Seminars in Fetal & Neonatal Medicine xxx (2015) 1e7

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Seminars in Fetal & Neonatal Medicine

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Review

Using physiology to guide time to cord clamping

Martin Kluckow a, *, Stuart B. Hooper b
a
University of Sydney and Royal North Shore Hospital, Sydney, Australia
b
The Ritchie Centre, MIMR-PHI Institute for Medical Research, Monash University, Melbourne, Australia

s u m m a r y
Keywords: Immediate clamping and cutting of the umbilical cord at birth has been the accepted standard of care for
Hemodynamics decades. The physiologic rationale relating umbilical cord clamping (UCC) to the events of the circulatory
Umbilical cord clamping
transition is not considered in arbitrarily recommended cord clamping times. Systematic review of early
Superior vena cava flow
Circulatory transition
versus deferred UCC shows significant hemodynamic benefits to the deferred group. Mechanisms for this
protective effect are considered in this review. The original concept of a placental transfusion with a
volume load and prevention of low cardiac output relies on the physiological end point of the amount of
blood transfused. The newer concept of an ordered physiological transition is increasingly supported.
This model places aeration of the lungs and an increase in pulmonary blood flow back at the centre of the
circulatory transition with timing of UCC being related to establishment of respiration. The need for
“physiologically based” UCC is discussed.
Crown Copyright © 2015 Published by Elsevier Ltd. All rights reserved.

1. Introduction of supply. Thus, cardiac output remains normal and stable

Clamping and cutting of the umbilical cord at birth is much
more than a symbolic separation of the infant from its mother [1].
While it is recognized that the transition to newborn life involves a
sequence of physiological events, recent studies have now shown
that the timing of umbilical cord clamping (UCC) within this
sequence can have a major impact on the infant's wellbeing [2]. In
animal studies, UCC before ventilation onset results in a profound
(~50%) reduction in venous return, ventricular preload and cardiac
output [1,3]. Cardiac output is restored only after ventilation onset
due to the resulting increase in pulmonary blood flow (PBF), which
restores venous return and ventricular preload. Consequently, if
there is a significant delay between UCC and ventilation onset, the
newborn is exposed to a prolonged period of low cardiac output,
placing the infant at risk of a hypoxic/ischemic insult. As this period
of low cardiac output is immediately followed by a rapid increase in
output, due to the increase in PBF [1], the risk of an intraventricular
haemorrhage (IVH) caused by large swings in blood pressure and
flow is also increased [2]. However, if ventilation onset precedes
UCC, the increased PBF can immediately replace umbilical venous
return as the primary source of ventricular preload without any loss
throughout the transition sequence, thereby avoiding a reduction
in output and large fluctuations in pressure and flow [1].
The concept of the need for “delayed cord clamping” has been an
ongoing debate for centuries, but until recently has primarily
focused on the potential for fetal-to-placental blood transfusion if
delayed for 1e3 min [4,5]. This presumes that net placental-to-fetal
blood transfusion is simply time dependent [6], but there are
several other potential benefits apart from placental transfusion.
These include: prevention of low cardiac output syndrome, keeping
the transition in sequence and avoiding an overly vigorous resus-
citation (suction, mask application, attempted intubation) in an
infant who may transition and commence spontaneous breathing,
given sufficient time. In view of recent findings, we believe that it is
time to review our understanding of the transitional physiology at
birth and how the timing of UCC could influence this. This review
discusses the sequence of physiological events that underpin the
transition to newborn life, the impact of UCC and effects on the
postnatal cardiovascular system and how this knowledge can be
translated into improving outcomes for newborn infants.
2. Physiological transition to newborn life

The primary event that underpins the transition to newborn life

* Corresponding author. Address: Royal North Shore Hospital, Reserve Road, St
is lung aeration, which is commonly linked with the switch from
Leonards, NSW 2065, Australia. Tel.: þ61 2 94632180. placental to pulmonary gas exchange. However, lung aeration also
E-mail address: martin.kluckow@sydney.edu.au (M. Kluckow). initiates the circulatory changes at birth, by stimulating an increase

http://dx.doi.org/10.1016/j.siny.2015.03.002
1744-165X/Crown Copyright © 2015 Published by Elsevier Ltd. All rights reserved.

