1. Dallas 2015 TFQO: Name EVREV 1: Jonathan Wyllie COI #282 EVREV 1: Jeff Perlman COI #262 Taskforce: Newborn Temperature Maintenance in the Delivery room NRP589

2. Dallas 2015 COI Disclosure (specific to this systematic review) EVREV Jonathan Wyllie Commercial/industry None Potential intellectual conflicts ERC, RC (UK) Newborn chair EVREV Jeff Perlman Commercial/industry None Potential intellectual conflicts None

3. Dallas 2015 2010 CoSTR Topic not reviewed in 2010.

4. Dallas 2015 C2015 PICO Population: Non-asphyxiated newborn babies Intervention: Temperature maintained between 36.5-37.5 degrees centigrade from delivery to admission Comparison:Hypothermia or hyperthermia Outcomes: Survival (9), Intraventricular Haemorrhage (7), Hypoglycaemia (6), Respiratory Distress (6) Sepsis (6)

5. Dallas 2015 Inclusion/Exclusion & Articles Found List Inclusions/Exclusions Included human, comparative studies (prospective and retrospective), case series and reviews reporting outcomes for the temperature management of term and preterm neonates between birth and admission. Excluded animal studies and studies that did not specifically address the PICO question. Excluded unpublished studies, and studies only published in abstract form, unless accepted for publication. 2315 Articles initially identified 79 Included in Evidence Profile tables Refined to 67 included 3 RCTs but without any of these outcomes as primary outcomes 64 non-RCTs 2248 excluded

6. Dallas 2015 2015 Proposed Treatment Recommendations Draft Treatment Recommendations from SEERs We recommend that the temperature of newly born infants be maintained above 36.5 degrees centigrade after birth through admission and temperature check. Hyperthermia should be avoided (Strong recommendation, Moderate quality of evidence). This should be a standard of care. We suggest that the temperature on admission be recorded as a predictor of mortality and potential morbidity as well as a quality indicator.

7. Dallas 2015 Risk of Bias in studies RCT bias assessment StudyYearDesignTotal PatientsPopulation Industry Funding Allocation: Generation Allocation: Concealment Blinding: Participants Blinding: Assessors Outcome: Complete Outcome: Selective Other Bias Meyer 2001RCT60<33 weeksNoHighLowHigh Low Unclear Vohra 1999RCT62<32 weeksNoLow High LowHighLow Vohra 2004RCT55<28weeksUnclearLow High LowHighLow

8. Dallas 2015 Risk of Bias in studies Non-RCT bias asssesment StudyYearDesignTotal PatientsPopulationIndustry Funding Eligibility Criteria Exposure/Outcome Confounding Follow up Abd-El Hamid 2012 Non-RCT 100VLBWnoLow UnclearLow Anderson 1993 Non-RCT 226Term babiesNoLowUnclear Low Acolet 2005 Non-RCT3,522 27/28 weeksNoLow Audeh 2011 Non-RCT 271VLBW <33 weeksNoLow Bartels 2005 Non-RCT 1,623VLBWNoLow Unclear Bateman 2012 Non-RCT 59Outborn >500gNoHigh UnclearLow Bambea 2010 Non-RCT 547PaediatricNoUnclearLow High Bhoopalam 1991 Non-RCT 137 Outborn NoUnclearHigh Low Billimoria 2013 Non-RCT209VLBWNo LowHighUnclear Boo 1997 Non-RCT720 VLBWNoLowHigh Boo 2013 Non-RCT3,768 VLBWNoLow Buch 2001 Non-RCT3,235 NeonatesNoLow HighLow Buetow 1964 Non-RCT185 1000-1500gNoLow HighLow Carroll 2010 Non-RCT70 ELBWNoLow HighLow Costeloe 2000 Non-RCT811 <26 weeksNoLow Costeloe 2012 Non-RCT1,781 <26 weeksNoLow da Mota 2003 Non-RCT320 Newborn BabiesNoLow UnclearLow Daga 1991 Non-RCT1,747 Newborn BabiesNoLowUnclear de Almeida 2013 Non-RCT1,764 <33 weeksNoLow DeMauro 2013 Non-RCT80 <=1250gNoLow HighLow Dincsoy 1990 Non-RCT82 LBWNoHighUnclear Low García-Muñoz 2013 Non-RCT635 VLBW <30 weeksNoLow HighLow Gleissner 2000 Non-RCT3,721 <37 weeksNoHighUnclearHighUnclear Harms 1994 Non-RCT1,132 <34 weeksNoHigh Unclear Harms 1996 Non-RCT1,190 <34 weeksNoHigh Unclear Harms 1997 Non-RCT1,109 <1500gNoHighLowHighUnclear Hazan 1991 Non-RCT559 <1500gNoUnclearLowHighUnclear Herting 1992 Non-RCT343 700-2000gNoLow HighLow Jain 2004 Non-RCT3,522 26-29+6 weeksNoLow Jakuskiene 2009 Non-RCT338 VLBW +ELBWNoLowHigh Unclear

