Objective To conduct a systematic review and meta-analysis of the efficacy and safety of umbilical cord milking in preterm infants.
Design Randomised controlled trials comparing umbilical cord milking with delayed cord clamping/immediate cord clamping in preterm infants were identified by searching databases, clinical trial registries and reference list of relevant studies in November 2019. Fixed effects model was used to pool the data on various clinically relevant outcomes.
Main outcome measures Mortality and morbidities in preterm neonates.
Results Nineteen studies (2014 preterm infants) were included. Five studies (n=922) compared cord milking with delayed cord clamping, whereas 14 studies (n=1092) compared milking with immediate cord clamping. Cord milking, as opposed to delayed cord clamping, significantly increased the risk of intraventricular haemorrhage (grade III or more) (risk ratio (RR): 1.95 (95% CI 1.01 to 3.76), p=0.05). When compared with immediate cord clamping, cord milking reduced the need for packed RBC transfusions (RR:0.56 (95% CI 0.43 to 0.73), p<0.001). There was limited information on long-term neurodevelopmental outcomes. The grade of evidence was moderate or low for the various outcomes analysed.
Conclusion Umbilical cord milking, when compared with delayed cord clamping, significantly increased the risk of severe intraventricular haemorrhage in preterm infants, especially at lower gestational ages. Cord milking, when compared with immediate cord clamping, reduced the need for packed RBC transfusions but did not improve clinical outcomes. Hence, cord milking cannot be considered as placental transfusion strategy in preterm infants based on the currently available evidence.
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What is already known on this topic?
Umbilical cord milking from the placental side towards the newborn is an alternative to placental transfusion from delayed cord clamping.
Cord milking has shown to be feasible in infants requiring resuscitation at birth.
Umbilical cord milking has shown to improve haemoglobin levels and short-term clinical outcomes in preterm infants.
What this study adds?
Placental transfusion through cord milking, as compared to delayed cord clamping, significantly increased the risk of severe intraventricular haemorrhage in preterm infants <34 weeks of gestation.
When compared to immediate cord clamping, cord milking significantly reduced the need for packed RBC transfusions but did not result in improved clinical outcomes.
When the umbilical cord is clamped immediately after birth (ie, immediate cord clamping, ICC), a significant amount of the fetal blood remains in the placenta leading to relatively lower red blood cell (RBC) volume in the newborn infant. Delayed cord clamping (DCC) and umbilical cord milking (UCM) are two main placental transfusion strategies in the delivery room to increase the RBC volume of neonates. DCC involves delaying the clamping of the cord for 30–180 s after birth or until the cessation of cord pulsations. On the other hand, UCM consists of gently grasping the umbilical cord and squeezing it from the placental end towards the infant. While UCM is usually performed before clamping the umbilical cord (intact UCM), milking after clamping and cutting of the umbilical cord (cut UCM) has also been reported.1
Systematic reviews2 3 have reported that DCC, when compared with ICC reduces the incidence of mortality, intraventricular haemorrhage (IVH), necrotising enterocolitis (NEC) and need for blood transfusions in preterm infants. Hence, many professional organisations have endorsed DCC as a standard delivery room practice for vigorous preterm infants.4 5 However, DCC could be difficult to implement in critically ill and apneic preterm infants in the delivery room needing resuscitation. Hence, UCM has been investigated as a potential alternative to DCC because resuscitative measures can proceed shortly after delivery.
Systematic reviews comparing UCM with immediate/delayed cord clamping have reported that UCM lowered the incidence of IVH, mortality and the need for oxygen at 36 weeks postmenstrual age, among preterm infants.6 7 However, results from a recent large trial suggested an increased risk of severe IVH with cord milking when compared with DCC, especially in extremely preterm infants.8
Majority of the trials on cord milking were not powered to assess mortality and other important morbidities. The impact of this intervention on long-term neurodevelopment of preterm infants is also unclear. There is a need to synthesise available evidence to inform clinical practice and the design of future clinical trials. Hence, we conducted this systematic review to evaluate the efficacy and safety of UCM in preterm infants.
