Abstract
While umbilical cord clamping (UCC) at birth is considered to be an innocuous act, whether or not it is depends upon when it occurs during the infant’s transition to newborn life. Before birth, the placenta receives a large proportion of cardiac output and is the site of fetal gas exchange. As such, umbilical venous return provides highly oxygenated blood for the fetus and is a major source of preload for cardiac output, particularly for the left ventricle. This is because fetal pulmonary blood flow (PBF) is low so the left ventricle depends upon umbilical venous return to sustain its output, which flows via the foramen ovale into the left atrium. At birth, aeration of the lungs not only allows the lungs to take over the role of gas exchange, but by stimulating a large increase in PBF, it also allows pulmonary venous return to replace umbilical venous return as the main source of left ventricular preload. Consequently, UCC before lung aeration not only separates the infant from its gas exchange organ, but also deprives the left ventricle of preload. This understanding provides the rationale for delaying UCC until after the infant has initiated air-breathing and explains much of the beneficial cardiovascular effects of delayed UCC. However, the debate about the timing of UCC has almost entirely focused on the concept of a time-dependent placental transfusion after birth; a process that is complex and difficult to explain physiologically. As it is possible that in some circumstances the infant may lose blood to the placenta, it is important to understand the underlying factors determining the distribution of blood between the infant and placenta during delayed UCC to avoid this situation. Whatever the mechanisms, we now know that labor and vaginal birth are major determinants of this distribution. As such, it is possible that “placental transfusion” is the act of rebalancing the blood volume distribution between infant and placenta during following vaginal birth.
Keywords
birth, cardiovascular transition, lung aeration, umbilical cord clamping
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There is a new and emerging understanding of the importance of the transitional circulation and the role that the timing of cord clamping plays in this.
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The cardiorespiratory transition at birth is a complex series of changes that begins with lung aeration and results in a chain of respiratory and cardiovascular events.
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The benefits of a delay in the clamping of the cord may be more than simply a placental transfusion, with time to transition also being a potential benefit.
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Placental transfusion volume is not just about time—there are other determinants including gravity, oxytocics, breathing, and crying.
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There are good animal data and a physiologic rationale that stabilization of the immediate postnatal hemodynamics is more likely with a deferral in cord clamping and initiation of breathing/lung inflation prior to clamping.
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A physiologic end point for determining cord clamping time is logical. This could be determined by either the onset of regular respirations or a particular volume of placental transfusion, which would require a specific way to quantitate the amount of transfusion, such as change in weight or real-time Doppler flow measurements.
The transition from intra- to extrauterine life involves a remarkable sequence of physiologic events that allow the fetus to survive after birth independent of the in utero milieu and a gaseous environment. While these physiologic events are often studied and viewed independently, they are intimately linked and triggered by the one event that cannot occur in utero, lung aeration. Before birth, the developing lungs are liquid-filled and gas exchange occurs across the placenta. At birth, the airways must be cleared of liquid to allow the entry of air and the onset of pulmonary ventilation so that the infant’s site of gas exchange can transfer from the placenta to the lungs. To facilitate the onset of pulmonary gas exchange, lung aeration also triggers a large decrease in pulmonary vascular resistance (PVR). As a result, right ventricular output is redirected through the lungs, rather than flowing through the ductus arteriosus (DA), causing a large increase in pulmonary blood flow (PBF). In turn, the increase in PBF plays a vital role in sustaining the infant’s cardiac output by replacing the venous return and ventricular preload lost due to clamping of the umbilical cord and removal of the placental blood flow. Before birth, as PBF is low, the majority of venous return and preload for the left ventricle is supplied by umbilical venous return which flows via the ductus venosus and foramen ovale directly into the left atrium. As a result, at birth, clamping the umbilical cord before pulmonary ventilation has commenced and PBF has increased is potentially problematic, causing a large reduction (up to 50%) in cardiac output.
Recognizing that the physiologic transition at birth is a sequence of interdependent events is vital to fully understand the consequences of clinical staff intervening in this process. In particular, umbilical cord clamping (UCC) at birth is the most common clinical intervention and is often viewed as an innocuous act. However, whether or not it is innocuous depends upon when it occurs during the progression through this physiologic sequence. For instance, if it occurs before the lung has aerated and PBF has increased, the infant is at increased risk of hypoxia and ischemia. Thus, it is important to understand the physiologic changes that occur at birth, as well as being able to recognize the stage within this transitional process that the infant has reached, in order to choose the correct timing for UCC after birth.
