Evidence-Based Medicine Journal Club

1. Evidence-Based Medicine Journal Club Honey E. Sward, MD March 25, 2008

2. Patient Ex-27 week male born via NSVD to mom secondary to PROM Developed grade IV intraventricular hemorrhage (IVH) What can be done to reduce the risk of IVH?

3. Article Delayed Cord Clamping in Very Preterm Infants Reduces the Incidence of Intraventricular Hemorrhage and Late-Onset Sepsis: A Randomized, Controlled Trial Authors: Judith S. Mercer, Betty R. Vohr, Margaret M. McGrath, James F. Padbury, Michael Wallach, and William Oh. PEDIATRICS Vol. 117 No. 4 April 2006, pp. 1235-1242

4. Background Current obstetric practice is immediate cord clamping (ICC) Delayed cord clamping (DCC) increases transfer of blood from placenta to infant 9 randomized, controlled trials have documented the safety and efficacy of DDC DCC has numerous benefits Previous studies had limitations -Current obstetric practice is to clamp the umbilical cord of the VLBW infant immediately after delivery (< 10 seconds) -But, delaying cord clamping to 30-45 seconds and lowering the infant below the perineum or incision site at C-section have been shown to increase transfer of blood from the placenta to the infant. Why is this important in the preterm infant? The preterm infant has less fetal-placental blood volume in his body at any point in time. So when the C.O. to the lung increases from 8% during fetal life to 45% immediately after birth, the infant needs an adequate blood volume to prevent hypoperfusion to other organs like the brain and GI tract. Theoretically, the additional blood received as a result of DCC would help reduce neonatal morbidity by providing more blood volume and improving cardiovascular stability. -ICC may deprive the VLBW infant of essential blood volume and create a state of potential circulatory compromise resulting in hypotension and poor perfusion states -9 randomized controlled trials have documented the safety and efficacy of DCC in LBW and VLBW infants. Benefits include: higher BP, higher HCT, more optimal O2 transport and higher red blood cell flow, fewer days on O2 and ventilation, fewer blood transfusions, and lower rates of IVH. -Previous studies of cord clamping interventions, however, have been limited by small sample size, inconsistent definition of variables, and lack of f/u beyond 6 weeks.-Current obstetric practice is to clamp the umbilical cord of the VLBW infant immediately after delivery (< 10 seconds) -But, delaying cord clamping to 30-45 seconds and lowering the infant below the perineum or incision site at C-section have been shown to increase transfer of blood from the placenta to the infant. Why is this important in the preterm infant? The preterm infant has less fetal-placental blood volume in his body at any point in time. So when the C.O. to the lung increases from 8% during fetal life to 45% immediately after birth, the infant needs an adequate blood volume to prevent hypoperfusion to other organs like the brain and GI tract. Theoretically, the additional blood received as a result of DCC would help reduce neonatal morbidity by providing more blood volume and improving cardiovascular stability. -ICC may deprive the VLBW infant of essential blood volume and create a state of potential circulatory compromise resulting in hypotension and poor perfusion states -9 randomized controlled trials have documented the safety and efficacy of DCC in LBW and VLBW infants. Benefits include: higher BP, higher HCT, more optimal O2 transport and higher red blood cell flow, fewer days on O2 and ventilation, fewer blood transfusions, and lower rates of IVH. -Previous studies of cord clamping interventions, however, have been limited by small sample size, inconsistent definition of variables, and lack of f/u beyond 6 weeks.

5. Answerable Clinical Question P: In infants < 32 weeks gestation I: Does DCC C: As compared to ICC O: Decrease the risk of IVH, late- onset sepsis, BPD, and ROP PICO format: P for patient and problem, I for intervention, C for control/comparison group. And O for outcome of interest. In infants <32 weeks, does DCC, as compared to ICC (standard protocol), decrease the risk of BPD, LOS, IVH, and ROPPICO format: P for patient and problem, I for intervention, C for control/comparison group. And O for outcome of interest. In infants <32 weeks, does DCC, as compared to ICC (standard protocol), decrease the risk of BPD, LOS, IVH, and ROP

6. Analysis of the study: Are the results likely to be valid? Were the groups similar at the start of the trial? Aside for the experimental intervention, were the groups treated equally? Was the assignment of patients to treatment randomized? Primary Guides: Was the assignment of patients to treatments randomized? Were all patients who entered the trial properly accounted for and attributed at its conclusion? Was followup complete? Were patients analyzed in the groups to which they were randomized? Secondary Guides: Were patients, health workers, and study personnel "blind" to treatment? Were the groups similar at the start of the trial? Aside from the experimental intervention, were the groups treated equally? Primary Guides: Was the assignment of patients to treatments randomized? Were all patients who entered the trial properly accounted for and attributed at its conclusion? Was followup complete? Were patients analyzed in the groups to which they were randomized? Secondary Guides: Were patients, health workers, and study personnel "blind" to treatment? Were the groups similar at the start of the trial? Aside from the experimental intervention, were the groups treated equally?