Guidelines from the Cochrane Neonatal Review Group, Centre for Reviews and Dissemination and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement were used for conducting and reporting this systematic review.9
Randomised controlled trials (RCTs) comparing UCM with DCC/ICC were included in the review.
Types of participants
Studies done in preterm infants born at a gestational age (GA) <37 weeks were included.
I-UCM or C-UCM at birth.
DCC or ICC.
The following analyses were planned: (1) intact UCM (I-UCM) vs DCC; (2) I-UCM vs ICC; (3) cut UCM (C-UCM) vs ICC/DCC.
(1) All-cause mortality, (2) IVH (all grades), (3) severe IVH (grade III or more), (4) patent ductus arteriosus (PDA) needing treatment, (5) NEC (stage not reported), (6) definite NEC (stage II or more on modified Bell staging), (7) retinopathy of prematurity (ROP) all stages, (8) ROP needing intervention, (9) periventricular leukomalacia, (10) bronchopulmonary dysplasia (BPD), (11) need for packed RBCs during NICU stay, (12) need for phototherapy, (13) duration of hospital stay and (14) neurodevelopmental outcomes at 24 months.
The databases MEDLINE, EMBASE, CINAHL, Cochrane Central Register of Controlled Trials and clinical trial registries were searched in November 2019. ‘Google Scholar’ was searched for articles that might not have been cited in the standard medical databases. The reference lists of eligible studies and review articles were searched to identify additional studies. Reviewers HB, AA, VJ and SCR conducted the literature search independently. All the authors of the included studies were contacted through emails to obtain additional data and clarification of methods. The search criteria for this systematic review have been included in the supplement file.
The studies were assessed for eligibility by reviewers HB, AA, VJ and SCR independently using the predefined eligibility criteria and data were extracted using a data collection form designed for this review. Care was taken to ensure that multiple publications of the same study were excluded to avoid data duplication. Discrepancies during the data extraction process were resolved by group discussion.
Assessment of risk of bias
Risk of bias (ROB) was assessed using the Cochrane ‘Risk of Bias Assessment Tool’.10 Authors HB and AA independently assessed the ROB in all domains including random number generation, allocation concealment, blinding of intervention and outcome assessors, completeness of follow-up, selectivity of reporting and other potential sources of bias. For each domain, the ROB was assessed as low, high or unclear risk based on the Cochrane Collaboration guidelines.
Assessment of quality of evidence
The key information concerning the quality of evidence, based on the (1) sample size for clinically important outcomes, (2) magnitude and precision of the treatment effect of the intervention, (3) ROB, (4) directness of evidence, (5) consistency of results (statistical heterogeneity), has been presented as per GRADE guidelines (Grades of Recommendation, Assessment, Development and Evaluation).11
Meta-analysis was conducted using Review Manager 5.3 (Cochrane Collaboration, Nordic Cochrane Centre). Fixed effects model (FEM) was used. Random effects model (REM) analysis was conducted to recheck the results if there was significant statistical heterogeneity on FEM. Effect size was expressed as risk ratio (RR) and 95% CIs. Statistical heterogeneity was assessed by the I2 statistic and was interpreted as per the Cochrane handbook guidelines.12 Publication bias could not be assessed since the meta analyses for the outcomes included less than 10 studies.13 We used the method described by Wan et al to estimate mean and SD for the continuous outcomes that were primarily reported as median and range/IQR in the individual studies.14
Sensitivity analysis was performed after excluding RCTs with high ROB in the domain of allocation concealment and those where the mean GA of the included infants was greater than 32 weeks.