Please cite this article in press as: Kluckow M, Hooper SB, Using physiology to guide time to cord clamping, Seminars in Fetal & Neonatal
Medicine (2015), http://dx.doi.org/10.1016/j.siny.2015.03.002
2 M. Kluckow, S.B. Hooper / Seminars in Fetal & Neonatal Medicine xxx (2015) 1e7
in PBF. As such, lung aeration should be viewed as the central
precipitating event that initiates a sequence of interdependent
changes in physiological function that characterize the transition to
newborn life.
Before birth, the fetal cardiovascular system is different from the
adult circulation [7,8] mainly due to the presence of large vascular
shunts, a high pulmonary vascular resistance (PVR) and a low-
resistance placental circulation that is connected in parallel across
the lower body. In the fetus, the majority of right ventricular output
bypasses the lungs and flows from the main pulmonary artery into
the descending aorta via the ductus arteriosus (DA). This is due to
the high PVR, which in combination with a low placental vascular
resistance results in a low PBF during fetal life [7,8]. Thus, pulmo-
nary venous return is also low and therefore left ventricular preload
depends primarily on umbilical venous return. This passes from the
placenta, via the ductus venosus (DV), inferior vena cava and fo-
ramen ovale to directly enter the left atrium, therefore bypassing
the right side of the heart and the lungs [7]. Thus, umbilical venous
blood is the major source of preload for the left ventricle, with little
derived from PBF. PVR decreases with increasing gestational age
due to growth and development of the pulmonary vascular bed, but
the small increases in PBF seen with these changes are insignificant
compared to the much larger increases in PBF seen at birth.
Before birth, the liquid filling the future airways maintains the
lungs in a distended state, which is vital for fetal lung growth and
development [9]. However, at birth this liquid acts as an obstacle
that restricts the entry of air and the onset of pulmonary gas ex-
change. As such, the airways must be cleared of liquid to allow air to
enter the distal airways so that gas exchange can commence.
Although a number of mechanisms likely contribute to airway
liquid clearance [10,11], recent imaging studies in newborn rabbits
demonstrate that airway liquid is predominantly cleared by trans-
epithelial pressure gradients generated during inspiration [12e14].
Thus, inspiration drives liquid movement from the airways into
peri-alveolar tissue, where it is cleared by the lymphatics and blood
vessels [15].
Lung aeration at birth also triggers a large decrease in PVR and
an increase in PBF [3], which along with UCC, drives the transition
of the fetal circulation into the adult phenotype. As increases and
decreases in fetal oxygenation can increase and decrease PBF,
respectively [16], it is widely assumed that the increase in PBF at
birth is mediated by an increase in oxygenation [8]. However,
previous experimental studies have questioned whether increased
oxygenation has an over-arching dominant role or is a contributor
that provides the fine control for ventilation/perfusion matching
after birth [17]. Indeed, ventilation of lambs can increase PBF in the
absence of an increase in oxygenation [18] and when arterial
oxygenation levels both increase and decrease compared to the
fetal state [19]. More recently, an imaging study in newborn rabbits
has shown that unilateral aeration of the lung causes a global in-
crease in PBF [17], resulting in a large ventilation perfusion
mismatch in unventilated lung regions. Despite this mismatch, the
lack of a spatial relationship between lung aeration and the in-
crease in PBF at birth has some adaptive advantages (see below).
3. Cardiovascular consequences of UCC and lung aeration at
birth
As the placental circulation is normally a low-resistance, highly
compliant vascular bed that receives a large proportion (30e50%)
of total cardiac output [20], UCC causes an immediate (stepwise)
increase in systemic peripheral resistance. This results in a rapid
(within four heart beats or ~1 s) increase (~30%) in arterial pressure
[1] that drives a similar rapid increase in cerebral blood flow [1].
Thus, within this time frame, the cerebral circulation is pressure
Please cite this article in press as: Kluckow M, Hooper SB, Using physiology to guide time to cord clamping, Seminars in Fetal & Neonatal
Medicine (2015), http://dx.doi.org/10.1016/j.siny.2015.03.002
passive and vulnerable to large changes in flow in response to rapid
fluctuations in pressure. As UCC also reduces cardiac output (see
below) this elevation in systemic arterial pressure and cerebral
blood flow is transient and followed by a rapid reduction and then a
rapid increase again after ventilation onset [1].