7. Analysis of the study: Are the resulsts likely to be valid? Were patients and clinicians kept blind to treatment? Were patients analyzed in the groups to which they were randomized? Were all patients who entered the trial properly accounted for and attributed at its conclusion?

8. Question: Were the groups similar at the start of the trial? Infants in both groups were between 24 and 31.6 weeks gestation Same exclusion criteria for both groups Similar maternal and neonatal demographics Answer: Yes -Infants in both the ICC and DCC groups were between 24 weeks and 31.6 weeks gestation -Infants were excluded from both groups for the same reasons including: obstetrician�s refusal to participate, major congenital anomalies, multiple gestations, intent to withhold care, severe maternal illness, or placenta abruption or previa. -Similar maternal demographics with respect to age, parity, race, insurance, antenatal steroids, antenatal mag, type of delivery, reasons for preterm birth (PROM, PTL, presumed chorio, incompetent cervix, PIH) -Similar neonatal demographics with respect to GA, male to female ratio, APGARs, temp on admission, initial HCT, max serum bili. -Infants in both the ICC and DCC groups were between 24 weeks and 31.6 weeks gestation -Infants were excluded from both groups for the same reasons including: obstetrician�s refusal to participate, major congenital anomalies, multiple gestations, intent to withhold care, severe maternal illness, or placenta abruption or previa. -Similar maternal demographics with respect to age, parity, race, insurance, antenatal steroids, antenatal mag, type of delivery, reasons for preterm birth (PROM, PTL, presumed chorio, incompetent cervix, PIH) -Similar neonatal demographics with respect to GA, male to female ratio, APGARs, temp on admission, initial HCT, max serum bili.

9. Question: Aside from the experimental intervention, were the groups treated equally? Warming mattress for both sets of infants Similar number of patients in each group received low-dose indomethacin for IVH prophylaxis Answer: Yes -After the cord was clamped, infants in both groups were moved to the radiant warmer and were supplied with a warming mattress to assist in maintaining temperature. -At this hospital, infants between the age of 24 and 27 weeks were given indomethacin for IVH prophylaxis. Similar number of patients each group received indomethacin, 59% in the DCC and 62% in the ICC.-After the cord was clamped, infants in both groups were moved to the radiant warmer and were supplied with a warming mattress to assist in maintaining temperature. -At this hospital, infants between the age of 24 and 27 weeks were given indomethacin for IVH prophylaxis. Similar number of patients each group received indomethacin, 59% in the DCC and 62% in the ICC.

10. Question: Was the assignment of patients to treatment randomized? Two sets of cards labeled for randomization were enclosed in sequenced, opaque envelopes containing group assignment Research assistants screened potentially eligible women, enrolled them, and attended the births Research assistants opened the next randomization card, informed the staff of the group assignment, reviewed the protocol with the attending, attended the birth and timed the cord clamping Answer: Yes -A statistician who was not involved in the trial developed a computer-generated random number system. -Block-stratified randomization was used to assign the intervention to the subjects above and below 28 weeks with a prescribed equal probability to avoid unequal numbers of participants in each gestational age group. -Two sets of cards labeled for randomization were enclosed in sequenced, opaque envelopes containing group assignment and kept in the labor unit. -Research assistants who were registered nurses and the principal investigator shared and on-call schedule to screen potentially eligible women, enroll them and attend the births. -When called to the subjects impending birth, the principal investigator or RN opened the next randomization card, informed the staff of the group assignment, reviewed the protocol with the attending, attended the birth, and timed the cord clamping. -A statistician who was not involved in the trial developed a computer-generated random number system. -Block-stratified randomization was used to assign the intervention to the subjects above and below 28 weeks with a prescribed equal probability to avoid unequal numbers of participants in each gestational age group. -Two sets of cards labeled for randomization were enclosed in sequenced, opaque envelopes containing group assignment and kept in the labor unit. -Research assistants who were registered nurses and the principal investigator shared and on-call schedule to screen potentially eligible women, enroll them and attend the births. -When called to the subjects impending birth, the principal investigator or RN opened the next randomization card, informed the staff of the group assignment, reviewed the protocol with the attending, attended the birth, and timed the cord clamping.

11. Question: Were patients and clinicians kept �blind� to treatment? The nurse at the delivery and OB were aware of the intervention The infant�s grouping in the medical charts was withheld Answer: Yes and No Because of the obvious nature of the intervention, the study could not be blinded. The OB and the nurse at the delivery were aware of the intervention, but were asked not the reveal the infant�s grouping in the infant�s medical chart.Because of the obvious nature of the intervention, the study could not be blinded. The OB and the nurse at the delivery were aware of the intervention, but were asked not the reveal the infant�s grouping in the infant�s medical chart.