The Transition to Newborn Life
In utero, the fetus grows and develops in a liquid environment that is very different from the gaseous environment that it must survive in after birth. Gas exchange occurs across the placenta and the future airways are filled with a liquid that is produced by the lung and plays a vital role in stimulating fetal lung growth and development. This liquid is actively retained within the airways by the fetus and keeps the lungs under a constant state of distension, resulting in a resting lung volume that is significantly larger than the functional residual capacity of the newborn lung. This constant state of distension provides a mechanical stimulus for lung growth, which if absent, results in severe lung hypoplasia that is either lethal or causes significant morbidity in the newborn. However, while airway liquid is essential for fetal lung growth, its presence is a major obstacle for the entry of air and the onset of pulmonary gas exchange after birth. As such it is important that the airways are cleared as rapidly as possible during the birth process to ensure that air can enter the terminal gas exchange regions of the lung and facilitate the onset of gas exchange.
Airway Liquid Clearance
Much interest has focused on the mechanisms of airway liquid clearance at birth, as reduced or heterogeneous airway liquid clearance is a major cause of perinatal morbidity, particularly in premature infants or term infants born by cesarean section. Until recently, it was commonly thought that adrenaline-induced Na + reabsorption was the primary driver of airway liquid clearance at birth. However, as this mechanism develops late in gestation and requires high circulating adrenaline levels to be activated, it doesn’t readily explain how airway liquid is cleared in premature infants or in many of the infants born by cesarean section without the stress of labor. Clearly, this is not the only mechanism and recent evidence even suggests that it is not the primary mechanism, accounting for less than 5% of airway liquid clearance in spontaneously breathing rabbits at birth.
There are potentially three mechanisms that can contribute to airway liquid clearance at birth, which likely contribute to different degrees depending upon the timing and mode of delivery. As the fetal respiratory system is highly compliant, any small increase in transthoracic pressure will greatly reduce the volume of airway liquid. It is well established that the loss of amniotic fluid and uterine contractions increase fetal spinal flexion which increases both abdominal and intrathoracic pressures resulting in lung liquid loss and a reduction in lung expansion. Increased spinal flexion, caused by uterine contractions that force the fetal head through the cervix and vagina, likely explains the “gushes” of liquid from the nose and mouth that have been described following delivery of the head. While this mechanism can account for large reductions in airway liquid at birth, it does not explain how residual volumes of liquid are cleared from the airways after birth.
It has been proposed that increased circulating adrenaline levels during labor activate amiloride-sensitive Na + channels located on the apical surface of pulmonary epithelial cells. The resulting uptake of Na + from the lung lumen and its transport across the epithelium into the pulmonary interstitium also increases the electropotential gradient for Cl − ion flux in the same direction. This reverses the osmotic gradient driving fetal lung liquid secretion, leading to liquid reabsorption from the airway lumen. While this mechanism has been extensively studied and described, as indicated earlier, it only develops late in gestation, requires very high levels of circulating adrenaline, and at maximally stimulated rates (30 mL/h), it would take hours to clear all airway liquid.
In a recent breakthrough, phase contrast x-ray imaging has allowed researchers to visualize the entry of air into the lungs at birth in both spontaneously breathing and mechanically ventilated term and preterm rabbits. These studies clearly show that the air/liquid interface only moves distally during inspiration or during positive pressure inflations ( Fig. 4.1 ). Between breaths or inflations, the air/liquid interface either remains stationary or moves proximally, indicating that some airway liquid reentry may occur between breaths. Based on these results, it was concluded that after birth, airway liquid clearance primarily results from transepithelial hydrostatic pressures generated during inspiration/inflation. That is, inspiration-induced hydrostatic pressure gradients between the airways and surrounding tissue drive the movement of liquid out of the airways across the pulmonary epithelium. This process was found to be extraordinarily rapid, with some newborn rabbits completely aerating their lungs in three to five breaths, generating an FRC of 15 to 20 mL/kg in that time (∼30 seconds).