UCC causes a profound reduction in venous return and ven-
tricular preload because the umbilical circulation receives a large
proportion of combined ventricular output in the fetus [20].
Consequently, both right and left ventricular output decreases (by
as much 50% in lambs [1,3] and remains low until the lung aerates
and PBF increases. This is because the increase in PBF restores
venous return and preload to the left ventricle and possibly the
right ventricle via left-to-right flow through the FO. This increase in
PBF results from both a redirection of right ventricular output to
entirely pass through the lungs and a reversal in net flow through
the DA [3] because downstream resistance in the pulmonary cir-
culation decreases below that in the lower body. As a result, blood
preferentially flows left to right through the DA, from the aorta and
into the pulmonary circulation. While net flow is left to right,
instantaneous flow is largely bidirectional, because the pressure
waves emanating from the left and right ventricles reach either end
of the DA at different times after ventricular contraction [3,21,22].
That is, the pressure wave leaving the right ventricle reaches the
pulmonary arteryeDA junction before the pressure wave from the
left ventricle reaches the DAeaorta junction. This creates a pul-
monary artery-to-aorta pressure gradient that facilitates right-to-
left flow early in systole, which is reversed when the pressure
wave from the left ventricle reaches the DAeaorta junction, causing
left-to-right flow during late systole and throughout diastole
[3,21,22].
As UCC at birth causes a large reduction in cardiac output [1,3], if
there is a significant delay between UCC and lung aeration after
birth, the infant will not only be exposed to a hypoxic episode, but
also to a protracted period of low cardiac output. The primary
physiological mechanism that protects vital organs such as the
brain from hypoxia involves an increase and redistribution in car-
diac output, which results in a large increase in cerebral blood flow
[20,23,24]. Consequently, during the period between UCC and
ventilation onset, when cardiac output is compromised, the infant
is at significant risk of hypoxic/ischemic brain injury. On the other
hand, even normoxic infants will be exposed to large swings in
arterial pressure and cerebral blood flow if UCC significantly pre-
cedes ventilation onset and the increase in PBF. This is because UCC
causes a rapid increase in arterial pressure and cerebral blood flow,
which is followed by a reduction in pressure and flow due to a
reduction in preload and cardiac output, which in turn is followed
by a rapid increase in cardiac output when PBF increases and re-
stores ventricular preload [1]. These large swings in cardiac output
and arterial pressure increase the risk of perinatal brain injury [2],
but can be avoided if UCC occurs after the lungs have aerated and
ventilation has commenced.
4. Lung aeration before UCC: a physiological approach to cord
clamping
As venous return and left ventricular preload must switch from
umbilical to pulmonary venous return after birth, it seems logical to
initiate pulmonary ventilation and increase PBF before UCC. We
have termed this “physiologically based cord clamping”. If the
umbilical circulation remains intact while the lung aerates and PBF
increases, then the reduction in venous return and cardiac output
associated with UCC is minimized. This is because venous return
and the supply of ventricular preload can immediately switch from
umbilical to pulmonary venous return without any diminution to
supply [1]. As a result, there is no loss in cardiac output and the
 M. Kluckow, S.B. Hooper / Seminars in Fetal & Neonatal Medicine xxx (2015) 1e7
large swings in arterial pressure and cerebral blood flow associated
with UCC are greatly mitigated. The rapid increase in arterial
pressure (over four heart beats) caused by UCC is also greatly
reduced [1], because a low-resistance pulmonary circulation can
become an alternate pathway for left ventricular output due to left-
to-right flow through the DA.
It is widely considered that the benefits of not immediately
clamping the umbilical cord primarily concern the net transfusion
of blood between the placenta and infant. Largely based on studies
done in the late 1960s, it is assumed that placental-to-infant blood
transfusion is a time-dependent process that commences within
seconds and is completed within ~3 min of birth, resulting in the
net transfer of up to 30 mL/kg of blood [6]. This has led to a time-
based approach to “delayed cord clamping” in many resuscitation
guidelines, irrespective of the infant's physiology [25]. However,
recent observations in humans have indicated that net blood flow
into and out of the infant via the umbilical vessels is more complex
than previously considered [26]. Flow continues for much longer
than previously considered and can cease in the umbilical vein
before the artery, potentially leading to blood loss for the infant.
