1. Dallas 2015 TFQO: Masanori Tamura #147 EVREV 1: Masanori Tamura #147 EVREV 2: Susan Niermeyer #252 Delayed Cord Clamping in Preterm Infants Including those Receiving Resuscitation (PICO ID NRP 787)

2. Dallas 2015 COI disclosure ( specific to this systematic review ) EVREV 1 Masanori Tamura #147 Commercial/industry N/A Potential intellectual conflicts N/A EVREV 2 Susan Niermeyer #252 Commercial/industry N/A Potential intellectual conflicts Site investigator – proposed VentFirst trial of DCC (Kattwinkel, PI)

3. Dallas 2015 2010 Treatment Recommendation Delay umbilical cord clamping for at least 1 minute for newborn infants not requiring resuscitation. However, there is insufficient evidence on which to base a recommendation of when to clamp the cord in babies requiring resuscitation.

4. Dallas 2015 2010 Consensus on Science and Treatment Recommendation Treatment Recommendation Delay umbilical cord clamping for at least 1 minute for newborn infants not requiring resuscitation. However, there is insufficient evidence on which to base a recommendation of when to clamp the cord in babies requiring resuscitation. Consensus on Science “…For the otherwise uncomplicated preterm birth, there is evidence of a benefit to delaying cord clamping for a minimum time ranging from 30 sec to 3 min following delivery. Those who experienced delayed clamping in this group had higher blood pressures during stabilization, a lower incidence of intraventricular hemorrhage and received fewer blood transfusions, but were more likely to receive phototherapy. However, there are limited data on the hazards or benefits of delayed cord clamping in the non-vigorous infant.”

5. Dallas 2015 C2015 PICO In preterm infants, including those who received resuscitation (P) does delayed cord clamping (> 30 sec) (I) compared with immediate cord clamping (C) improve survival, long-term developmental outcome, cardiovascular stability, occurrence of intraventricular hemorrhage and necrotizing enterocolitis, temperature on admission to a newborn area, and hyperbilirubinemia (O)?

6. Dallas 2015 Inclusion/exclusion and articles found Inclusion/exclusion criteria Included all studies with concurrent controls Excluded review articles, studies with historical controls, animal studies, and studies that did not specifically answer the question. Excluded unpublished studies, studies only published in abstract form, unless accepted for publication Fifteen articles are finally included RCTs 12 articles (691 cases) Non-RCTs 3 articles (760 cases) Excluded 231 articles

7. Dallas 2015 Outcomes ・ Infant death (critical 9) ・ Long-term developmental (critical 8) → No report ・ Severe IVH (critical 8) ・ PVH/IVH all grade (critical 7) ・ Cardiovascular stability (critical 7) ・ NEC (critical 7) ・ Temperature on admission (critical 7) ………………………………………………………. ・ Hyperbilirubinemia (important 6)

8. Dallas 2015 Risk of bias in studies RCT bias assessment StudyYearDesign Total Patients Population Duration of DCC (sec.) Industry Funding Allocation: Generation Allocation: Concealment Blinding: Participants Blinding: Assessors Outcome: Complete Outcome: Selective Other Bias Alagandy 2006RCT4624-32w30-90Unclear Low HighUnclearLowHighLow Baenziger 2007RCT3924-32w 60-90Unclear LowUnclearHigh Unclear Hofmeyr 1988RCT38<35w60Unclear Low Unclear Hofmeyr 1993RCT86<200060-120Unclear Low Unclear Kinmond 1993RCT3627-33w30Unclear High LowUnclear Kugelman 2007RCT6524-35w30-45Unclear Low Unclear McDonnell 1997RCT4626-33w30Unclear High Unclear Mercer 2003RCT32<32w30-45Unclear Low UnclearLow Mercer 2006RCT72<33w30-45Unclear Low HighLowUnclear Low Oh 2011RCT3324-27w30-45Unclear Low Unclear LowUnclear Rabe 2000RCT40<33w45Unclear Low Strauss 2008RCT158<3660Unclear LowUnclear HighUnclear Non-RCT bias asssesment StudyYearDesign Total Patients Population Duration of DCC (sec.) Industry Funding Eligibility Criteria Exposure/ Outcome Confounding Follow up Aziz 2012 Non-RCT 23623-3245Unclear HighLowHighUnclear Kaempf 2012 Non-RCT 494<35w45Unclear LowUnclear Meyer 2011 Non-RCT 30<30w30-45Unclear HighLowUnclear