Nineteen RCTs [5 RCTs (n=922) comparing UCM with DCC,8 15–18 14 RCTs (n=1092) comparing UCM with ICC19–32] were included in this systematic review. Milking was performed on an intact cord (I-UCM) in 16 RCTs, while cut UCM was performed in 3 studies.20 26 30 Eighteen studies were available as full articles and one was a conference abstract.23 The flow diagram of study selection process is given in figure 1. Authors of three studies8 17 27 provided additional information on important clinical outcomes.
All the five studies comparing UCM with DCC included infants less than 34 weeks of gestation; however, three studies comparing UCM with ICC26–28 included preterm infants>34 weeks. Three RCTs included only extremely preterm infants (<28 weeks).22 23 29 The characteristics of the included studies are given in table 1. The cord milking technique followed in the included studies is described in online supplementary table 1. The details of ROB are given in table 2 and the overall evidence according to GRADE guidelines is summarised in online supplementary table 2. The results of sensitivity analyses are given in online supplementary table 3 and the neonatal outcomes with cut UCM are depicted in online supplementary table 4.
We also identified fourteen ongoing studies (six comparing UCM with DCC, eight comparing UCM with ICC) from clinical trial registries (online supplementary table 5).
Meta-analysis found no significant effect on mortality with UCM when compared with DCC (RR 0.93 (95% CI 0.55 to 1.55), p=0.77, I2=0%, 4 studies8 16–18 (n=890)) (figure 2) .There was no significant difference in mortality between the I-UCM and ICC groups (RR 0.85 (95% CI 0.49 to 1.46), p=0.56, I2=27%, 10 studies19 21–24 27–29 31 32 (n=698)) (figure 3). Cut UCM did not have a significant effect on mortality when compared with ICC (RR 1.00 (95% CI 0.35 to 2.90), p=1.00, I2=34%, 2 studies26 30 (n=260)) (online supplementary table 4).
IVH (grade 3 or more)
Meta-analysis estimated a significant increase in the risk of severe IVH in the UCM group when compared with DCC (RR 1.95 (95% CI 1.01 to 3.76), p=0.05, I2=0%, 4 studies8 15–17 (n=718)) (figure 2). Number needed to treat with UCM that could result in IVH >grade 3 in one additional infant (NNTH) was 29 (95% CI 500 to 15). When compared with ICC, intact cord milking was not associated with an increased risk of IVH (grade 3 or more) (RR 0.69 (95% CI 0.38 to 1.24), p=0.22, I2=0%, 8 studies19 21 22 24 27–29 32 (n=598)) (figure 3). Only one study on cut UCM reported on this outcome30 and found no difference (online supplementary table 4).
For the other prespecified outcomes—IVH (all grades), NEC, PDA, BPD, ROP and duration of hospital stay, there were no statistically significant differences between the UCM and DCC/ICC groups (figures 2 and 3, and online supplementary figure 1, 2 and table 4).
Need for packed RBC transfusion
Transfusion requirements were similar between UCM and DCC groups (online supplementary figure 1). Meta-analysis estimated a significant reduction in the incidence of RBC transfusion in the I-UCM group when compared with ICC (RR 0.56 (95% CI 0.43 to 0.73), p<0.00001, I2=73%, 4 studies)19 22 24 28 (figure 3). The results were found to be significant even on REM. Number needed to treat with I-UCM to prevent a packed RBC transfusion in one additional infant (NNTB) was 4 (95% CI 2.6 to 6.3).
Need for phototherapy
There was no difference in the phototherapy requirement between the UCM and DCC groups (online supplementary figure 1). However, our analysis showed a significant increase in the need of phototherapy in I-UCM group when compared with ICC (RR 1.17 (95% CI 1.04 to 1.31), p=0.01, I2=85%, 4 studies).21 27–29 The results were not found to be significant by REM (RR 1.13 (95% CI 0.90 to 1.41), p=0.29) (online supplementary figure 2).
Cut UCM when compared with ICC, significantly increased the need for phototherapy (RR 4.00 (95% CI 2.57 to 6.24), p<0.001, I2=0%, 2 studies) (online supplementary table 4).