The flow is also heavily influenced by inspiratory efforts, with flow
in the umbilical vein mostly occurring during inspiration [26].
Expiratory breath holds and crying can cause flow in both the
umbilical artery and vein to cease and the bidirectional flow in the
umbilical artery is thought to be due to uterine contractions [26].
Clearly, therefore, the infant's physiology is important and the
relationship with time is incidental and likely to be due to the fact
that the underlying physiological changes take time to unfold after
birth.
5. Physiological factors affecting umbilical blood flow after
birth
Although there is considerable potential benefit for the infant if
the lungs aerate and PBF increases before UCC, in addition to
breathing and crying there are likely to be many factors that in-
fluence blood distribution between the placenta and infant after
birth. For instance, as the placental circulation is connected in
parallel with the infant's lower body, if the infant has a vaso-
constricted peripheral vascular bed then blood flow will be re-
directed towards the placental circulation [24]. This can arise in
response to hypoxia or cooling and would increase the risk of blood
loss from the infant to the placenta during “delayed cord clamping”.
It is also unclear whether delaying UCC would be beneficial or
detrimental in severely asphyxic bradycardic infants requiring
chest compressions. This is because the presence of a persisting
low-resistance placental circulation may reduce or restrict the in-
crease in diastolic pressure required to restore spontaneous circu-
lation during resuscitation.
Several practical issues may also impact on the physiological
benefits of “delayed cord clamping”, although none of these relate
to the practicalities of resuscitating an infant next to the mother
following either vaginal or cesarean section delivery [27]. Instead,
these relate to the vertical positioning of the infant, relative to the
mother, and the timing of uterotonic administration, as this could
greatly impact upon cardiovascular benefits of initiating lung
aeration before UCC. Until recently, it was widely recommended
that the mother be given a uterotonic (e.g. syntocinon) upon de-
livery of the infant's anterior shoulder, which is followed by im-
mediate UCC and gentle cord traction to hasten delivery of the
placenta [28,29]. Whereas this active management strategy reduces
the risk of postpartum haemorrhage (PPH), it is also associated with
a significant reduction in infant birth weight, which is thought to be
due to a reduction in infant blood volume [28]. As oxytocin is
equally effective when given following delivery of the placenta [29],
Please cite this article in press as: Kluckow M, Hooper SB, Using physiology to guide time to cord clamping, Seminars in Fetal & Neonatal
Medicine (2015), http://dx.doi.org/10.1016/j.siny.2015.03.002
3
it may be preferential to administer it at the end of third stage to
avoid interfering with the placental circulation as the lung aerates.
Importantly the meta-analysis of delayed cord clamping shows no
increased risk of postpartum haemorrhage in mothers of infants
who received delayed cord clamping [30].
Clinical studies suggest that, while the umbilical circulation
remains intact, uterine contractions enhance the blood transfusion
between the placenta and infant by “squeezing” umbilical blood
towards the infant [31]. However, this suggestion is not consistent
with the interpretation of fetal heart rate variability associated with
uterine contractions during the second stage of labour [32]. Dif-
ferential occlusion of umbilical venous and arterial vessels (intra-
placental) during a uterine contraction is thought to cause the
placental accumulation of blood. This is due to the earlier occlusion
and later release of the more compliant venous vessels, compared
with the arteries, leading to increased venous return and an in-
crease in heart rate at the end of the contraction [32]. As a sustained
and intense uterine contraction causes umbilical blood flow to
reduce or to cease, oxytocin administration may negate the benefits
of this procedure.
The effect of positioning the infant above or below the placenta
is another factor that could influence the cardiovascular transition
if UCC is delayed. It is assumed that placing the infant above the
placenta increases blood flow into the placenta, whereas placing
the infant below the placenta increases blood flow into the infant.