9. Dallas 2015 Risk of Bias in studies Jones 2011 Non-RCT83 24-35 weeksNoLowHigh Unclear Kalimba 2013 Non-RCT382 <=900gNoLow HighUnclear Kambarami 2003 Non-RCT1,313 Admitted to NNUNoLowUnclearHighUnclear Kent 2008 Non-RCT156 <31 weeksNoLow UnclearLow Laptook 2007 Non-RCT5,277 401-1499gNoLow Lazić-Mitrović 2010 Non-RCT143 Term IUGRNoUnclearHigh Unclear Lee 2008 Non-RCT304 <1500gNoUnclear LowUnclear Lee 2014 Non-RCT12,528 <1500g, <30 weeksNoLowUnclear Low Lenclen 2002 Non-RCT120 <33 weeksNoLowUnclearHighUnclear Levene 1982 Non-RCT146 <=34 weeksNoLowUnclearHighUnclear Levi 1984 Non-RCT71 <800gNoLowUnclearHighUnclear Manani 2013 Non-RCT289 <33 weeksNoLowUnclearHighLow Manji 2003 Non-RCT1,633 Admissions to NICUNoHigh Unclear Mathur 2005 Non-RCT100 extramural hypothermic babiesNoHigh Unclear Miller 2011 Non-RCT8,782 VLBWNoLow Unclear Mullany 2010 Non-RCT23,240 Newborns in NepalNoUnclearHighUnclearHigh Nayei 2006 Non-RCT940 Newborn BabiesNoLow HighUnclear Nayeri 2005 Non-RCT898 Newborn BabiesNoLow HighUnclear Obladen 1985 Non-RCT182 Neonates who diedNoLowHigh Unclear Oglunesi 2008 Non-RCT150 Babies admitted in NigeriaNoLowUnclearHighUnclear Pal 2000 Non-RCT578 Newborn BabiesNoLowUnclearHighUnclear Rong 2012 Non-RCT <37 weeksNoLowHighLowUnclear Russo 2014 Non-RCT361 <35 weeksNoLow UnclearLow Sasidharan 2004 Non-RCT604 Newborns in IndiaNoLow Shah 2012 Non-RCT1,502 admitted to NICU in EritreaNoUnclearLow High Singh 2012 Non-RCT154,669 Pregnant mothersNoLowHigh Sodemann 2008 Non-RCT2,926 Live births in Guinea- BissauNoLowUnclear Low Stanley 1978 Non-RCT692 <2000gNoLowUnclear Szymonowicz 1984 Non-RCT50 <1250gNoLow HighUnclear Van 1986 Non-RCT49 <34 weeksNoLowUnclearHighUnclear Wykoff 2004 Non-RCT65 Outborn `babiesNoLow Zayeri 2005 Non-RCT1,952 Inborn babiesNoUnclear HighUnclear

