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Abstract
Objective To investigate whether umbilical cord milking (UCM) at birth improves systemic blood flow and short-term outcomes, as compared with immediate cord clamping (ICC).
Design Randomised clinical trial.
Setting Single tertiary care centre.
Patients Infants born to eligible women presenting in preterm labour between 24 and 31 weeks’ gestation.
Interventions UCM three times at birth or ICC.
Outcome measures Primary outcome included systemic blood flow as represented by echo-derived superior vena cava(SVC) flow at 4–6 hours after birth. The echocardiographer and interpreter were blinded to the randomisation. Secondary outcomes included cardiac output, neonatal morbidities and mortality. Analysis was by intention to treat.
Results A total of 73 infants were randomised (37 to UCM and 36 to ICC). Mean (SD) gestational age was 27 (2) weeks and mean (SD) birth weight was 1040 (283) g. Haemoglobin on admission was higher in the UCM than in the ICC group (16.1 vs 15.0 g/L), p=0.049 (mean difference 1.1, 95% CI 0.003 to 2.2). No statistically significant differences were found between groups in SVC flow at 4–6 hours (88.9±37.8 and 107.3±60.1 mL/kg/min), p=0.13 (mean difference −18.4, 95% CI −41.7 to 5.0 mL/kg/min) or at 10–12 hours of age (102.5±41.8 and 90.6±28.4 mL/kg/min), p=0.17 (mean difference 12.0, 95% CI −4.7 to 28.7 mL/kg/min), cardiac output or neonatal morbidities.
Conclusions Cord milking was not shown to improve functional cardiac outcomes, neonatal morbidity or mortality. More research is needed before routine cord milking can be recommended for very preterm infants.
Trial registration NCT01487187.
- neonatology
- resuscitation
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What is already known on this topic?
Unlike delayed cord clamping, umbilical cord milking has not yet been endorsed as an alternative for placental transfusion despite some studies showing its potential benefits.
What this study adds?
In preterm infants, cord milking improved haemoglobin level as compared with immediate clamping. However, it was not shown to improve systemic blood flow, neonatal morbidity or mortality.
Introduction
Despite the improvement of the survival rate of very preterm infants, the rate of developmental impairment is still of concern.1 2Haemodynamic instability, in the form of low blood pressure and low systemic blood flow, has been linked to cerebral injuries and neurodevelopmental disabilities. To date, no intervention has been found to effectively prevent this initial haemodynamic instability.1 3–5
Placental transfusion at birth is a simple intervention that may provide better postnatal adaptation and improve neonatal outcomes including brain injuries such as intraventricular haemorrhage (IVH).6–8 The International Liaison Committee on Resuscitation (ILCOR) and other governing bodies have recommended placental transfusion by delayed cord clamping (DCC) to replace immediate cord clamping (ICC) as the standard of care for most preterm and full-term infants at birth.9–12 However, the alternative procedure for placental transfusion at birth, umbilical cord milking (UCM), has not received the same endorsement despite several studies reporting clinical benefits.8 12–14 The lack of support for UCM is partly attributable to insufficient evidence from large trials comparing UCM to ICC or DCC and partly to the uncertainty of the physiological impact of the rapid blood transfusion by UCM especially if breathing and pulmonary circulation have not yet been established.12 14 A recent meta-analysis of UCM at birth attributed some benefits without clear adverse effects in the immediate postnatal period in preterm infants.14 As the findings were limited by the heterogeneity and small sample size of the included studies, the authors recommended restricting the use of UCM to randomised controlled trials until further evidence is available. Similarly, ILCOR in 2015 recommended against the routine use of UCM due to the insufficient evidence but encouraged more research in the area.9 In a more recent article, the European Consensus Guidelines recommend UCM as a reasonable alternative if DCC is not possible, but rated this recommendation as weak.15
As there were some reports of better neonatal adaptation and short-term clinical outcomes in preterm infants receiving UCM as compared with those receiving ICC,16–18 and as the physiology behind these effects was not very clear, we further investigated whether the claimed benefits of UCM were attributable to a resulting increase in systemic blood flow. Measuring superior vena cava (SVC) flow has been recommended as a better way of assessing systemic blood flow in the very preterm infants shortly after birth due to the presence of shunts that affect the reliability of measuring cardiac output.19–21 Early low SVC flow has been reported as a predictor for brain injury and poor neurodevelopmental outcome.22 23 Thus, studying SVC flow after UCM may help us understand the physiological impact of the procedure that could mitigate different clinical effects during postnatal adaptation in these infants.