This assumption is supported by studies [6,33,34] showing that
placental transfusion is maximized when neonates are placed
below the placenta [33]. Although the effects were explained by the
ability of gravity to assist or reduce the placental to infant blood
transfusion, the hemodynamics are likely to be considerably more
complex. Nevertheless, a recent non-inferiority clinical trial has
found no adverse effects (on infant weight used as a proxy for
placental transfusion) of placing the infant above the placenta [35],
which is consistent with the current common practice of placing
the infant on the mother's abdomen or chest after birth. Whereas
this does not appear to influence infant outcome, the science un-
derpinning this practice has not been investigated.
Although numerous factors are likely to influence flow in the
umbilical vessels after birth, previous studies have detected a time-
dependent increase in blood transfer after birth. These changes
were measured either by weight gain [36] or by direct measures of
blood volume [6,31]. As we now know the impact that immediate
cord clamping can have on cardiovascular function at birth, it is
possible that the measurement technique (dilution of 125I-labelled
albumin) used by Yao et al. [6] was not optimized for newborn
infants. Indeed, it is possible that the lower blood volumes
measured in the early clamp group simply reflect lower cardio-
vascular function over the 5 min period between label injection and
sampling time [31]. Reduced cardiovascular function will reduce
the mixing efficiency of the labelled albumin throughout the cir-
culation, which is required to obtain an accurate volume estimate.
The weight gain technique of measuring increased blood volumes
would appear more robust, although the authors do report the
problem of movement artefact and unfortunately infants subjected
to immediate UCC were not included for comparison [35].
6. Postnatal myocardial adaptation of the preterm infant
The effects of the timing of UCC manifest long beyond the im-
mediate post-clamping period. The circulatory transition is a
complex series of cardiorespiratory events occurring in a sequence
that allows safe conversion from a fetus with placental-dependent
circulation to a neonate with an independent circulation. In the
term infant this sequence of events occurs rapidly, usually with
spontaneous respiration established within a short period after
4 M. Kluckow, S.B. Hooper / Seminars in Fetal & Neonatal Medicine xxx (2015) 1e7
birth. In the preterm infant with more immature lungs and a more
immature myocardium, the circulatory transition occurs more
slowly. Consequently there is an increased risk of delay in estab-
lishing spontaneous respiration that can adversely affect the tran-
sitional sequence, with the cord being clamped during or even
before the first breath. As discussed, this potentially creates an
abnormal physiological state, which has more profound implica-
tions for the immature cardiorespiratory system of the preterm
infant than the term infant. Following premature birth, a delay in
UCC not only allows placental transfusion but gives more oppor-
tunity for the preterm infant to establish spontaneous respiration
prior to UCC.
The newborn myocardium and cardiac function are more
vulnerable to both preload and afterload changes than are older
infants and adults [37], and this vulnerability is even greater in
preterm infants (see also S. Noori and I. Seri, Chapter 4, this issue).
They have a simpler structure with fewer mitochondria, and dif-
ferences in the myofibrils themselves result in less reserve and
ability to compensate for changes in blood volume and peripheral
resistance [38]. Consequently, the increased afterload and
decreased preload associated with UCC before lung aeration may
result in significant physiological instability and severely restrict
the infant's ability to compensate to any additional adverse events.
7. Loss of circulating blood volume and placental transfusion
Before birth, there is a shared blood volume between the
placenta and fetus, and the distribution is determined by the
relative resistances between the two circulations as well as the
differential flow in the umbilical vein and arteries. Following de-
ferred UCC, placental transfusion can be as much as an absolute
increase in blood volume of the infant of 20% [35] corresponding to
80 mL of blood at 1 min and 100 mL after 3 min [6]. As discussed
above, there is significant variability in how much blood is trans-
ferred from the placenta to the neonate in a given period of time. A
single time point for cord clamping to maximize the benefits is
unlikely to be physiologically feasible. Rather the time to UCC
should be described as a physiological end point such as when a
particular volume of blood has been transfused e possibly based on
a change in weight or measured flow in the umbilical vessels.
Further refinement of practical ways to measure these outcomes is
needed e changes in weight require accurate scales that stabilize
rapidly and allow for movement, and use of real-time ultrasound to
detect flow is dependent on Doppler angle, separating arterial from
venous flow, and user experience to prevent partial occlusion of the
vessel. Further assessment of the adequacy of the transition may be
via either non-invasive measurement of cardiac output during the
period of postnatal transfusion or postnatal measurement of car-
diac output/systemic blood flow following UCC. Use of previously
validated techniques to measure right ventricular output or supe-
rior vena cava flow is subject to the limitations of these techniques,
which include user variability and inter-observer variation of up to
20%.