Increase in Pulmonary Blood Flow at Birth in Response to Lung Aeration
At birth, lung aeration increases PBF 20- to 30-fold, which not only enhances pulmonary gas exchange capacity but also plays a critical role in taking over the supply of preload for the left ventricle. Numerous mechanisms are believed to mediate the pulmonary vasodilation in response to lung aeration, including increased oxygenation leading to the release of vasodilators such as nitric oxide, a reduction in lung distension caused by the formation of surface tension, and more recently, a vagally mediated vasodilation caused by the movement of liquid out of the airways into the surrounding tissue. The latter mechanism was identified using simultaneous phase contrast x-ray imaging and angiography, designed to examine the spatial relationship between ventilation and perfusion during transition. While the imaging was expected to show that partial lung aeration would increase PBF in only aerated lung regions, unexpectedly the imaging unequivocally demonstrated that partial lung aeration caused a global increase in PBF ( Fig. 4.2 ). As ventilation with 100% nitrogen was able to produce a similar response as well as an increase in heart rate, it appears that increased oxygenation is not a prerequisite for pulmonary vasodilation at birth, which is a consistently reported finding. Nevertheless, ventilation with 100% oxygen enhanced the increase in PBF, but only in ventilated lung regions, indicating that the increase in PBF in response to lung aeration is multifactorial, with different mechanisms working independently. As vagal nerve section abolished the increase in PBF induced by partial lung ventilation with 100% nitrogen, it was suggested that the movement of airway liquid into lung tissue activated receptors (possibly J receptors), which signaled via the vagus to stimulate a global increase in PBF.
While the global increase in PBF that is stimulated by partial lung aeration causes a large ventilation/perfusion mismatch after birth, this is not necessarily problematic. Indeed, as lung aeration is usually quite heterogeneous, restricting the overall increase in PBF by only increasing PBF in aerated lung regions will reduce pulmonary venous return and may affect cardiac output. This is because, following UCC, pulmonary venous return becomes the primary source of preload for the left ventricle and restricting the increase in PBF restricts cardiac output. As a result, the importance of clamping the umbilical cord at the appropriate time within this physiologic sequence (lung aeration followed by PBF increase) becomes self-evident.
The Cardiovascular Transition at Birth: Effect of Umbilical Cord Clamping
The fetal circulatory system is very different from that of the newborn and is incompatible with independent life after birth. As such, the circulatory system must undergo substantial and rapid changes to transform from a fetal into a newborn phenotype. Before birth, PBF is low and the majority of right ventricular output bypasses the lung and enters the descending thoracic aorta via the DA. As a result, both left and right fetal ventricles pump in parallel, with both providing output for the systemic circulation; this circulation also includes perfusing an organ (the placenta) which at times during pregnancy is as big as, if not bigger than, the fetus.
As the placenta receives a high percentage (30% to 50%) of fetal cardiac output, umbilical venous return must also provide a large proportion of venous return to the heart, which flows via the ductus venous and the liver via the IVC. Of the umbilical venous return flowing through the ductus venosus, the majority of this blood bypasses the right atrium, right ventricle, and the lungs by flowing through the foramen ovale into the left atrium. This has two important consequences. The first is that the relatively highly oxygenated umbilical venous blood can pass directly into the left side of the heart resulting in higher blood oxygen levels in preductal arteries perfusing the head and upper body. The second, often overlooked consequence, is that umbilical venous blood provides a large percentage of the left ventricular preload in the fetus, particularly as PBF is low.
The consequences of UCC at birth are multifactorial. The healthy placenta has a low-resistance, highly compliant vascular bed that receives a large percentage of fetal cardiac output. As a result, clamping the umbilical cord at birth not only separates the infant from its site of gas exchange, but also greatly increases systemic vascular resistance and therefore increases afterload on both the left and right ventricles. This causes an instantaneous (within four heart beats) increase in arterial blood pressure (by ∼30%), which results in an equally rapid increase in cerebral blood flow. In addition, upon clamping the umbilical cord, umbilical venous return is lost, which significantly reduces left ventricular preload and, combined with the increase in afterload, greatly reduces cardiac output. The loss in cardiac output persists until the lung aerates and PBF increases to restore ventricular preload. As such, if this period of reduced cardiac output at birth coincides with even a mild level of birth asphyxia, then the infant is at risk of further hypoxic/ischemic injury. This is because the fetus’s primary defense against periods of hypoxia is to increase and redistribute cardiac output to increase blood flow to vital organs such as the brain. However, if cardiac output is reduced, as occurs after cord clamping and before the onset of pulmonary ventilation, then the capacity of the fetus to defend itself from hypoxia is severely limited.
