The hierarchy of research methods Eileen K. Hutton RM PhD McMaster University Hamilton, Canada

1. The hierarchy of research methods Eileen K. Hutton RM PhD McMaster University Hamilton, Canada

2. Systematic reviews and meta-analysis

3. Evidence based practice “Integration of research evidence with clinical expertise and patient values” * * From Sackett et al. Evidenced Based Medicine, 2000

4. Evidence based practice “Integration of research evidence with clinical expertise and patient values” * * From Sackett et al. Evidenced Based Medicine, 2000

5. Research • Single original research studies are the building blocks of clinical knowledge • Systematic reviews bring together and assess all relevant studies • Meta-analyses give single estimate of efficacy and effectiveness

6. Research • Single original research studies are the building blocks of clinical knowledge • Systematic reviews bring together and assess all relevant studies • Meta-analyses give single estimate of efficacy and effectiveness

7. Research • Single original research studies are the building blocks of clinical knowledge • Systematic reviews bring together and assess all relevant studies • Meta-analyses give single estimate of efficacy and effectiveness

8. Number of citations for RCT 1986-2003

9. Number of citations for RCT 1986-2003

10. Number of citations for RCT 1986-2003

11. “Systematic reviews - the critical links in the great chain of evidence” - 1998, Mulrow C. Cook D. Davidoff F.

12. Number of Systematic Reviews published between 1986-2007 Adapted from: Systematic Reviews: Egger M, Smith GD, O’Rourke K

13. Number of Systematic Reviews published between 1986-2007 Adapted from: Systematic Reviews: Egger M, Smith GD, O’Rourke K

14. Number of Systematic Reviews published between 1986-2007 Adapted from: Systematic Reviews: Egger M, Smith GD, O’Rourke K

15. Number of Systematic Reviews published between 1986-2007 Adapted from: Systematic Reviews: Egger M, Smith GD, O’Rourke K

16. Timing of umbilical cord clamping in term infants

17. Background • Fetal circulation includes circulation through cord and placenta • < 37 weeks 50% • > 37 weeks 30%

18. Background • What happens at birth? • Without intervention, a significant amount placental circulation  infant • Clamping of cord interrupts this “placental transfusion”

19. Question • Is this important to neonatal wellbeing?

20. “Another thing very injurious to the child is the tying and cutting of the navel string too soon, which should always be left till the child has not only repeatedly breathed, but till all pulsation in the cord ceases.”

21. “Another thing very injurious to the child is the tying and cutting of the navel string too soon, which should always be left till the child has not only repeatedly breathed, but till all pulsation in the cord ceases.” Erasmus Darwin 1801

22. Delayed cord clamping • Increased: • Oxygen perfusion • Hbg; hct; iron stores • Less anaemia  fewer transfusions • Better cardiopulmonary adaptation • Higher blood pressure • Decreased RDS • Improved breast feeding success • Decreased risk of maternal-fetal transfusion

23. Early cord clamping • Allows for : • active management of 3rd stage  decreasing maternal blood loss • immediate resuscitation • Avoids: • Hypothermia • Polycythemia • Hyperviscosity • Hypervolemia • Hyperbilirubinemia • Increases cord blood collection

24. Delayed Cord Clamping - Term • Systematic Review and Meta-analysis • March 2007 Hutton EK. Hassan E. JAMA 2007;297:1241-1252

25. Objective • To compare potential benefits and harms of late vs early cord clamping in term infants

26. Data sources • Electronic search of 6 databases: • Cochrane trials registers (2) • Cochrane library, • MEDLINE • EMBASE • CINHAL • Hand search of references

27. Inclusion • Controlled trials • Term pregnancy (≥37 weeks) • Reported original data • At least one outcome of interest

28. Exclusion • Studies involving only preterm or low birth weight infants

29. Data extraction • Standardised extraction forms developed • Authors independently • assessed eligibility of identified studies • Extracted data

30. Analysis • Revman version 4.2 used • Double data entry • Mean and SD for continuous variables converted to WMD • Harmful effects reported as RR of adverse event