One of the potential consequences of interrupting the placental
transfusion by immediate UCC after birth is a reduced circulating
blood volume in the newborn infant. Term infants who experience
early UCC are less likely to be affected as they often start sponta-
neously breathing and crying before the cord is cut, thereby
enhancing the amount of placental transfusion within a short time
period [39]. In preterm infants, this is less likely to occur as they
may require more time between birth and cord clamping before
breathing or even initiation of resuscitation can commence. The
presence of reduced circulating blood volume is more evident in
the preterm infant. Systematic reviews show that preterm infants
who received early versus later UCC have reduced haemoglobin
Please cite this article in press as: Kluckow M, Hooper SB, Using physiology to guide time to cord clamping, Seminars in Fetal & Neonatal
Medicine (2015), http://dx.doi.org/10.1016/j.siny.2015.03.002
levels, more hypotension requiring treatment and a higher use of
inotropic support [30]. Many preterm infants who had early UCC,
particularly if they are then mechanically ventilated, appear to be
relatively hypovolemic and respond well to a volume bolus if they
have hypotension or evidence of low cardiac output [40]. Addi-
tionally there is now a series of clinical studies suggesting lower
systemic blood flow/cardiac output in preterm infants who had
early UCC [41,42]. The consequences of increased hypotension
treatment and reduced systemic blood flow are significant, with
associations between adverse neurological outcome and other
significant morbidities. Concerns regarding a higher incidence of
polycythemia, hyperbilirubinemia or other respiratory disorders
potentially associated with later UCC have not been confirmed in
randomized controlled trials and systematic reviews [30].
8. Assessing cardiovascular impairment: hypotension and
low systemic blood flow
As blood pressure in neonates provides limited information on
cardiovascular function, there is much interest in measuring car-
diac output or systemic blood flow, particularly in preterm infants.
Cardiac output is a direct determinant of systemic oxygen delivery,
and therefore may be the more relevant measure to assess. Variable
peripheral vascular resistance alters the relationship between
systemic blood flow and blood pressure. An infant who is vaso-
dilated can have a low systemic blood pressure but have good
perfusion, no evidence of acidosis, and have a cardiac output within
or even higher than the normal range. Similarly, when an infant is
exposed to a sudden increase in SVR, although the blood pressure
may be within a normal range, cardiac output may be low, resulting
in reduced perfusion and eventually acidosis.
Consequently techniques to measure the cardiac output of an
infant have become increasingly important. In newborn infants the
use of catheters and thermodilution are problematic due to phys-
ical size and the presence of cardiac shunts. The use of non-invasive
Doppler ultrasound to measure cardiac output has increased, and
there are normative values for both left and right ventricular output
in newborn infants with well-demonstrated validity [43]. In
newborn infants, ventricular outputs are altered due to the pres-
ence of both a ductal and a patent foramen ovale (PFO) shunt,
meaning that true systemic blood flow may be underestimated. The
presence of a large left-to-right ductal shunt will increase left
ventricular output, which means that true systemic blood flow is
overestimated. If there is a PFO shunt, the right ventricular output
will similarly overestimate systemic blood flow [44]. To avoid this,
superior vena cava (SVC flow) has been used as a measure of sys-
temic blood flow [45]. This measure estimates systemic blood flow
by assessing the inflow to the heart from the upper body, head and
brain; it has been clinically validated; and low SVC flow has been
demonstrated to be associated with significant adverse outcomes.
The heart is dependent, among other factors, on filling to provide
an output, so measures of inflow are a valid way to assess changes
in cardiac output. SVC flow therefore is the presently available
most-tested assessment tool for the adequacy of the postnatal
cardiovascular system immediately after birth when fetal shunts
are patent. This measure has been utilized in several studies of early
versus late cord clamping to assess the systemic blood flow,
particularly in preterm infants where postnatal fetal shunts are
most prominent. These studies have found evidence of reduced
systemic blood flow in infants who had early UCC compared to
those who had UCC after 45 s to 3 min of postnatal age [41,42].
