Physiological-Based Cord Clamping: When the Baby Is Ready for Clamping

Debate about the consequences of umbilical cord clamping at birth and its optimal timing has been ongoing throughout history. Over the centuries, both well-known and lesser-known historical figures have indicated that immediate cord clamping after birth might not be in the best interest of the newborn [1]. While waiting to clamp the cord has been, and still is, commonly practiced by some midwives and obstetricians, it is not entirely clear when or why early cord clamping became the standard of care worldwide. Early cord clamping was incorporated into clinical guidelines as part of active management of the third stage of labor to reduce the risk of maternal blood loss after birth [2]. However, this occurred despite a significant reduction in infant birth weight after immediate clamping and a meta-analysis showing no difference in maternal blood loss between early and late cord clamping [3]. But even before guidance around active management of the third stage of labor, early cord clamping became the standard of care in the early 20th century which also coincided with an increase in hospital births [2].

It took some time before the policy of immediate cord clamping was corrected. Studies in the 1960s found that delaying cord clamping resulted in higher blood volumes in newborns, suggesting that blood is transferred from the placenta into the infant (placental transfusion) [4, 5], which was confirmed by meta-analyses showing an increase in birth weight. Other meta-analyses over the last 2 decades have shown that delaying cord clamping (by at least 30 s) compared to immediate cord clamping (0–30 s) provides significant health benefits for (near) term newborns [6, 7]. These include higher birth weight and hematocrit and lower incidence of anemia and iron deficiency. For preterm infants, there was a greater chance of survival, higher hematocrit with fewer blood transfusions, and a trend toward fewer brain hemorrhages [7]. This led to the recommendation in international guidelines to wait at least 60 s before clamping the cord in newborns who do not require assistance with breathing, whereas if stabilization or resuscitation is necessary, immediate cord clamping is recommended [8]. In addition, the latest meta-analysis comparing different clamping strategies demonstrated the effect on increased survival was greatest when clamping was delayed by 2 min or longer [9].

The benefits of delayed cord clamping have mainly been attributed to the concept of placental transfusion. Although there are many beliefs about the mechanism of placental transfusion, the scientific explanation is still lacking. Gravity and uterine contractions do not appear to be the driving forces behind the transfusion [10‒12], although pressure changes during spontaneous inhalations could play a role [13]. This is thought to result from a reduction in intrathoracic pressure associated with inspiration, which has been shown to accelerate the movement of blood into the infant. If this is the primary mechanism, it indicates that spontaneous breathing is needed to drive placental transfusion and so ideally one should wait until breathing has commenced before clamping the cord.

Recent animal experiments have demonstrated that the large respiratory and circulatory changes that need to occur during transition at birth, are intricately linked [14, 15]. This understanding provided the physiological rationale for why there is a hemodynamic benefit to wait with cord clamping until the lungs have been aerated [16, 17]. This is referred to as physiological-based cord clamping (PBCC). Several experimentalists and clinicians have been involved in a research program investigating the biology underpinning PBCC and translating the findings into clinical settings. This program of research had its origins in trying to understand the clinical dilemma as to why a high proportion of normal, healthy, well-oxygenated infants would have a low heart rate at birth. This prompted experimental studies to describe the underlying mechanism and was followed by a randomized trial evaluating efficacy in preterm infants. Together, this program has taken us more than a decade to complete. In this review, we will discuss the insights gained and lessons learned from the project’s implementation.

It is well established that during fetal life the placenta is a well-perfused organ with a low vascular resistance so that it can provide the fetus with all of its oxygen and nutrient requirements during pregnancy [18]. Indeed, the placenta receives a large proportion (30–50%) of fetal cardiac output and, therefore, supplies 30–50% of venous return to the heart, with most of this blood passing through the foramen ovale directly into the left side of the heart [19]. As such, clamping the umbilical cord causes a sudden loss in cardiac output (due to a loss in venous return) and an increase in systemic vascular resistance, unless another mechanism can be activated to compensate for this [19]. The loss in venous return and cardiac output associated with immediate cord clamping was used to explain why healthy infants can have a low heart rate at birth. It also led to the hypothesis that this loss in cardiac output and increase in systemic vascular resistance can be avoided by simply aerating the lung prior to cord clamping. As lung aeration is the main trigger for the decrease in pulmonary vascular resistance and increase in pulmonary blood flow after birth [14], the large increase in pulmonary venous return associated with lung aeration could compensate for the loss in placental venous return caused by cord clamping. This hypothesis was then investigated in a series of experimental studies.

