Delayed cord clamping in the very preterm

I haven’t written about this issue in a while, the APTS trial, and the systematic review which was published at about the same time appeared to show definitively that there was a reduction in mortality with delayed clamping compared to immediate clamping in very preterm infants. The mechanism is still uncertain; individual common causes of mortality are not clearly affected by delayed clamping, NEC, late-onset sepsis, severe intracranial bleeding, lung injury (as defined by O2 need at 36 weeks) are not different in most of the trials and are not affected in the meta-analyses, including the Cochrane review, so how delayed clamping decreases mortality remains a question.

Delayed cord clamping should be standard of care for very preterm, moderately preterm, late preterm and full-term infants. In other words, for everyone. In full-term infants, there is no impact on mortality, of course, but iron status and developmental outcomes are improved.

The majority of the evidence with regard to preterms is from studies with delayed cord clamping in which the umbilical cord was clamped early if the infant was considered to need immediate intervention. The alternative, more physiological approach, clamping delayed until after breathing is established, has a lot to recommend it, from a physiological and animal research base, but in terms of a clinical evidence-base, the extra equipment and training required to be able to give positive pressure ventilation while the baby is still attached to the placenta, has not yet been clearly shown preferable. In fact, I think one of the benefits of delayed cord clamping is that it keeps people like me away from the baby, I have to stand far from the baby wielding my laryngoscope in my right hand and the face mask and T-piece resuscitator in the other, while the baby makes some spontaneous efforts, the obstetrician suctions the airway, the baby wriggles around and no one tries to take the heart rate or place a pulse oximeter. To be less facetious, I think negative intrathoracic pressure from spontaneous respirations has much to recommend it over positive pressure from an external source. Although data from lambs suggests that inspiratory efforts may actually decrease umbilical venous blood flow.

One outcome which was not included in the currently available SRs (including the Cochrane review) is the long term results of neurological and developmental outcomes. I am not suggesting that the studies should have examined “death or disability”! If mortality is decreased, then it would have to be an at least equivalent increase in very profound disability to be able to counter-balance the improved survival, to my mind, and therefore to have an impact on the decision to institute universal delayed clamping.

That would be a truly surprising result if it occurred, and unique in the history of neonatology, almost all of our patients have a quality of life which is somewhere between acceptable and excellent. An intervention which increased survival, but only of patients whose quality of life was worse than being dead, has never happened.

The longer-term outcomes of the CORD PILOT trial were published this year. (Armstrong-Buisseret L, et al. Randomised trial of cord clamping at very preterm birth: outcomes at 2 years. Arch Dis Child Fetal Neonatal Ed. 2020;105(3):292-8). This is the follow up of a delayed clamping trial where the initial stabilisation procedures were supposed to take place with the cord intact. (Duley L, et al. Randomised trial of cord clamping and initial stabilisation at very preterm birth. Arch Dis Child Fetal Neonatal Ed. 2018;103(1):F6-F14).
The intention was that the intervention group babies would be placed on a flat surface right next to the mother, and initial steps of the NRP performed before clamping the cord, which was planned to be after at least 2 minutes. Babies were eligible if they delivered before 32 weeks; only a few were the most immature <26 weeks (n=35). Some of them were intubated while still attached to the cord, and one even had an umbilical catheter inserted before cord clamping.

The planned clamping delay actually happened in almost 60% of the babies randomized to that group. The remaining 40% were clamped earlier, about half of them because the cord was too short, and in 12 cases because of a “clinical decision”; the remaining who had immediate clamping in the delayed group were for largely unavoidable reasons, such as the baby being born with the placenta, or with a large abruption, or a rupture of the cord. There were about 260 babies overall, half with planned delayed clamping and half with clamping within 20 seconds. Those in the delayed clamping group who actually had their clamping delayed were mostly clamped soon after 2 minutes, and almost all by 3 minutes, with a small number of later outliers.

The initial publication of this trial showed that delayed clamping led to fewer blood transfusions and somewhat lower rates of late-onset sepsis and lung injury. Mortality was lower in the delayed clamping group, 7 deaths vs 15, with wide confidence intervals, of course (and mortality among the babies of 28 weeks and more in the immediate clamping group seeming to me to be on the high side, perhaps skewing the results).

The longer-term outcomes among the approximately 80% of babies with data at 2 years of age (either the Ages and Stages questionnaire or a Bayley assessment) were very similar. Some small differences were generally in favour of the delayed clamping group. It isn’t clear from this follow-up publication how many of the infants actually had delayed clamping. Although intention-to-treat analyses are, appropriately, the standard for evaluating the impact of an intervention in the real world, pilot studies often also have a “per-protocol” analysis to try and determine the impact of the intervention itself, isolated from other issues which may impede the performance of the intervention. It would be nice to know how many of the delayed clamping follow-up group actually had delayed clamping, and whether that was associated with better scores.

When you put together the small, possibly random, difference in mortality, with the small, possibly random, differences in some developmental scores, you end up with a very unhelpful conclusion “Deferred clamping and immediate neonatal care with cord intact may reduce the risk of death or adverse neurodevelopmental outcome at 2 years of age for children born very premature.” Here is the table with the details of the primary outcome:

I really don’t think that that sentence is of much use to anyone, even if it is strictly scientifically accurate. What would be better? “Deferred clamping and immediate neonatal care with cord intact showed a potential advantage in terms of survival, and not much difference in terms of developmental outcomes” that sentence is also scientifically accurate, and, I would suggest more honest and useful.

About Keith Barrington

I am a neonatologist and clinical researcher at Sainte Justine University Health Center in Montréal
This entry was posted in Neonatal Research and tagged , , . Bookmark the permalink.

1 Response to Delayed cord clamping in the very preterm

  1. drnrk says:

    I also want to do a neonatal delayed cord clamping

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