10. Dallas 2015 Evidence

11. Dallas 2015 Evidence profile table(s)

12. Dallas 2015 Evidence profile table(s)

13. Dallas 2015 Proposed Consensus on Science statements For the critical outcome of mortality, there is evidence from 35 observational studies, (Costeloe 2000, 2012, Laptook 2007, Miller 2011, Mullany 2010, Boo 2013, Garcia-Munoz 2014, de Almeida 2014) (Low quality of evidence but upgraded to moderate quality due effect size, dose effect, (Laptook 2007, Miller 2011, Mullany 2010, Boo 2013) and single direction of evidence) of increased risk of mortality associated with hypothermia at admission. We did not identify any evidence to address the critical outcome of “neurologically intact survival”. There is evidence of a dose effect on mortality suggesting an increased risk of approximately 28 percent for each 1 degree below 36.5 degrees centigrade body temperature at admission (Laptook 2007) and effect size (Miller 2011, Mullany 2010, Boo 2013).

14. Dallas 2015 Proposed Consensus on Science statements 1 small RCT (Meyer 2001) (moderate quality, downgraded for indirectness and imprecision) showed a reduction in adverse events, including death, intracranial haemorrhage, NEC and oxygen dependence with improved temperature management but two RCTs (Vohra 1999, 2004) (Very low quality as downgraded for indirectness and imprecision) did not show any significant improvement in mortality with significantly improved temperature control. 4 observational studies (Manani 2013, Billmoria 2013, Kent 2008, Lee 2008)(very low quality) did not find any improvement in mortality with improved admission temperatures but they were not powered to do so.

15. Dallas 2015 Proposed Consensus on Science statements There is evidence from nine observational studies (Costeloe 2000, Boo 2013, DeMauro 2013, Lee 201, Russo 2014 )(Low quality) showing an association between hypothermia and respiratory disease. 8 observational studies (Low Grade) have shown an improvement in respiratory outcomes following improved admission temperature maintenance. Two of these have shown a decrease in respiratory support with improved temperature maintenance). (DeMauro 2013, Russo 2014). There are 7 observational studies (Low Grade) showing a significant association between hypothermia (< 36 OC) and hypoglycaemia (Anderson 1993, Lenclen 2002). Two of these (Grade Low), using historical controls, showed improved glycaemic control with improved normothermia (Lenclen 2002, A Abd-El 2012).

16. Dallas 2015 Proposed Consensus on Science statements 9 observational studies (Grade Low to Mod) show hypothermia (< 36 OC) in preterm infants is associated with an increased likelihood of developing intraventricular hemorrhage (Boo 2013, Carroll 2010, Garcia-Munoz 2013, Miller 2011). 8 observational studies (Grade Low to Mod) found no association (Audeh 2011, Dincsoy 1990, Laptook 2007). There is evidence from two observational studies (Low Grade) of an association between hypothermia on admission and late sepsis (Laptook 2007). One observational study (Low Grade) found no association after multivariate analysis Miller 2011. There was no published evidence addressing any effect of delivery room hypothermia upon survival to admission. There was no published evidence about newborn hyperthermia at admission.

17. Dallas 2015 Draft Treatment Recommendations We recommend that the temperature of newly born infants be maintained above 36.5 degrees centigrade after birth through admission and temperature check. Hyperthermia should be avoided (Strong recommendation, Moderate quality of evidence). This should be a standard of care. We suggest that the temperature on admission be recorded as a predictor of mortality and potential morbidity as well as a quality indicator. Values and preferences: In making these statements we place a higher value on the strong association of hypothermia with mortality, the apparent dose effect, the single direction of the evidence and the universal applicability over the lack of evidence for intervention changing mortality.

18. Dallas 2015 Knowledge Gaps Further studies are required to find if improved admission temperature improves mortality and other outcomes. Further studies are required to find if late inadvertent hypothermia is associated with the same risks and whether there are any long term morbidities associated with hypothermia at admission.

19. Dallas 2015 Next Steps This slide will be completed during Task Force Discussion (not EvRev) and should include: Consideration of interim statement Person responsible Due date