MANUSCRIPT CITATION

Krueger MS, Eyal FG, Peevy KJ, Hamm CR, Whitehurst RM, Lewis DF. Delayed cord clamping with and without cord stripping: a prospective randomized trial of preterm neonates. Am J Obstet Gynecol. 2015 Mar;212(3):394.e1-5. doi: 10.1016/j.ajog.2014.12.017. PMID:25526873

REVIEWED BY

Peter Davis MD, FRACP
Professor/Director of Neonatal Medicine
The Royal Women’s Hospital, Melbourne, Australia

Brett Manley PhD, FRACP
Consultant Neonatologist
The Royal Women’s Hospital, Melbourne, Australia

Louise Owen MD, FRACP
Consultant Neonatologist
The Royal Women’s Hospital, Melbourne, Australia

TYPE OF INVESTIGATION

Treatment

QUESTION

In preterm infants between 22.0 and 31.6 weeks’ gestation, does cord milking and delayed cord clamping, as compared to delayed cord clamping alone increase the first hematocrit taken in the first 30 minutes of life?

METHODS

• Design: Single center, randomized controlled trial
• Allocation: Concealed allocation using opaque envelopes, equal numbers of envelopes “scrambled by a third party registered nurse”.
• Blinding: The caregivers of the infant at delivery were not blinded to the treatment received. No record of the intervention received was made in the clinical notes to attempt to blind caregivers in the neonatal intensive care unit. The degree to which blinding of caregivers was successful is unclear. Primary outcome assessment (hematocrit) was presumably performed by a technician unaware of the infant’s allocated group. Secondary clinical outcomes could, at least in theory, have been influenced by clinicians who were made aware of the allocated treatment group.
• Follow-up period: Infants were followed until hospital discharge
• Setting: Single US neonatal unit: University of Alabama Children’s and Women’s Hospital.
• Patients:
  • Inclusion criteria: Singleton deliveries (both caesarean section and vaginal) with estimated gestational ages between 22.0 and 31.6 weeks’ whose parents had agreed to full active management.
  • Exclusion criteria: Known fetal anomalies or suspected placental abruption.
  • Thirty six percent of deliveries were vaginal and 64% were caesarean. Mean (SD) birth weights (g) and gestational ages were similar in control and experimental group (See Table 1). No data on rates of antenatal steroid administration, maternal ethnicity, or delivery room resuscitation were provided.
• Intervention: Randomization immediately prior to delivery to either control arm [30 seconds delayed cord clamping (n=32)] or intervention arm [30 seconds delayed cord clamping with cord stripping performed by the surgeon or assistant 4 times with a 4-5 seconds interval between each stripping (n=35)]. In both arms, the baby was placed below the level of the perineum following vaginal births and to the mother’s side following cesarean deliveries.
• Outcomes:
  • Primary outcome: first arterial or venous performed within the first 30 minutes of life.
  • Secondary outcomes: days on ventilation, days in hospital, neonatal mortality, peak bilirubin, number of days of phototherapy, intraventricular hemorrhage, bronchopulmonary dysplasia and retinopathy of prematurity.
• Analysis and Sample Size: Sample size of 64, based on a “typical” mean (SD) hematocrit of 50% and a clinically important difference of 5% with an alpha of 0.05 and power of 80%. A subanalysis is presented on the basis of gestational age (<28 weeks’ vs. ≥28 weeks’) but infants were not stratified at randomization.
• Patient follow-up: Whilst a figure showing the number of eligible infants and reasons for exclusion during the study period is not provided, the authors report in the discussion that the recruitment rate was only 32%. Three patients (4%) of randomized patients were subsequently excluded because on review they did not meet inclusion criteria. The details of why these subjects were excluded were unspecified. Data are complete for the remaining 67 patients.

MAIN RESULTS

CONCLUSION

Adding cord stripping to delayed cord clamping does not result in an increased hematocrit.