We hypothesised that, in preterm infants less than 31 weeks’ gestation, milking the umbilical cord three times prior to clamping, as compared with ICC at birth, would improve systemic blood flow as assessed by SVC flow, neonatal transition and clinical outcomes.
Methods
This randomised controlled trial was conducted in Halifax, Nova Scotia, at the IWK Health Centre, a tertiary care perinatal centre with approximately 5000 births/year. The Neonatal Intensive Care Unit (NICU) is a regional tertiary care unit with 900–1000 annual admissions. Written informed consent was obtained antenatally from all women participating.
Study population
Preterm infants born between 24 and 30+6 weeks’ gestation were eligible for enrolment.
Exclusion criteria included monochorionic twins, major congenital anomalies, placental abruption, fetal anaemia and intention to withhold resuscitation.
Randomisation and masking
Eligible fetuses were randomised to receive UCM (intervention group) or ICC (control group) prior to delivery once inevitable preterm labour was established using variable block sizes randomisation table. Concealed opaque envelopes were prepared ahead of time and were opened just before the time of delivery. Each enrolled baby was assigned to the next sealed opaque envelope from the study kit. A log was maintained to ensure commitment to allocation. Dichorionic twins were assigned to the same group. Randomisation was stratified into singleton and twin births.
Study procedures
Infants in the UCM group were placed at or below the level of the placenta and about 20 cm of the cord (or if less, the available length of cord) was milked towards the umbilicus three times, holding the cord at the end of each strip to allow for refilling in between strips, before clamping. Speed of milking was approximately 10 cm/s.16 Obstetricians were fully oriented with the procedure before the start of the study. The type of intervention was not documented in the mother’s or infant’s chart and was not communicated to the neonatal team at birth. Infants in the ICC group had their umbilical cords clamped within 10 s of birth as per standard practice at that time.
Echocardiography studies, using 12 MHz transducer of iE33 Ultrasound System (Philips Medical Systems, Andover, Massachusetts, USA), were conducted at 4–6 and 10–12 hours after birth by WE or DS to assess SVC flow, ventricular output and function and patent ductus arteriosus (PDA) characteristics. Measurements of SVC flow and cardiac output were calculated by averaging 10 consecutive cardiac cycles to allow for the variation caused by respiration and also for any variation within the cardiac cycle. Superior Vena Cava flow and cardiac output were calculated from the formula: Flow/output (mL/kg/min)=(velocity time integral mL/min×π (mean vessel diameter(cm)2/4)×heart rate (beats per min))/body weight (kg). The technique and measurements were performed as previously described in the literature.21 24 Every patient was scanned by the same sonographer at the two study time points. Both the echocardiographer and the offline reader (AH) were blinded to patient’s assignment. All cardiorespiratory variables including heart rate, blood pressure, details of respiratory support, blood gases, oxygen saturation as well as management details as fluid boluses, medications and fluid intake at the time of echocardiographic assessments were recorded. Head ultrasounds were conducted at the age of 3 days, 2 weeks, 6 weeks and term equivalent, consistent with routine unit practice.
Maternal, perinatal and neonatal clinical course data were collected during the infant’s hospital stay.
Study outcomes
The primary outcome was systemic blood flow as represented by mean SVC flow at 4–6 hours after birth.
Secondary outcomes included SVC flow at 10–12 hours after birth, other echocardiographic and clinical markers of haemodynamic status, short-term clinical outcomes and mortality during NICU stay.