Long-term neurodevelopmental outcomes
Neurodevelopmental follow-up at 24 months of age was reported only in two studies (n=174)16 17 comparing UCM with DCC. Meta-analysis of the Bayley III neurodevelopmental scores revealed no difference in the motor scores but significantly improved cognitive and language scores in the UCM group (online supplementary figure 3). None of the studies comparing UCM with ICC reported long-term neurodevelopmental outcomes.
Quality of evidence
The quality of evidence for the UCM vs DCC comparison was deemed moderate for the outcomes of all-cause mortality, IVH (all grades), severe IVH, definite NEC, PDA requiring treatment, BPD, ROP requiring intervention, need for packed RBC transfusions and the need for phototherapy. The evidence was graded low for the outcomes of NEC (stage not specified), ROP (all stages) and duration of hospital stay. For the intact UCM vs ICC comparison, the quality of evidence was rated moderate to low for the various outcomes analysed. The evidence for cut UCM was rated very low for all the outcomes studied (online supplementary table 2).
The results were similar to the main meta-analysis even after excluding studies where the mean GA was >32 weeks and those that had high ROB in the domain of allocation concealment (online supplementary table 3).
Our systematic review found that cord milking, when compared with DCC significantly increased the risk of severe IVH (grade III or more) in preterm infants born <34 weeks of gestation. When compared with ICC, milking significantly reduced the need for packed RBC transfusions but did not result in improved clinical outcomes.
To our knowledge, this is the most recent and comprehensive systematic review of UCM with exclusive focus on clinical outcomes in preterm infants. The consistency of our results even after excluding studies involving mature preterm neonates (>32 weeks of gestation), and those with high ROB, is another strength.
We identified at least four systematic reviews published on UCM in preterm infants. The systematic review by Dang et al compared UCM vs ICC (6 studies, 587 preterm infants<37 weeks) and found a reduced incidence of mortality and IVH, besides the reduced need for packed RBC transfusions in the UCM group. However, of the six included studies in their review, two were non-RCTs that contributed to nearly 63% of the total sample size.7
The systematic review on UCM by Al-Wassia et al (5 RCTs, 277 preterm infants<33 weeks of gestation) reported a lower risk of IVH of any grade and lower oxygen requirement at 36 weeks postmenstrual age with UCM,6 without a significant reduction in the need for RBC transfusions. However, the control intervention in their review was ICC or DCC, whereas in our review, the effects of UCM were analysed separately with respect to the control intervention—immediate or delayed cord clamping. The systematic review by Nagano et al (2 RCTs, 255 preterm infants<33 weeks) reported that UCM may lower the risk of IVH and improve long term neurodevelopmental outcomes, when compared with DCC.33
The recent Cochrane review (2019) on placental transfusion strategies in preterm neonates included 14 RCTs comparing cord milking with either ICC (11 trials, n=1183) or DCC (3 trials, n=322). The authors found no significant benefits or harms from UCM; however, the overall quality of evidence was graded low to very low.34 In our systematic review, 10 additional studies8 15 18 20 21 27 28 30–32 have been included besides those summarised in the Cochrane review. While the Cochrane review included few studies that allowed cord milking as a cointervention in the DCC group,35 36 we excluded those studies in order to determine the standalone effects of UCM in preterm neonates.
DCC is now considered the standard of care in vigorous preterm infants; however, its implementation in high risk preterm infants could be challenging.37 Approximately 70% of moderately preterm infants born less than 34 weeks and nearly 90% of extremely preterm infants born <29 weeks are reported to require resuscitation at birth.38 Second, placental transfusion from DCC in the absence of tonic uterine contractions as in caesarean delivery may be insufficient or ineffective.16 Hence, there remains a need to identify an alternative to DCC in high risk preterm infants.