Neonatal Cardiovascular Responses to Umbilical Cord Clamping
Realization that the supply of left ventricular preload must switch from umbilical venous return to pulmonary venous return after birth underpins the rationale for delaying UCC until after the onset of pulmonary ventilation. That is, if PBF increases before the umbilical cord is clamped, pulmonary venous return can immediately replace umbilical venous return as the primary source of preload for the left ventricle without any diminution in supply. Under these circumstances, UCC does not result in a reduction in cardiac output. It is also important to recognize that the increase in pulmonary venous return following ventilation onset also increases right ventricular output, which increases rapidly with the increase in PBF. For this to occur, blood flow through the foramen ovale (FO) must reverse to allow blood to flow from the left into the right atrium and contribute to right ventricular preload. While it has long been considered that the FO is a one-way valve, only flowing from right to left, both experimental evidence and clinical observations indicate that this is not entirely accurate.
Ventilating the lung and reducing PVR before clamping the umbilical cord also greatly mitigates the increase in arterial pressure caused by UCC, because the vasodilated lungs provide an additional low-resistance pathway for blood flow. This initiates a competitive interplay between the pulmonary and placental circulations, whereby flow into either circulation depends upon the downstream resistance (or more precisely, impedance) in each vascular bed. As such, following the reduction in PVR, the proportion of right ventricular output passing through the DA into the descending aorta is reduced and redirected into the pulmonary circulation. The result is a substantial reduction in umbilical blood flow entering and leaving the placenta. It is interesting to speculate whether the decrease in PVR contributes to reduced flow and gradual closure of the umbilical vessels after birth. Indeed, anything that alters resistance in either vascular bed will alter the distribution of cardiac output between the two vascular beds and may contribute to umbilical vessel closure when flow into the pulmonary circulation is favored. For instance, as uterine contractions increase placental vascular resistance and reduce umbilical blood flow, they increase the distribution of cardiac output into the pulmonary circulation. Similarly, the effect of gravity, caused by positioning the newborn above or below the placenta, induces the same response. That is, following ventilation onset, while umbilical artery flow is reduced as PBF increases, the reduction is much greater if the newborn is placed above the placenta compared with below the placenta.
UCC following ventilation onset markedly alters the distribution of cardiac output within the newborn. The loss of the low-resistance placental vascular bed causes a large increase in PBF, due to (1) the redirection of the entire right ventricular output into the lungs and (2) the very rapid reversal of blood flow through the DA, leading to a large left-to-right DA shunt. As a result, both left and right ventricles contribute to PBF after birth, with the contribution of the left gradually diminishing as the DA closes. It has been suggested that this ensures that pulmonary venous return and left ventricular preload are sufficient to maintain or increase (as needed) left ventricular output in the newborn period. It also allows the output of the two ventricles to gradually (over a few hours) come into balance before the two circulations separate, as at that time the outputs of the two ventricles must be equal. Indeed, a continuing but gradually diminishing communication between the two atria (via the FO) and between the two arterial circulations (via the DA) should theoretically facilitate the gradual balancing of the two ventricular outputs.
Neonatal Cardiovascular Consequences of Umbilical Cord Milking
Many commentators have assumed that umbilical cord milking (UCM) equates to delayed UCC, mainly because they believe that the primary benefit of delayed UCC is placental to infant blood transfusion (see below). However, this neglects the effect that total or intermittent occlusions of the umbilical cord has on the newborn’s circulation. A variety of different UCM strategies have been proposed and include: (1) clamping the cord, but leaving a long segment open so that blood remaining in the cord can be “milked” into the infant and (2) leaving the cord intact and gradually “milking” blood into the infant, allowing the cord to refill with blood between milks.
Recent animal studies have clarified the physiologic consequences of UCM procedures. As expected, UCM necessitates that the cord is occluded during the milking procedure, which as previously described causes both a rapid increase in arterial pressure and cerebral blood flow and presumably a decrease in cardiac output, similar to that seen after actual cord clamping. As arterial pressures are quickly restored following release of the cord to allow it to refill, the resulting changes in arterial blood pressure and cerebral flow in subsequent “milks” are precisely replicated. The net result is a concerning picture of several rapid increases and decreases in arterial pressure and cerebral blood flow, which resemble a “saw tooth” and are in stark contrast to the very stable pressures and flows that occur during delayed UCC. In a newborn infant with either an immature or inflamed cerebral vascular bed, these large “see-sawing” changes in arterial pressures and flows may be of even more concern ( Fig. 4.3 ).