Sample size calculation and statistical analysis
Mean SVC flow has been reported in very low birth-weight infants as 70.4 mL/kg/min with a SD of 39.5 mL/kg/min.25 To detect an increase in mean SVC flow of 40% to about 98 mL/kg/min, we required 31 infants in each group for 80% power and 0.05 alpha. We planned to recruit 35 subjects in each group. Agreement between the two examiners for both first and second echocardiographs was assessed using intraclass correlation coefficients for the SVC flow. This was done though 13 of study participants in which both echocardiographers measured SVC flow for the same patient within a few minutes of each other. Normally distributed continuous variables were compared with t-tests, means and SD; non-normally distributed variables were compared with the Mann-Whitney U test. Categorical variables were analysed by Χ2 or Fisher’s exact test. Analysis was by intention to treat.
Study safety
All recruited infants were carefully monitored as part of routine NICU care for any possible adverse effects such as polycythaemia, hyperbilirubinaemia, hyperkalemia or intolerance of echocardiographic studies. An independent Data Safety Monitoring Committee assessed the study halfway into recruitment with the decision to continue the study as designed.
Results
A total of 329 women were assessed for eligibility during the study period from November 2011 to November 2014. From these, 73 fetuses from 59 mothers were randomised to either UCM or ICC. Five infants in the UCM group did not receive the allocated intervention. All 37 infants in the UCM group and the 36 in the ICC were included in the final analysis (figure 1). Mean (SD) gestational age at birth was 27.2 (2.0) weeks and mean (SD) birth weight was 1040 (283) g. Baseline characteristics were similar between both groups except for having more women with gestational diabetes in the ICC group (table 1). Haemoglobin concentration on NICU admission was higher in the UCM group (mean g/L±SD 16.1±2.3 vs 15.0±2.4), p=0.049 (mean difference 1.1, 95% CI 0.003 to 2.2).
Consolidated Standards of Reporting Trials flow diagram.
Maternal and infantile baseline characteristics
Cardiorespiratory variables were not significantly different between the groups at the time of performing echocardiography studies (table 2).
Echocardiographic and cardiorespiratory outcomes at 4–6 and 10–12 hours of age
No significant difference was found in the primary outcome, mean SVC flow at mean age of 5 hours or at the second point of 11 hours of age, between those who received UCM (88.9±37.8 and 102.5±41.8 mL/kg/min) and those who received ICC (107.3±60.1 and 90.6±28.4 mL/kg/min), p=0.13 (mean difference −18.4, 95% CI −41.7 to 5.0 mL/kg/min) and p=0.17 (mean difference 12.0, 95% CI −4.7 to 28.7 mL/kg/min). Similarly, there were no significant differences in the other echo-derived variables at the two study time points (table 2). The median (IQR) PDA diameter was 1.6 (1.0–2.2) and 1.6 (1.4–2.3) mm in the patients with UCM and ICC, respectively (p=0.89). PDA flow direction, pressure gradient and left atrial aortic root ratio were not significantly different between the two groups. Left ventricular shortening fraction (FS) and mean velocity of circumferential fibre shortening (mVCFc) were also similar. Interobserver variability for SVC flow between the two echocardiographers suggested excellent agreement (intraclass correlation=0.97, 95% CI 0.92 to 0.99). All measured clinical outcomes including resuscitation outcomes at birth (table 3), acuity score (the Clinical Risk Index for Babies (CRIB) II score) on admission to NICU, peak bilirubin level, incidence of hypotension (mean blood pressure<corresponding gestational age number for >30 min) in the first 48 hours, number of transfusions during hospital stay and all major morbidities were not significantly different between both groups (table 4). Of those 10 infants who had severe IVH (grade III or IV), four (40%) had low SVC flow <55 mL/kg/min at 4–6 hours of age. Three of them were in the ICC group, while one was in the UCM group (p=0.22). The incidence of severe IVH among those who had SVC flow >55 mL/kg/min was 6.3%.
