Optimising cord clamping in preterm infants: one strategy does not fit all
- 1Middlemore Hospital, New Zealand
- 2The University of Auckland, New Zealand
Whilst ILCOR (International Liaison Committee On Resuscitation) regards delayed cord clamping (DCC) as clamping after 30 sec, (1), the optimal timing has not been determined. Guidelines and practices show considerable variation and achieving lung expansion prior to clamping may be an important physiologic consideration (2). A recent meta-analysis (3), showed a significant reduction in mortality in preterm infants when delayed cord clamping (DCC) of greater than 30 sec was undertaken. Mortality was not significantly different when clamping occurred after 30 sec or after 120 sec (in most studies clamping was between 45-60 sec (3). Almost 1400 preterm infants have been allocated to receive DCC in these studies. The procedure was generally well tolerated, but some preterm infants were not vigorous and in the largest studies over 20% did not receive the intervention. In addition, some infants were ineligible for maternal reasons. What should be done in these cases? Should infants receive resuscitation support and remain attached to the placenta, or should the procedure be terminated, and/ or the cord milked? Are there options to ensure placental transfusion in infants excluded for maternal reasons? Our aim was to review current evidence in these different situations and we show that umbilical cord milking (UCM) may be a viable alternative where > 30 sec DCC cannot be achieved.
It is not only preterm infants that benefit from DCC. Term infants have less anaemia and iron deficiency following DCC (4). Such effects may be of greater benefits in resource-poor settings (5, 6). There have been relatively few studies of the effect of DCC in moderate to late preterm infants (over 32wks), although observational studies have reported a reduction in respiratory distress and need for resuscitation (7,8).
Preterm infants <32 weeks, however, are most likely to benefit from DCC and numerous randomized studies, most of which were small in size, have been carried out. More recently, several larger studies, the Australian Placental Transfusion Study (APTS) and the Cord Pilot Trial have been performed (9,10). In the APTS study, which randomized 1566 infants <30 weeks to 60 sec or more of DCC or immediate cord clamping (ICC) of ≤10sec, the primary outcome was death or major morbidity (severe brain injury, necrotizing enterocolitis (NEC), severe retinopathy or late onset sepsis) at 36 weeks. There were no significant differences in mortality or other major morbidities. A systematic review, however, noted reduced hospital mortality in infants <37 weeks undergoing DCC of 30 sec or more compared to ICC (3). There were 2834 preterm infants in 18 randomized trials; DCC took place ≥45 sec and up to 60 sec for the majority of infants. Hospital mortality was reduced in the group undergoing DCC (RR 0.69, 95% CI 0.52 to 0.91) compared to clamping before 30 secs. There was no heterogeneity (I2 = 0) and the GRADE quality of evidence was high. In the subgroup of infants ≤28 weeks gestation, DCC reduced hospital mortality (RR 0.70, 95% CI 0.51 to 0.95). Apart from reduced receipt of blood transfusion, other neonatal outcomes were not improved. An increase in cases of polycythaemia and a small increase in serum bilirubin levels were noted but no unwanted clinical effects were apparent. There is currently little information on neurodevelopment.
DCC in preterm infants: the current standard
As a result of the above studies, DCC is the current method of choice in preterm infants. The strength of evidence means that future studies comparing DCC with ICC are unnecessary. What can be expected from getting this research into practice?
How often do preterm infants receive the intervention in practice?
This can be divided into experience from randomized trials or observational studies.
Randomized trials where DCC was an intended intervention
In the APTS, of 784 infants <30 weeks randomized to DCC, the planned intervention of 60 sec DCC was not achieved in all infants and 163 (21%) had up to 30 sec DCC (9). This does not include those that were excluded because of maternal reasons (unspecified).
In the Cord Pilot Trial, exclusions for maternal reasons (prior to randomisation) were not detailed, but of 945 women approached 41 (4.3%) either were not eligible or were excluded for clinical reasons (10). Altogether, 276 preterm infants <32 weeks were randomized with 135 allocated to receive >120 sec DCC with immediate neonatal care to be given with the cord intact. Of the 135, 31 (23%) did not receive longer than 30 sec DCC (12.6 % were clamped before 10 secs). Of those where DCC was curtailed, 13/135 (10%) were either born with intact membranes and the placenta or there was an abruption.
There were 2 other multicentre randomized trials with over 150 infants. In one study, eligible infants <32 weeks were randomized to DCC for 60 sec or respiratory support in the form of CPAP or positive pressure T piece ventilation for 60 sec prior to clamping (V-DCC). Twenty four percent (24%) were excluded prior to randomisation for placental or maternal reasons, although all randomized infants received the intervention (11). In the other study, DCC for 60 secs was compared with cord milking. Prior to randomization 15% were excluded and a further 17% did not receive the planned 60 sec DCC. By comparison, in only 2% of cases was milking not achieved (12).
Observational and implementation studies where DCC was an intended intervention
Liu et al 2017 compared a 2 year period before and after implementation of a protocol for 30 sec DCC in infants 23 to 32 weeks gestation (13). Compliance improved over time. Exclusion criteria included multiple birth, general anaesthesia and major fetal anomalies (numbers not supplied). The procedure could be terminated at any time at the discretion of attending clinicians. In 100 of 187 (53%) eligible infants, 30 sec DCC was achieved.
Aziz et al 2012 implemented a policy of 45 sec DCC in preterm infants 23 to 33 weeks gestation (14). There were 480 eligible because of gestation. Following exclusion of 131/480 (27%) for obstetric reasons, only 349 were deemed eligible for DCC. However, clinicians attempted DCC in 236 infants and in 12 cases (5%), the procedure was abandoned prior to 45sec. Therefore of the initial 480 infants, only 224 (46.6%) achieved 45 sec DCC.
