1. Dallas 2015 TFQO: Marya Strand, MD, MS; COI#222 EVREV 1: Marya Strand, MD, MS; COI#222 EVREV 1: Takahiro Sugiura, MD; COI#224 Taskforce: NLS Umbilical Cord Milking (NRP #849)

2. Dallas 2015 COI Disclosure Marya Strand, MD, MS COI#222 Commercial/industry None Potential intellectual conflicts None Takahiro Sugiura, MD COI#224 Commercial/industry None Potential intellectual conflicts None

3. Dallas 2015 2010 Treatment Recommendation Evidence from a single, small, randomized controlled trial (LOE 1, Hosono 2008, p.F14) suggest that, among premature newborns (24-28 weeks gestation), milking the umbilical cord immediately after birth may decrease the need for packed red blood cells transfusions during the initial hospital stay. This single study was not adequately powered to fully assess the safety or efficacy of this intervention. A secondary analysis of data from this small randomized trial (LOE 1, Hosono 2009, p.F328) suggests that, among premature newborns (24-28 weeks gestation), milking the umbilical cord immediately after birth may increase hemoglobin at birth, improve hemodynamic stability during the first 5 days of life, and decrease the incidence of chronic lung disease at 36 weeks postmenstrual age.

4. Dallas 2015 C2015 PICO Population: Very preterm infants (≤28 weeks’) Intervention: Umbilical cord milking Comparison: Immediate umbilical cord clamping Outcomes: 9—Death 8—Neurodevelopmental outcome at 2-3 years 8—Cardiovascular stability –Need for pressors, need for fluid bolus, initial mean blood pressure 6—ICH –Any grade, severe grade 6—Temperature on admission 5—Hematologic indices –Initial hemoglobin, need for transfusion 3—Hyperbilirubinemia –Need for phototherapy, need for exchange transfusion

5. Dallas 2015 Inclusion/Exclusion & Articles Found Inclusions/Exclusions Randomized or observational studies Infants born at ≤28 weeks’ gestation Search terms initially identified 690 potential articles Number Included in Evidence Profile tables RCTs: 4 non-RCTs: 1

6. Dallas 2015 2015 Proposed Treatment Recommendations When delayed cord clamping cannot be accomplished, we suggest that cord milking be performed at delivery for VLBW infants as opposed to immediate cord clamping. (Moderate recommendation, moderate level of evidence)

7. Dallas 2015 Risk of Bias in studies

8. Dallas 2015 Outcome- Infant death

9. Dallas 2015 Evidence profile table -Infant death

10. Dallas 2015 Outcome- CV stability

11. Dallas 2015 Outcome- CV stability

12. Dallas 2015 Evidence profile table -CV stability

13. Dallas 2015 Outcome- ICH

14. Dallas 2015 Evidence profile table-IVH

15. Dallas 2015 Outcome- hematologic indices

16. Dallas 2015 Evidence profile table -hematologic indices

17. Dallas 2015 Outcome- temperature Evidence profile table-temperature

18. Dallas 2015 Outcome- bilirubin indices

19. Dallas 2015 Evidence profile table -bilirubin indices

20. Dallas 2015 Proposed Consensus on Science Statements For the critical outcome of death we found moderate quality evidence from 3 RCTs that there is no difference in death (OR 0.76, 95% CI 0.25-2.29). We did not identify any evidence to address the critical outcome of “neurologic outcome at 2-3 years”. For the critical outcome of cardiovascular stability we found low quality evidence from 2 studies that the intervention group received fewer pressor (OR 0.44, 95% CI 0.19-0.98). We found moderate quality evidence that the initial mean blood pressure was 5.43 mm Hg higher (1.98-8.87 mm Hg) in the intervention group.

21. Dallas 2015 Proposed Consensus on Science Statements For the important outcome of IVH, we found moderate quality evidence from 2 studies of a reduction of any IVH (OR 0.37, 95% CI 0.18-0.77) but no difference (from 1 study) in severe IVH (OR 0.44, 95% CI 0.07-2.76). For the important outcome of hematologic indices, we found moderate quality evidence from 2 studies that cord milking increased the initial hemoglobin measurement (2.27 g/dl, 95% CI 1.57-2.98 g/dl) and high quality evidence from 3 studies that cord milking decreased the need for transfusion (OR 0.2, 95% CI 0.09-0.44). For the important outcome of temperature on admission, we found low quality evidence from 1 study that the milking group temperature was not different on admission.

22. Dallas 2015 Proposed Consensus on Science Statements For the outcome of bilirubin indices we found moderate quality evidence that the maximum bilirubin measurement and need for phototherapy was not different between groups. Cost: There is little or no cost associated with the intervention of umbilical cord milking.

23. Dallas 2015 Draft Treatment Recommendations When delayed cord clamping cannot be accomplished, we suggest that cord milking be performed at delivery for VLBW infants as opposed to immediate cord clamping. (Moderate recommendation, moderate level of evidence) All studies included in this evidence review milked 20 cm of umbilical cord toward the umbilicus 3 times while the infant was held at the level of the introitus or below the level of the placenta.

24. Dallas 2015 Values and Preferences Statement: In making this recommendation we place a high value on the simplicity/economy of this intervention with no demonstrated negative outcome.

25. Dallas 2015 Knowledge Gaps Specific research required Cord milking vs Delayed cord clamping One RCT [Rabe 2011] demonstrated similar hematologic indices between cord milking and delayed cord clamping. There is no evidence regarding neurodevelopmental outcomes for cord milking compared to immediate cord clamping.