The physiological effect of cord clamping before versus after lung aeration on cardiovascular function in preterm lambs has now been examined in detail. Cord clamping before lung aeration leads to a decrease in heart rate and right ventricular output which, as predicted, is due to a sudden loss of placental venous return. It was also noted that the sudden increase in systemic vascular resistance rapidly increased arterial carotid blood flow (within 4 heartbeats) and blood pressure, followed by a decrease caused by a reduction in left ventricular output due to the loss in venous return [16]. This loss of cardiac output was restored after ventilation established lung aeration and stimulated a large increase in pulmonary blood flow that restored venous return and left ventricular output; henceforth, pulmonary venous return becomes the sole source of venous return for the left ventricle. This hemodynamic instability was prevented by aerating the lung prior to cord clamping, which led to a more gentle (stable) circulatory transition [16]. Subsequent experiments in lambs have also demonstrated that cord clamping after lung aeration also results in higher systemic and cerebral oxygenation, despite requiring less supplemental oxygen to reach the target range [17].

Based on these experiments, it became very clear that from a physiological point of view, it would be better to wait with cord clamping until after the lungs have aerated. As most healthy newborns who transition independently will aerate their lungs and begin air-breathing almost immediately after birth, this will be of minor consequence. However, hypoxic full-term newborns and premature newborns, for different reasons, usually need assistance to transition at birth and, therefore, require respiratory support to achieve lung aeration. As preterm infants have a very immature cerebral vascular bed, they are particularly susceptible to these large swings in blood flows and pressures. Thus, PBCC could have a large impact on their outcome.

To translate the experimental findings in preterm lambs to preterm infants we first needed to define when infants were stabilized and lung aeration had been established. Based on studies where we used video recordings and physiological parameters, we defined that this would be when heart rate was above 100 bpm, their oxygen saturation had reached 85% with a supplemental oxygen requirement of less than 40% and the infants were breathing [20, 21]. This was then chosen to be the moment of cord clamping. To make sure that placental transfusion was complete we set a minimum of 3 min. A maximum time was set at 10 min in order to provide the infant its greatest opportunity to aerate its lungs.

In order to integrate cord clamping into the process we used to stabilize infants we had to make sure that preterm infants could be stabilized close to the mother safely and effectively without compromising standard care. Indeed, as providing respiratory support is a subtle balancing act performed within narrow safety margins, we did not want to stabilize with the cord attached to benefit from PBCC at the cost of the quality of the support provided [21]. We also did not want to rush and knew we had time to stabilize the infants on the cord and monitor their vitals. We wanted to ensure that this approach could be performed in most preterm infants and that the length of the umbilical cord would not be an issue, particularly in regard to stretching or kinking the cord. In addition, as neonatologists were now required to work within the operational space of the obstetrician, we acknowledged that we had to stabilize infants without interfering with the obstetrician. As available resuscitation tables did not meet these preconditions, we decided, in collaboration with technical engineers from Leiden University Medical Center (LUMC, Leiden, the Netherlands), to develop a resuscitation table that met all of our requirements: the concord table (“with cord”) [21].

Using the prototype of the Concord table, we performed a pilot study testing the feasibility and safety of resuscitating infants on the cord (ABC-1 study) [22]. In this single-center study, we began with more mature preterm infants and only started using this approach in more preterm infants when the feasibility and safety were evaluated and approved. We observed that it was feasible in most infants (90%), which was higher than in previous studies where infants were stabilized on the cord. This was the first study where a variable and long cord clamping time was noted (4:23 [3:00–5:11] minutes:seconds). It also appeared that stabilizing infants on the table and performing PBCC was safe: there were no maternal or neonatal adverse events. However, we did observe hypothermia, the average admission temperature was 36.0 (0.7) Celsius. Although this needs improvement, hypothermia also occurred in preterm infants delivered at the LUMC in Leiden when using the standard resuscitation table [23].

We found that less bradycardia occurred and that there was no decrease in oxygen saturation in the first minutes after birth. We also noted that when the cord was clamped, the heart rate remained stable, which indicated that we could maintain the clinical definition of PBCC. These findings in heart rate and oxygen saturation in this first clinical study were comparable to the experimental findings and encouraged us to design the first randomized study (ABC-2).

Before embarking on a large RCT evaluating the efficacy of PBCC, we wanted to make sure that stabilization using the Concord was as effective as standard stabilization [24, 25]. For this, we performed a non-inferior RCT (ABC-2 study) in two Dutch academic centers (LUMC, Leiden and Erasmus MC, Rotterdam) where we randomized infants <32 weeks’ gestation to stabilization on the cord (PBCC) using the Concord or DCC of 30–60 s followed by stabilization on the standard resuscitation table.

We established the non-inferiority of the approach, and we even observed that infants undergoing PBCC achieved stability significantly faster compared to those managed with the standard approach. However, this outcome may have been influenced by the earlier initiation of stabilization in the PBCC group. Additionally, the duration of waiting with cord clamping also in this trial exceeded that reported in previous DCC studies. There were no safety issues, no difference in maternal blood loss and the temperature management was improved and was similar to standard care (36.5 ± 0.8 vs. 36.7 ± 0.6 Celsius). Based on these findings, we decided to design a protocol for a large multicenter trial to evaluate the efficacy of PBCC in very preterm infants.