12. Questions: Were all patients who entered the trial properly accounted for and attributed? 296 women admitted in PTL; 54 were missed; 57 excluded 185 approached for enrollment; 34 refused; 79 not randomized 72 randomly assigned; 36 to each group 7 protocol violations: All infants remained in the assigned groups for analysis 3 deaths in ICC group; all were analyzed if the condition diagnosed before death No deaths in DCC group; all were analyzed Answer: Yes -296 women were admitted in PTL to the Women and Infants� Hospital of Rhode Island b/w Aug 2003 and Nov 2004 and screened for eligibility -54 were missed b/c delivered too quickly (n=39) or staff was not notified (n=15) -57 were excluded because of suspected abruption or previa (n=23), social factors (n=13), enrolled in another study (n=7), multiple maternal morbidities (n=5), and anomalies or other (n=9) -185 were approached for enrollment -34 refused to participate -79 not randomized either because delivered too quickly (n=15), undelivered by 32 weeks (n=63), or the diagnosis changed to abruption (n=1) -72 randomly assigned; 36 to each group -7 protocol violations: -6 in DCC group: the was cord claming b/w 2-18 seconds, instead of the allocated 30-45 seconds; this was due to miscommunication at the births. -1 in ICC group: the cord clamping was delayed to 25 seconds instead of the desired 10 seconds or less; this was due to misunderstanding of the protocol. -ALL INFANTS REMAINED IN THE ASSIGNED GROUPS FOR ANALYSIS -3 deaths in ICC group (from NEC for n=2, and from resp failure for n=1): all were analyzed for primary outcome variable of BPD and excluded from analysis of secondary outcome variables unless condition diagnosed b/f death -No deaths in DCC group; all were analyzed for primary and secondary outcome variables- -THIS INFORMATION CAN ALSO HELP US ANSWER THE QUESTION: Were patients analyzed in the groups to which they were randomized? Yes-296 women were admitted in PTL to the Women and Infants� Hospital of Rhode Island b/w Aug 2003 and Nov 2004 and screened for eligibility -54 were missed b/c delivered too quickly (n=39) or staff was not notified (n=15) -57 were excluded because of suspected abruption or previa (n=23), social factors (n=13), enrolled in another study (n=7), multiple maternal morbidities (n=5), and anomalies or other (n=9) -185 were approached for enrollment -34 refused to participate -79 not randomized either because delivered too quickly (n=15), undelivered by 32 weeks (n=63), or the diagnosis changed to abruption (n=1) -72 randomly assigned; 36 to each group -7 protocol violations: -6 in DCC group: the was cord claming b/w 2-18 seconds, instead of the allocated 30-45 seconds; this was due to miscommunication at the births. -1 in ICC group: the cord clamping was delayed to 25 seconds instead of the desired 10 seconds or less; this was due to misunderstanding of the protocol. -ALL INFANTS REMAINED IN THE ASSIGNED GROUPS FOR ANALYSIS -3 deaths in ICC group (from NEC for n=2, and from resp failure for n=1): all were analyzed for primary outcome variable of BPD and excluded from analysis of secondary outcome variables unless condition diagnosed b/f death -No deaths in DCC group; all were analyzed for primary and secondary outcome variables- -THIS INFORMATION CAN ALSO HELP US ANSWER THE QUESTION: Were patients analyzed in the groups to which they were randomized? Yes

13. Analysis of this study: Are the results likely to be valid? Were the groups similar at the start of the trial? Yes Aside for the experimental intervention, were the groups treated equally? Yes Was the assignment of patients to treatment randomized? Yes Primary Guides: Was the assignment of patients to treatments randomized? Were all patients who entered the trial properly accounted for and attributed at its conclusion? Was followup complete? Were patients analyzed in the groups to which they were randomized? Secondary Guides: Were patients, health workers, and study personnel "blind" to treatment? Were the groups similar at the start of the trial? Aside from the experimental intervention, were the groups treated equally? Primary Guides: Was the assignment of patients to treatments randomized? Were all patients who entered the trial properly accounted for and attributed at its conclusion? Was followup complete? Were patients analyzed in the groups to which they were randomized? Secondary Guides: Were patients, health workers, and study personnel "blind" to treatment? Were the groups similar at the start of the trial? Aside from the experimental intervention, were the groups treated equally?

14. Analysis of this study: Are the results likely to be valid? Were patients and clinicians kept blind to treatment? Yes and No Were patients analyzed in the groups to which they were randomized? Yes Were all patients who entered the trial properly accounted for and attributed at its conclusion? Yes

15. Analysis of this study: Are the results likely to be valid? YES Were patients and clinicians kept blind to treatment? Yes and No Were patients analyzed in the groups to which they were randomized? Yes Were all patients who entered the trial properly accounted for and attributed to its conclusion? Yes

16. RESULTS