9. Dallas 2015 Outcome: infant death

10. Dallas 2015 Infant death

11. Dallas 2015 Outcome: Severe IVH (gr III/IV)

12. Dallas 2015 Outcome: PVH/IVH (gr I-IV)

13. Dallas 2015 Intracranial hemorrhage

14. Dallas 2015 Outcome: cardiovascular stability

15. Dallas 2015 Cardiovascular stability

16. Dallas 2015 Outcome: Necrotizing enterocolitis

17. Dallas 2015 Necrotizing enterocolitis

18. Dallas 2015 Outcome: Temperature on admission

19. Dallas 2015 Temperature on admission

20. Dallas 2015 Outcome: Hyperbilirubinemia (treated)

21. Dallas 2015 Outcome: Serum bilirubin peak (mmol/L)

22. Dallas 2015 Hyperbilirubinemia

23. Dallas 2015 Proposed Consensus on Science Statements (1) For the critical outcomes of Infant death we identified moderate quality evidence from 11 RCTs enrolling 591 patients showing no benefit (OR 0.6, 95% CI 0.26,1.36) Severe IVH we identified moderate quality evidence from 5 RCTs enrolling 265 patients showing no benefit (OR 0.85, 95% CI 0.20,3.69) We did not identify any evidence to address the critical outcome of long-term neurodevelopment.

24. Dallas 2015 Proposed Consensus on Science Statements (2) For the critical outcomes of PVH/IVH we identified moderate quality evidence from 9 RCTs enrolling 499 patients showing benefit (OR 0.49, 95% CI 0.29, 0.82) Cardiovascular stability mBP – 2 RCTs, 97 patients showing benefit (MD 3.52, 95% CI 0.6, 6.45) mBP 4 hrs – 3RCTs, 143 patients showing benefit (MD 2.49, 95% CI 0.74, 4.24) Blood volume – 2 RCTs, 81 patients showing benefit (MD 8.25, 95% CI 4.39, 12.11)

25. Dallas 2015 Proposed Consensus on Science Statements (3) For the critical outcomes of Necrotizing enterocolitis we identified moderate quality evidence from 5 RCTs enrolling 241 patients showing benefit (OR 0.3, 95% CI 0.19, 0.8) Temperature on admission we identified moderate quality evidence from 4 RCTs enrolling 208 patients showing no statistically significant benefit (MD 0.1, 95% CI -0.04, 0.24)

26. Dallas 2015 Draft Treatment Recommendation We suggest delayed umbilical cord clamping over immediate cord clamping for preterm infants not receiving resuscitation after birth. (weak recommendation, moderate quality of evidence) Grade 2B There is insufficient evidence to recommend the approach to cord clamping for preterm infants who do receive resuscitation immediately after birth.

27. Dallas 2015 Basis for Recommendation Overall quality of evidence: Moderate Balance of consequences Desirable consequences probably outweigh undesirable consequences in most settings Preference (Babies’ or Parents’) Strong popular support for delayed clamping Heightened importance in resource-limited settings Acceptability to staff at delivery Acceptable in the context of a quality improvement process Cost Cheap

28. Dallas 2015 Knowledge Gaps Results of ongoing large randomized controlled trials Other specific systematic reviews that would be helpful Comparison of delayed vs. immediate cord clamping among preterm infant who receive resuscitation with positive-pressure ventilation Comparison of delayed cord clamping and cord milking Outcome data of high importance Need for resuscitative intervention at delivery Long-term neurodevelopment Hyperbilirubinemia among high-risk populations