31. Search Results

32. Systematic Review and Meta-analysis • 15 Controlled trials • 1912 infants • Late n = 1001 • Early n = 911

33. Definitions • Majority defined “early” : • “immediate” or within 10 seconds • One study within 60 seconds

34. Definitions • Shortest time in “late” group: • 2 minutes • Most trials 3 minutes or after cord pulsation cessation

35. 01 haematocrit 6 hours 02 haematocrit 24 - 48 hours 03 haematocrit 5 days 04 hematocrit at 6 months 05 haemoglobin ~7 hours 06 haemoglobin at 2-3 mo. 07 haemoglobin at 6 mo. 08 Blood volume 2 - 4 hours 09 Plasma viscosity 24 hours 10 Plasma viscosity 5 days 11 Blood viscosity 2 - 4 hours 12 Blood viscosity 5 days 13 Bilirubin levels 24 hours 14 Bilirubin levels 72 hours 15 Ferritin levels 2 - 3 months 16 Ferritin <50ug/L 3 months 17 Ferritin levels 6 months 18 Anaemia at 24 - 48 hours 19 Anaemia at 2 - 3 months 21 Anaemia at 6 months 22 Jaundice 24 - 48 hours 23 Jaundice 3-14 days 24 Use of phototherapy 25 Polycythemia at 7 hours 26 Polycythemia at 24 - 48 hours 27 Grunting or tachypnea 28 NICU admission Outcomes

36. 01 haematocrit 6 hours 02 haematocrit 24 - 48 hours 03 haematocrit 5 days 04 hematocrit at 6 months 05 haemoglobin ~7 hours 06 haemoglobin at 2-3 mo. 07 haemoglobin at 6 mo. 08 Blood volume 2 - 4 hours 09 Plasma viscosity 24 hours 10 Plasma viscosity 5 days 11 Blood viscosity 2 - 4 hours 12 Blood viscosity 5 days 13 Bilirubin levels 24 hours 14 Bilirubin levels 72 hours 15 Ferritin levels 2 - 3 months 16 Ferritin <50ug/L 3 months 17 Ferritin levels 6 months 18 Anaemia at 24 - 48 hours 19 Anaemia at 2 - 3 months 21 Anaemia at 6 months 22 Jaundice 24 - 48 hours 23 Jaundice 3-14 days 24 Use of phototherapy 25 Polycythemia at 7 hours 26 Polycythemia at 24 - 48 hours 27 Grunting or tachypnea 28 NICU admission Findings

37. Findings • Delaying clamping at least 2 minutes: • Improved short & long term hematological and iron status • No significant impact on bilirubin, plasma viscosity in first week • Increases in polycythemia • No increase in rates of NICU or phototherapy

38. Results - Physiological parameters Blood volume at 2 - 4 hours • (n = 60) • WMD 9.07mL/kg • 95% CI (5.81, 12.32)

39. Results - Physiological parameters Blood viscosity at 2 - 4 hours (n=90): WMD 1.39; 95% CI (1.19, 1.59) Blood viscosity at 5 days (n=90): WMD 0.94; 95% CI (0.72, 1.16)

40. Results - Physiological parameters HCT level at 5 days (n=120): WMD 11.97%; 95% CI (8.50, 15.45)

41. Results - Physiological parameters Hbg at 7 hours (n=354): WMD 0.60 g/dL; 95% CI (0.11, 1.09) • No difference at 2 - 3 or at 6 months

42. Results - Physiological parameters ferritin 2-3 months (n=144): WMD 17.89 µg/L; 95% CI (16.58, 19.21)

43. Results - Physiological parameters Ferritin <50 µg/L at 3 months: RR, 0.67; 95%CI, (0.47 to 0.96) Ferritin 6 months (n=315): WMD 11.80 µg/L; 95% CI (4.07, 19.53) Stored iron at 6 months (n=315): WMD, 19.90 mg; 95% CI (7.67, 32.13)

44. Results – clinical outcomes Risk of anaemia 2-3 months (n=119): RR 0.53; 95% CI (0.40, 0.70)

45. Results - Physiological parameters Bilirubin 24 hours (n=163): WMD 3.81 mmol/L; 95% CI (-17.55, 25.18) Bilirubin 72 hours (n=91): WMD 18.27 mmol/L; 95% CI (-2.47, 39.00)

46. Results – clinical outcomes Risk of neonatal jaundice in first 24 - 48 hours: RR, 1.35; 95% CI ( 1.0, 5.36 )

47. Results – clinical outcomes Jaundice at 3 – 14 days (n=332): RR, 1.27; 95%CI (0.76 – 2.10)

48. Results – clinical outcomes Phototherapy for jaundice: RR 1.78; 95% CI (0.71, 4.46)

49. Results – clinical outcomes Risk of polycythaemia: RR 3.82; 95% CI (1.11, 13.21)

50. Authors’ conclusions “We believe that this meta-analysis supports incorporating into clinical practice a minimum delay of 2 minutes before clamping the umbilical cord in all full-term newborns.” Hutton EK, Hassan ES.. JAMA 2007;297:1241-52.