Outcomes at birth
Clinical outcomes during hospital stay
On secondary analysis according to the actual intervention given, no significant difference was found between both groups in terms of the SVC flow at 4–6 hours (p=0.25), other echo-derived variables or clinical outcomes. Comparison of the two groups based on gestational age (<28 weeks and ≥28 weeks at birth) showed only a lower SVC flow at 4–6 hours in the UCM subgroup ≥28 weeks, n=18 (82±28.1 mL/kg/min) as compared with the ICC subgroup, n=18 (107.7±43.2 mL/kg/min), p=0.04 (95% CI −50.4 to –1.03) but not in those <28 weeks’ gestation at birth. Otherwise, there was no significant difference in any of the other outcomes.
Discussion
In this randomised controlled study, UCM was not shown to improve systemic blood flow as represented by SVC flow or by cardiac output as compared with ICC. We elected to measure SVC flow at the two time points previously reported to have the lowest values during postnatal adaptation to better investigate the potential for any beneficial effect.4 Theoretically, one would expect that the UCM would result in increased blood volume and a significant rise in systemic blood flow. Two previous studies reported UCM to increase SVC flow in very preterm infants.26 27 One study used historical controls26 and the other measured SVC flow at time points with a wide range up to 12 hours which could increase variability in these measurements.27 In our study, the time range for each echo study time point was strictly 2 hours. Recently, a larger trial of 266 infants comparing DCC for 60 s to ICC did not detect an increase in SVC flow or cardiac output in the DCC group despite an apparent increase in blood volume as reflected by significant increase in haemoglobin levels.28 In our study, the obstetricians were oriented to the cord milking technique before launching to ensure consistent adequate placental transfusion. Holding the cord to allow for the refilling at the end of each strip was not reported before in the original study of Hosono et al or that of Katheria et al.16 27 Allowing for refilling of the cord between stripping has been recently described in premature sheep to be superior to UCM without placental refill (36). We maintained blinding of the echocardiographer and the interpreter to allocation. As in other studies,14 16 27 the haemoglobin levels on admission were significantly higher in the UCM group which suggests an achieved successful placental transfusion and contradicts the assumption that the lack of increase of systemic blood flow could be attributed to inconsistent procedure or insufficient placental transfusion. Our SVC flow values were higher than those reported originally by Kluckow and Evans.4 However, our SVC flow values which were measured offline by a single blinded cardiologist were higher in both groups. Others have also reported higher SVC flow values; Sommers et al found the mean (SD) of SVC flow after ICC in preterm infants at 6 hours of age to be 89 (24) mL/kg/min.29 Popat et al reported SVC flow in 133 preterm infants after ICC at 3 hours of age to be 92.1 (35.4) mL/kg/min.28 In our study, the mean SVC flow in the ICC group dropped from 107.3 mL/kg/min to 90.6 mL/kg/min at 10–12 hours of age. This could represent physiological differences within normal values reported before at the same age. Popat et al also showed a drop in SVC flow values between 3 hours and 9 hours of age in their study groups.28 Despite the fact that measuring SVC flow can be a challenging procedure with a questioned variability between echocardiographers or interpreters,30 31 our intraclass correlation (0.97, 95% CI 0.92 to 0.99) for SVC flow suggested excellent agreement between the images taken by the two echocardiographers which led to very similar measurements by the single blinded reader. This is different from Popat et al’s study which reported moderate variability between the readers.32 We followed the same meticulous process used by Kluckow and Evans who also reported good interobserver agreement in SVC flow measurement.21 In view of the rapid changes in haemodynamics and fluid status of these infants during their early postnatal transition, it is possible that assessing systemic blood flow and cardiac output 4–12 hours after placental transfusion may not reflect a real measurable change in the intravascular compartment. Another possibility is that UCM may have a larger effect on peripheral than systemic blood circulation.
