comparing axillary vs. rectal temperature. Other studies also come to the conclusion that axillary and rectal temperatures are not interchangeable in preterm infants.²

Important, but not documented, are possible confounders like the mother´s temperature at birth or the time needed to transport the baby from the delivery room to the NICU. Other confounders like ventilation with a dry circuit or the use of fluids for resuscitation are not mentioned, as well. The authors included factors like these in their infants´ characteristics (Apgar score < 7 with 5 minutes, SNAP II > 20, resuscitation needed) and applied a univariate analysis which showed that these factors were associated with admission temperature.

In addition, the primary composite outcome may contain too many individual components. Schmidt et al presented a count of 3 major neonatal morbidities, namely bronchopulmonary dysplasia, brain injury and severe retinopathy of prematurity as the most important prognostic factors for neurodevelopmental outcome at 18 months.³ Bassler et al. showed that necrotizing enterocolitis and sepsis (except meningitis) are weaker predictors of a poor long-term outcome.⁴ Late-onset sepsis, on the other hand, has been shown to be inversely correlated with hypothermia,⁵ which might have been the reason for adding sepsis to the composite primary outcome.

For the secondary outcome the authors calculated the admission temperature at which each single adverse outcome was at its lowest rate. This is interesting on a theoretical basis, but not applicable for clinical everyday life.

In conclusion, the authors found an association between hypo- and hyperthermia and an adverse neonatal outcome, which calls for continuous monitoring of body temperature in extremely preterm infants as part of routine resuscitation.

REFERENCES

1. Craig JV, Lancaster GA, Williamson PR, Smyth RL. Temperature measured at the axilla compared with rectum in children and young people: systematic review. BMJ 2000;320:1174-8.
2. Hissink Muller PC, van Berkel LH, de Beaufort AJ. Axillary and rectal temperature measurements poorly agree in newborn infants. Neonatology 2008;94:31-4.
3. Schmidt B, Asztalos EV, Roberts RS, et al. Impact of bronchopulmonary dysplasia, brain injury, and severe retinopathy on the outcome of extremely low-birth-weight infants at 18 months: results from the trial of indomethacin prophylaxis in preterms. JAMA 2003;289:1124-9.
4. Bassler D, Stoll BJ, Schmidt B, et al. Using a count of neonatal morbidities to predict poor outcome in extremely low birth weight infants: added role of neonatal infection. Pediatrics 2009;123:313-8.
5. Laptook AR, Salhab W, Bhaskar B, Neonatal Research N. Admission temperature of low birth weight infants: predictors and associated morbidities. Pediatrics 2007;119:e643-9.