Umbilical cord milking with UCC at an earlier time point has also
been shown to have a similar effect on decreasing the incidence of
low systemic blood flow [46]. However, cord milking provides a
rapid transfusion over 10e20 s, often before the establishment of
 M. Kluckow, S.B. Hooper / Seminars in Fetal & Neonatal Medicine xxx (2015) 1e7
spontaneous breathing. Proponents of cord milking argue that it
allows a more rapid transfer of blood to the fetus and subsequently
allows earlier UCC in a fetus judged to require resuscitation.
However, the safety of a rapid placental transfusion in terms of both
volume transfer and the risk of cell debris or vasoactive factors from
the cord endothelial cells being transferred to the neonate is un-
certain. The premise of cord milking is that the main benefit in the
transition from umbilical/placental transfer strategies is the
increased blood volume, rather than facilitation of the normal
transitional sequence whereby respiration begins and PBF in-
creases prior to UCC. In the case of cord milking, the cord is still
likely to be clamped in a preterm infant prior to establishment of
breathing.
9. Hemodynamic complications of reduced systemic blood
flow including periventricular/intraventricular haemorrhage
(P/IVH)
An important association with low cardiac output/SVC flow is
periventricular/intraventricular haemorrhage (P/IVH), with low
cardiac output and SVC flow being more frequent in infants who
subsequently develop this significant complication of prematurity
(see S. Noori and I. Seri, Chapter 4, this issue). The mechanism is
thought to involve a period of postnatal ischemia/reduced blood
flow, which impairs cerebral autoregulation, eventually leading to
P/IVH after blood flow and blood pressure recovery [47]. It is of
particular interest that, in systematic reviews, preterm infants
who received later UCC had an overall decreased incidence of P/
IVH [30]. This association may be explained by the link between
interruption of the placental transfusion and improved myocardial
adaptation and subsequent reduced systemic blood flow in pre-
term infants, increasing the risk of P/IVH in patients in the im-
mediate UCC group. A large ongoing study e the Australian
Placental Transfusion study e will assess this link more closely
using early cardiac ultrasound to routinely assess the cardiovas-
cular function of infants randomized to early UCC at 10 s or a
deferral of 60 s.
10. The timing of resuscitation intervention
The new understanding of physiology surrounding the timing of
UCC challenges the previous assumption that early UCC and sepa-
ration of the mother and baby to allow resuscitation and initiation
of respiration is the priority in an apnoeic infant. The intervention
of early UCC was introduced into the care of the newborn infant
without any physiologic rationale in the baby or systematic study as
to the consequences. As mentioned earlier, the rationale was
related more to concerns regarding protection of the mother from
PPH, which was subsequently found to be not related to the timing
of UCC [48]. Similarly, protection of the infant from exposure to
maternal anesthetics and analgesics is also an untested assumption.
Concerns regarding risks of polycythemia and an increased need for
phototherapy were also cited but have been refuted in a series of
clinical trials in preterm infants undergoing deferred UCC [30]. As a
consequence of the belief that resuscitation of the newborn infant
is more important than allowing a physiological transition, our
labour wards, delivery suites and operating theatres have evolved
with separate areas for newborn resuscitation, resulting in the need
to cut the umbilical cord and separate mother and baby if resus-
citation is to be provided.
Increasingly this model of resuscitation is being questioned. It
is suggested that the first step in neonatal resuscitation should be
delayed UCC and/or a placental transfusion and allowing the in-
fant to initiate respirations while still attached to the placenta
[49]. As reviewed in this article, allowing the more natural
Please cite this article in press as: Kluckow M, Hooper SB, Using physiology to guide time to cord clamping, Seminars in Fetal & Neonatal
Medicine (2015), http://dx.doi.org/10.1016/j.siny.2015.03.002
5
transitional sequence to occur may result in less physiological
instability and subsequently a smoother transition. The initial
steps of resuscitation may sometimes be counterproductive to a
smooth cardiorespiratory transition with suctioning of the airway,
application of a facemask and attempts at intubation; all poten-
tially inhibiting attempts by the preterm infant to establish
breathing. Deferring UCC may allow more time for the infant to
commence respiration spontaneously, thus allowing a more
physiological transition. Heart rate is one of the main de-
terminants of the initiation of the various steps of resuscitation,
and it has been demonstrated in both animals [1] and human
infants [50] that early cord clamping, particularly in an apnoeic
infant, will result in a significant reflex bradycardia. In infants
who all received early UCC, 50% of the infants had HR<100 bpm
and 10% were <40 bpm at 1 min. The decreased heart rate may
lead a clinician to initiate resuscitation measures, whereas, if
there had been a deferral of UCC, transition may have occurred
without the need for resuscitation.