To test the effect of PBCC on clinical outcome, we designed a nationwide multicenter randomized clinical trial in which all nine Dutch NICU centers participated (trial protocol available in Trials 2022 [26]). In this trial, we compared PBCC with DCC (30–60 s), as DCC was at that time nationally recommended as standard care. Parents were antenatally approached for consent. Using antenatal consent in delivery room trials increases the chance to introduce a selection bias, but retrospective consent was not allowed since the investigated intervention was new. In addition, parents needed to be informed before entering the labor room with a resuscitation table.

Based on the experimental data and the findings in the first two clinical studies there was a clear scientific rationale for PBCC. Avoiding the large swings in blood flows and pressures during the transition, in combination with allowing time for completing the placental transfusion, has the potential to have an impact on important clinical outcomes. We hypothesized that this is observed especially in the incidence of cerebral injury and necrotizing enterocolitis. As this should not come at the cost of survival, for the primary outcome we opted for combining the effect with intact survival, which included mortality and/or cerebral injury (severe intraventricular hemorrhage (IVH grade 2 or more, cystic periventricular leukomalacia) and/or necrotizing enterocolitis (NEC grade 2 or more). Other outcomes (subgroup analysis, hematological parameters, safety, morbidities) were secondary, based on findings in previous trials and prespecified in the protocol and the statistical analysis plan (SAP also available in Trials 2024 [27]).

To avoid complications associated with the use of different resuscitation tables, we decided to restrict use to the Concord table. Thus, all caregivers (except in Leiden and Rotterdam) first had to be trained in the use of the Concord table. Only two centers, Leiden and Rotterdam, had previous experience of PBCC whereas the other 8 centers had no previous experience. As such, these centers required implementation and training before they could start recruiting into ABC-3, which delayed their contribution. The trial was started in Leiden and Rotterdam, where a large proportion of infants were recruited for the study (45%). Other centers started later at different time points during the trial, with some centers only including infants several months before the end of the trial. For this reason, Leiden and Rotterdam were responsible for almost half of the infants recruited. As we anticipated this, we were interested in the learning curve and whether the outcome improved with experience. This was then also defined in the analysis plan [27].

Based on the limited data on PBCC, a sample size of 660 infants was calculated to demonstrate an increase of 10% in intact survival. Funding, logistical, and time constraints prevented us from pursuing a larger sample size. Meta-analysis, combining our data with other similar trials could help us in terms of numbers, although in other trials the moment of cord clamping is still based on a fixed time point rather than being defined by physiological parameters. The trial started in 2019 and although it was temporarily halted during COVID, it took 4 years to reach full recruitment. The results of the trial will be published shortly.

We recently reported a study reporting parents’ opinions of reviewing recordings of resuscitation preterm infants at birth [28]. During the interviews, parents indicated they missed the first contact with the baby, and they appreciated seeing the recording of their infant, although for some it was a very emotional experience. Indeed, parents involved in designing the study protocol expressed that the experience of the parents should be included as an outcome. To measure the experience of parents, a questionnaire using a Likert scale was prepared. While we approached parents to participate in the ABC-3 trial, they frequently indicated that they preferred to have their baby stabilized on the Concord table and were disappointed when randomization allocated their baby to the standard approach.

Parents want their baby close to them right after birth. While a skin-to-skin approach would be the most preferable approach, stabilizing very preterm infants on the mother can be challenging. Over the last decade, studies have demonstrated that applying effective ventilation in preterm infants is precision work. Studies are planned where the Concord table is an in-between station, and after stabilization, the infants can be placed on the chest of the mother.

More than a decade of research into PBCC, during which we obtained good scientific rationale from experimental studies and translated this into the clinical setting, has yielded much knowledge and many new insights. We learned that the respiratory and circulatory changes during transition at birth are intricately linked. Lung aeration should precede cord clamping, as would normally occur in most healthy term infants. The timing of cord clamping is then not determined by a fixed time after birth, but by the physiological changes that must have occurred, which can vary in duration for each newborn. We learned from the feasibility (ABC-1) and effectiveness study (ABC-2) that using a purpose-built resuscitation table, it was possible to perform PBCC in preterm infants in a safe and effective manner without compromising the care infants needed and having to rush. The results of the efficacy study will be published soon and whether PBCC is the preferred approach is then open for academic debate. We should then also take into account what parents prefer.

The authors have no conflicts of interest to declare.

No funding was received for writing this review.

A.B.tP., R.K., E.L., T.H.vdA., and S.B.H. have contributed significantly to the development and writing of this manuscript.