In the study by Chiruvolu et al 2015, of 96 infants <32 weeks, 36 (34%) were deemed ineligible, mainly for maternal indications (15).
In summary, in the above studies, percentages of infants deemed ineligible for maternal reasons varied from 4 to 34% with a mean of 19% (Table). In addition, while the percentages of eligible infants that actually achieved DCC were variable, in the largest randomized trials, over 20% did not achieve more than 30 sec DCC. Currently we estimate that 19% (exclusion for maternal reasons) plus 20% where DCC was <30secs or 39% of infants <32 weeks did not get more than 30 sec DCC. However, in several studies compliance increased over time (13, 14, 16).
Is it possible to predict in which preterm infants DCC will be curtailed?
Most preterm infants quickly establish respiration (11, 14), but there is a group that do not. In the APTS, early cessation of DCC was more likely in infants <27 weeks, with lower birth weight and in multiple pregnancy (9). Observational studies have confirmed that failure to establish respiration during DCC was linked to worse outcomes (17,18). As a result of this and in keeping with findings in animal studies (19), investigators have been studying initial resuscitation with an intact cord (10,11).
Provision of respiratory support before cord clamping in preterm infants
This has been the subject of a recent Cochrane review (20) and there was one randomized trial in infants <32 weeks comparing 60 sec DCC with DCC with CPAP or positive pressure ventilation (11). Outcomes were not significantly different. In this study, 90% of the infants were breathing prior to cord clamping and this has been confirmed in several observational studies as noted previously. In the Cord Pilot Trial, ICC was compared with DCC in infants <32 weeks (10). It was planned to undertake initial resuscitation (including intubation and surfactant administration if needed) whilst DCC was taking place. The procedure was found to be feasible and safe.
The concept of physiologic based cord clamping relates to clamping the cord only after respiration is established, rather than waiting for a specific time. Although not a new concept, there has been a resurgence of interest following animal experiments and as noted in the Cochrane review above there are a number of clinical studies in progress.
Cord milking as an alternative to DCC in preterm infants
Umbilical cord milking (UCM) refers to holding the umbilical cord close to the placenta and squeezing the blood towards the infant while the cord remains attached to the placenta. The cord is milked 3 to 4 times, allowing it to refill for 2-5sec in between. Meta -analysis of milking compared to DCC indicated there may be some advantages (21). In two randomized controlled trials, 255 infants preterm infants <33 weeks were studied. The cord was milked as described and DCC was 45 sec in 1 study and 30 sec in the other. In the milking group there was a reduction in intraventricular haemorrhage (IVH) of any grade (RR 0.45 0.21-0.98) and a significantly higher proportion of infants had a Bayley III score of 85 or more for cognition and language at 2 yrs. The quality of evidence was regarded as low because of small numbers and wide confidence intervals. Of potentially eligible pregnancies, 15% were excluded for maternal reasons. More infants underwent cord milking and only 2/98 did not receive the intervention compared to 17/99 in the DCC group (p<0.001).
Cord milking after clamping in preterm infants
The umbilical cord can be milked after clamping by leaving a longer segment (20cm or more), unravelling the cord and then milking 2-3 times towards the infant (22). In a novel study, infants <30 weeks had milking of the cut umbilical cord performed if they were not spontaneously breathing and were deemed in need of resuscitation (23). Maternal complications were not an exclusion criterion. There were 158 infants eligible for cord milking and 160 controls. The composite outcome (death, severe IVH, NEC) was significantly higher in the controls (39% vs 22%; OR1.81 95% CI 1.06–3.10). For infants < 27 weeks the composite outcome was significantly worse in the control group (p<0.05). No adverse events were reported and there was no difference in neonatal resuscitation or Apgar scores.
A recent study examined the effects of milking the cut cord in preterm infants in need of resuscitation (infants who did not breathe or cry at birth), and found no adverse effects and significantly higher haemoglobin and serum ferritin levels in the milked group at 6 weeks postnatal age (24).
Current state in preterm infants
Even though a significant percentage of infants did not receive more than 30 sec DCC in the 2 largest randomized trials, meta-analysis based on intention to treat, demonstrated reduced mortality. This suggests that the DCC effect size on mortality is quite large but it remains to be seen what should be done for the high percentage of infants where DCC is not carried out. Providing respiratory support prior to clamping may reduce this number but is probably not presently an option outside of research studies. Limited data indicates UCM is more likely to be achieved than DCC. However, before UCM could be the method of choice, larger trials will be needed to determine that UCM is not inferior to DCC. Where infants are not vigorous by 20 -30 secs of DCC it seems reasonable to carry out cord milking. For situations where infants are deemed ineligible for DCC or milking for maternal reasons, there is limited evidence that milking the cut cord may still be preferable to ICC with no milking.
It is apparent that one size does not fit all with regard to placental transfusion, and most, if not all, the different techniques may be needed for individual preterm infants to derive benefit.
Keywords: preterm, delayed cord clamping (DCC), Transition, Resuscitation, umbilical cord milking
Received: 12 Oct 2018;
Accepted: 04 Feb 2019.
Edited by:Stuart B. Hooper, Monash University, Australia
Reviewed by:Anup C. Katheria, Sharp Mary Birch Hospital for Women & Newborns, United States
Copyright: © 2019 Meyer and Nevill. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Prof. Michael P. Meyer, Middlemore Hospital, Auckland, New Zealand, firstname.lastname@example.org