We have suggested the term “physiologically based cord
clamping” to describe the process of allowing a more natural
sequence of transition to occur. The timing of UCC is then not
defined as a particular time period between birth and UCC, but
rather, clamping the umbilical cord after regular respiration has
been established or after appropriate lung inflation has been ach-
ieved in depressed preterm or term neonates, at whatever time
point this may be. A natural evolution of this approach is
commencing resuscitation and initiating respiratory efforts while
the infant is still attached to the placenta. Facilitating this will
require a change in practice at the bedside with medical resusci-
tation equipment being brought to the place of birth. This is
increasingly feasible and the development and testing of a resus-
citation cot that can be brought to the bedside after the birth of a
preterm infant has already commenced [27]. The use of new
equipment to allow resuscitation and particularly lung inflation, of
the preterm infant while still receiving the placental circulation
with its oxygen and nutrient supply has the potential to substan-
tially change the way we approach postnatal care. It is important to
note that this suggested novel approach to neonatal resuscitation
must be vigorously tested in large trials before routine clinical use
can be recommended.
11. Conclusions
Professional bodies concerned with issuing guidelines con-
cerning management of labour and delivery have recommended
deferral of UCC in both term and preterm infants [49]. Despite this,
the correct physiological time point to clamp the umbilical cord is
still not clear. The benefits of deferring the time of UCC are
dependent on two main mechanisms with a physiological ratio-
nale. The first is the receipt of a placental transfusion with subse-
quent benefits in terms of preventing low blood pressure and
cardiac output with associated reduction in P/IVH, less inotropes
and less iron deficiency anaemia. The time point of UCC would thus
be related to a measured volume of transfusion, and the factors that
contribute to the volume are many. Validated techniques to assess
the volume of transfusion in real time are urgently needed. The
second mechanism is allowing an ordered sequence of physiolog-
ical events at birth with commencement of breathing/lung venti-
lation followed by a normal cardiovascular transition. In this case,
the time point of UCC is related to initiation of breathing and lung
inflation. To implement this physiological intervention requires
rigorous testing of the approach and, if the approach is found to be
effective and safe, a rethinking of the design of our labour and
delivery rooms to allow resuscitation of the infant with cord intact
by the mother's bedside.
6 M. Kluckow, S.B. Hooper / Seminars in Fetal & Neonatal Medicine xxx (2015) 1e7
Practice points
 The practice of immediate clamping of the umbilical cord
in both term and preterm infants is increasingly being
questioned, and systematic reviews suggest a range of
benefits resulting from deferral of cord clamping.
 The mechanism resulting in these benefits is not clear e
placental transfusion is important but there is increasing
evidence that the timing of the relationship between cord
clamping and lung aeration is also important.
 The term physiologically based cord clamping recognizes
the importance of using a physiological outcome to time
cord clamping rather than an arbitrary time point.
Research directions
 More evidence is needed regarding the benefits and risks
of deferred cord clamping in the setting of very preterm,
asphyxiated and apneic infants who are in need of
resuscitation. Several ongoing randomized clinical trials
will address this question.
 The best physiological outcome on which to base the
clamping of the cord is still not clear e more data on how
to assess placental function, umbilical arterial blood flow,
volume of blood transfused and commencement of the
circulatory transition process in the immediate time after
birth are needed to help define this.
 The benefits and risks of cord milking to enhance
placental transfusion and allow earlier cord clamping,
possibly in an apneic infant, need more study.
Conflict of interest statement
None declared.
Funding sources
None.
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Please cite this article in press as: Kluckow M, Hooper SB, Using physiology to guide time to cord clamping, Seminars in Fetal & Neonatal
Medicine (2015), http://dx.doi.org/10.1016/j.siny.2015.03.002