Our meta-analysis demonstrated a significantly increased risk of severe IVH with cord milking in preterm infants, primarily driven by the results of the recently published PREMOD 2 (premature infants receiving cord milking or DCC) trial. This multicentre non-inferiority trial8 involving preterm infants born at 23–31+6 weeks of gestation randomised to UCM or DCC at birth was prematurely terminated, since the first interim analysis revealed a significantly increased risk of severe IVH with cord milking (22% vs 6%, p=0.002) among infants born at 23–27+6 weeks of gestation. This risk was not evident in the 27–31+6 weeks subgroup and there were no differences in mortality between the UCM and the DCC group.
The results of our meta-analysis are in contrast to the findings from previous systematic reviews,6 7 recently published observational studies39 40 and even the recently published Cochrane review (2019)34 on cord milking practices. This is predominantly because we included the recent PREMOD 2 trial that contributed to 50% of the overall sample size in the UCM vs DCC comparison. Second, the risk of severe IVH with milking was apparent only in PREMOD 2 trial where the study population was representative of preterm infants at risk of IVH.
Cord milking-induced rapid changes in the blood volume has remained a matter of concern, especially in the context of extreme prematurity. In the first experimental study on the physiological effects of placental transfusion strategies, Blank et al studied 29 fetal lambs exposed to (1) UCM with placental refill, (2) UCM without placental refill, (3) Physiology based cord clamping (ventilation before DCC) and (4) ICC.41 Placental transfusion was the least in the UCM group without placental refill. Both UCM groups experienced large fluctuations in the mean arterial blood pressure and cerebral blood flows. This led them to predict that extremely preterm infants subjected to UCM could be susceptible to IVH. The largest clinical trial to date8 also reached that outcome. These findings could warrant restriction of milking related research to preterm neonates born greater than 30 weeks of gestation.
Reduction in the need for RBC transfusions, demonstrated with cord milking in our meta-analysis, could be an important clinical benefit. However, majority of the study infants were vigorous at birth and eligible for DCC. In addition, there were no benefits with milking over ICC for other clinically relevant outcomes. Thus, our meta-analysis lends support to the criticism over the current clinical relevance of comparing cord milking with ICC, especially when the feasibility of DCC has been demonstrated even in non-vigorous preterm neonates.42
Placental transfusion with cut UCM has been reported to be inferior to that with intact cord milking.43 In an observational cohort of 106 preterm neonates<35 weeks of gestation, cut UCM neither improved haemoglobin levels nor reduced neonatal morbidities when compared with historical controls exposed to early cord clamping.44 Hence, the effect of cut UCM was analysed separately in our meta-analysis.
The main limitations of our review are the relatively small sample size and the lack of adequate information from extremely preterm infants. This also precluded assessment of the effects of UCM across GA categories. Neonatal mortality or morbidity was the primary outcome in only 1 of the 19 included studies.8 The other limitation is the heterogeneity in the milking techniques employed in the included studies. The frequency, speed of the milking manoeuvre and the length of cord that was stripped varied between the studies. Few of the included trials allowed cord refill after each milking attempt. The time frame for completion of the cord milking procedure was reported only in four studies.8 16 18 32
In summary, UCM cannot be recommended as a placental transfusion strategy in preterm infants based on current evidence. Safety monitoring of ongoing trials and reporting of long-term neurodevelopmental outcomes of participants of RCTs would be essential.
We thank the authors Katheria A (Katheria 2019), Rabe H (Rabe 2011) and Bueno LP (Lago Leal 2018) for providing information on important clinical outcomes for our meta-analysis.
Contributors HB designed the study and drafted the initial manuscript. AA and VJ collected the data and carried out the initial analysis. NK conceptualised the study and critically reviewed the manuscript. SCR conducted literature search and critically reviewed the manuscript. Each author listed on the manuscript has seen and approved the submission of this version of the manuscript and takes full responsibility for the manuscript.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available on reasonable request.