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COMMENTARY

Interest in the management of the umbilical cord extends back many centuries. Erasmus Darwin stated in 1794 that “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. As otherwise the child is much weaker than it ought to be”.¹ Enthusiasm for immediate cord clamping is a relatively recent phenomenon and is linked to the active management of labor. Recently, suspicions that the transition of both term and preterm infants at birth may be enhanced by “capturing” fetal blood from the placenta and umbilical cord have been to some extent confirmed by a series of animal experiments and human randomized trials. International recommendations for the management of term infants now often include instruction to delay clamping and cutting of the umbilical cord for at least 60 seconds. The Cochrane review on cord clamping and milking in preterm infants suggests that although some benefits are seen with delayed cord clamping (less need for transfusion, less intraventricular hemorrhage and lower risk for necrotizing enterocolitis), long term benefits remain to be well examined.² Milking or stripping of the umbilical cord have been advocated as having additional benefits.³

Krueger and colleagues conducted an RCT to determine whether cord stripping in addition to delayed cord clamping resulted in improved outcomes compared with delayed cord clamping alone.⁴ Research in the Delivery Room is challenging and the authors are commended for completing their trial as planned. They describe both the control and intervention maneuver sufficiently for each to be replicated by other clinicians. However, there are a number of limitations. The method of treatment allocation is somewhat unusual. Rather than using a computer to generate a series of treatment allocations which are then placed in sequentially numbered, sealed opaque envelopes, this study had equal numbers of envelopes which were scrambled by a third party registered nurse. In theory, this is a form of random allocation but it lacks the robustness of more conventional methods. Since the surgeons and not the neonatal team were responsible for the intervention it would seem to have been feasible to blind the neonatal caregivers (and outcome assessors) to the allocated treatment. It is unclear whether the neonatal team was present during the allocated treatment, or whether they were able to see which intervention was .

The authors acknowledge that recruitment to this trial was challenging, with only 32% of eligible infants enrolled. This highlights the important issue of reliance on an antenatal consent process, particularly the limited generalizability inherent in delivery room studies which rely solely on antenatal consent.

The choice of primary outcome (hematocrit) is conventional in this field but unlikely, by itself, to convince clinicians to change their practice. It does however, allow the trialists to answer a question in a single center and can be viewed as a hypothesis generating single center study.

Having found no difference in their primary outcome, the authors present a subanalysis of their primary outcome by gestational age. This was apparently decided upon post hoc and the infants were not stratified for this baseline variable at randomization. It is unclear why the cut point of 28 weeks’ was chosen. The interesting observation that cord stripping reduced hematocrit in infants equal to or above 28 weeks’, but increased it in those less than 28 weeks’ is perhaps most likely due to chance.

The authors⁴ findings contrast with those of a recent meta-analysis of cord stripping which found that cord stripping increased hematocrit as well as reducing bronchopulmonary dysplasia and intraventricular hemorrhage.⁵ Two of the studies in that systematic review compared cord stripping with delayed cord clamping. The authors’ claim that they were evaluating the additional benefits of cord stripping on delayed cord clamping is worth closer examination. The control group had their cords cut at 30 seconds, shorter than conventional definition of at least one minute used in most randomized trials.⁶ The procedure in the intervention group occurred during the first 30 seconds but the 4 stripping events and 4-5 seconds between each event would have taken most of that time.

There are now at least eight RCTs including more than 500 infants investigating the safety and efficacy of umbilical cord stripping. The ground work has been done and agencies need to be encouraged to fund a large scale multicenter RCT of this therapy, powered to detect a difference in important outcomes including mortality and neurodevelopment in infancy. Such a trial is required before this promising technique becomes standard practice.

REFERENCES

1. Downey CL, Bewley S. Historical perspectives on umbilical cord clamping and neonatal transition. Journal of the Royal Society of Medicine 2012;105:325-9.
2. Rabe H, Diaz-Rossello JL, Duley L, Dowswell T. Effect of timing of umbilical cord clamping and other strategies to influence placental transfusion at preterm birth on maternal and infant outcomes. Cochrane Database Syst Rev 2012;8:Cd003248.
3. Hosono S, Mugishima H, Fujita H, et al. Umbilical cord milking reduces the need for red cell transfusions and improves neonatal adaptation in infants born at less than 29 weeks’ gestation: a randomised controlled trial. ArchDisChild Fetal Neonatal Ed 2008;93:F14-F9.
4. Krueger MS, Eyal FG, Peevy KJ, Hamm CR, Whitehurst RM, Lewis DF. Delayed cord clamping with and without cord stripping: a prospective randomized trial of preterm neonates. Am J Obstet Gynecol 2015;212:394.e1-5.
5. Al-Wassia H, Shah PS. Efficacy and safety of umbilical cord milking at birth: a systematic review and meta-analysis. JAMA pediatrics 2015;169:18-25.
6. McDonald SJ, Middleton P, Dowswell T, Morris PS. Effect of timing of umbilical cord clamping of term infants on maternal and neonatal outcomes. Cochrane Database Syst Rev 2013;7:Cd004074.