The incidence of low SVC flow values (<55 mL/kg/min) at 4–6 hours of age was comparable in each group. However, those who had low SVC flow were more likely to develop severe IVH (grade III/IV) as compared with those who had normal SVC flow. This is in keeping with earlier report by Kluckow and Evans.4 Our study did not detect any significant improvement in clinical outcomes including rates of necrotising enterocolitis (NEC), sepsis, bronchopulmonary dysplasia (BPD), retinopathy of prematurity (ROP), IVH or mortality. There is inconsistency in the literature about the impact of UCM on these clinical outcomes with conflicting reports of significant improvement in each outcome.16 27 33 In keeping with our findings, March et al reported no significant difference in BPD, ROP, sepsis, NEC or mortality between extreme preterm infants who had UCM as compared with those who had ICC.34 As in our study, their rates of blood transfusion were not significantly reduced after UCM despite reporting higher haemoglobin levels on admission. It is important to note that neither our study nor any of the previous studies were powered to detect any of these clinical outcomes.
A meta-analysis comparing UCM and DCC to ICC in preterm infants reported higher haemoglobin concentrations, reduced BPD and all grades of IVH in the UCM group.14 However, there was no significant difference in mortality or in other clinical outcomes. Of note, the meta-analysis included only five studies with a total of 219 preterm infants <33 weeks gestation.
As in other studies, our RCT did not show any increase in adverse outcomes related to UCM (polycythaemia, hyperkalemia or hyperbilirubinaemia) which adds to the growing evidence about the safety of the procedure on short-term outcomes.14 From the physiological point of view, there might be some concern related to the rapid transfusion of large volume of blood to the infant’s circulation especially before breathing or establishing an effective pulmonary circulation. Animal studies have shown the value of commencing ventilation and effective pulmonary circulation to improve the cardiac output, stabilise cerebral circulation and allow for a smoother cardiovascular transition at birth.35 A recent study by Blank et al demonstrated that milking the cord at birth resulted in swings in the arterial pressure and cerebral blood flow without increasing pulmonary blood flow in newborn lambs.36 This does not negate the potential value of UCM in improving haemoglobin levels and blood volume, especially in conditions where DCC may not be a viable option as in case of need for urgent resuscitation or in interrupted placental circulation.8 13 14 A recent follow-up study found that infants randomised to UCM had higher language and cognitive scores at 22–26 months corrected age than those who received DCC without a difference in neurodevelopmental impairment.37
Our study has limitations. The sample size was calculated for systemic blood flow and was underpowered to evaluate clinical outcomes. Despite our efforts to keep the healthcare providers blinded to the study intervention by not documenting the intervention in the charts, we cannot be absolutely sure that full blinding was achieved. Although the technique was carefully reviewed with all obstetricians, it is also not possible to be sure that the UCM was performed in the same standardised manner outlined in the protocol. We had a crossover rate of 13.5% (all crossovers were from UCM to ICC) but the per-protocol analysis did not change our findings. The crossover rate provides important information for future studies about the feasibility of this intervention. Finally, although we had an excellent agreement between the two sonographers, having a single sonographer would have been ideal.
We intend to report the long-term outcomes at 36 months of corrected age.
Conclusion
UCM was not shown to improve systemic blood flow as represented by SVC flow and functional cardiac outcomes, despite improving haemoglobin levels on admission. Milking of the umbilical cord at birth did not result in any adverse outcomes but was not shown to confer clinical benefit in terms of reducing morbidity or mortality in preterm infants <31 weeks’ gestation as compared with ICC. More research is needed before routine cord milking can be recommended for very preterm infants.
References
Footnotes
Contributors WE-N was involved in the study design, Research Ethics Board (REB) approval, performing echo-cardiography studies, data review and manuscript preparation. DS and AH were involved in conducting and reading and interpreting echocardiography studies, respectively, data review and manuscript reviewing. LD was involved in sample size calculation and randomisation process preparation. AA, LD, AW, RW and DM were involved in the study design, REB approval and manuscript reviewing. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
Funding This project was supported by grants from both Nova Scotia Health Research Foundation (PSO-EST-2013-9023 EGMS 1813) and IWK Research Foundation (1008052). No honorarium or other form of payment was given to anyone to produce this manuscript.
Competing interests None declared.
Patient consent Obtained from the parents/guardian.
Ethics approval IWK Health Centre Research Ethics Board.
Provenance and peer review Not commissioned; externally peer reviewed.
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