Whether or not UCM results in the net movement of blood from the cord into the infant likely depends on the method of UCM. Recent studies in sheep have shown that, following the “milk,” if the cord is released at the newborn end, the cord will refill both from the infant and from the placenta, thereby losing any blood volume that was milked into the infant. On the other hand, if the cord remains occluded at the infant end following the milk, blood refills the cord only from the placental end. This procedure results in net blood transfer into the newborn and has the added benefit of maintaining a relatively stable, albeit high, arterial blood pressure which is akin to normal UCC prior to ventilation onset.
Placental Transfusion During Delayed Umbilical Cord Clamping
The concept that blood volume will automatically shift from the placenta to the infant in a time-dependent manner after birth if UCC is delayed is complex and difficult to explain physiologically. This assumes that throughout the period of delayed UCC, umbilical venous flow will exceed umbilical artery flow, despite the vein being much more susceptible to reduced flow in response to external influences than the artery. However, the fundamental principles of circulatory physiology dictate that flow into an organ will always equal flow out of an organ unless there is a major change in vascular compliance. While a large change in compliance will cause an imbalance in flow, the flow difference will always be transient. As such, blood volume will not automatically shift from the placenta to the infant unless the compliance of the vascular beds within either the infant or the placenta changes. This is consistent with the fact that fetuses spend ∼9 months in utero perfusing the placenta and during this time the distribution of blood volume between the fetus and placenta must be balanced to avoid a continuing net shift of blood from one compartment to the other.
Potential Mechanisms for Placental Blood Transfusion
Numerous mechanisms have been suggested to enhance placental-to-infant blood transfusion after birth, including gravity, uterine contractions, the increase in PBF, and thoracic pressure changes arising during inspiration. On the other hand, an increase in thoracic and abdominal pressures arising from crying or grunting may lead to fetal-to-placental blood transfusion as would peripheral vasoconstriction possibly caused by birth asphyxia. Doppler ultrasound measurements in the umbilical cords of human infants have revealed that breathing, particularly inspiration, and crying have a profound impact on blood flow in both the umbilical arteries and veins. Large inspiratory efforts appeared to increase umbilical venous flow, whereas vigorous crying caused flow to cease in both vessels. As such it appears that breathing has a major influence on umbilical blood flows and more research is required to determine whether this mechanism could drive placental-to-infant blood transfusion.
Gravity and Uterine Contraction
While placing newborns below the placenta after birth reduces umbilical artery flow, it does not result in significant placental-to-newborn blood transfusion because umbilical venous flow is reduced by the same amount. On the other hand, placing the newborn above the placenta does not result in infant-to-placental blood transfusion as flows in both umbilical vessels are changed by this procedure. These findings are consistent with a clinical trial showing no effect of placing infants above the mother on placental transfusion.
Blood volume measurements in human infants suggest that uterine contractions facilitate blood transfusion into the infant after birth. However, during labor, uterine contractions are known to increase placental vascular resistance and decrease umbilical blood flow, having differential effects on umbilical arteries and veins. That is, as the veins are highly compliant low-pressure vessels, during contractions, the veins close earlier than arteries and then reopen after the arteries when the uterus relaxes. This reasoning explains the fetal heart rate response to uterine contractions during labor, causing a transient increase in placental blood volume, which is released back into the infant following the contraction. As such, uterine contractions do not readily explain placental-to-infant blood transfusion, but in particular do not “squeeze” blood out of the placenta and into the infant.
Increase in Pulmonary Blood Flow at Birth
A common explanation for placental-to-infant blood transfusion is the increase in PBF at birth which results in an increase in blood volume to accommodate the increased blood volume residing in the lung at any moment in time. However, while the increase in PBF after birth leads to a 40% increase in pulmonary blood volume, as the lung’s blood volume is so small, this increase only accounts for a 2% overall increase in total blood volume (i.e., 2 mL/kg). The mathematical explanation for this is simple. Dilation of a blood vessel increases its volume by the square of the radius change ( r 2 ), whereas the resistance decreases by the change in radius to the fourth power ( r 4 ). As such, the increase in PBF resulting from vasodilation is two orders of magnitude greater than the volume change, which explains why a large increase in organ blood flow does not necessarily translate into a large increase in organ blood volume.
Vaginal Birth
The early observations demonstrating a time-dependent increase in infant blood volume during delayed cord clamping only provide measurements made after birth in vaginally born infants. The question therefore arises, what happens to an infant’s blood volume during labor before birth? It is possible that during labor, the forces imposed on the infant increases abdominal and thoracic pressures, causing a net shift of blood from the infant into the placenta, which is then restored or “re-balanced” following delivery. As measurements have only been made after birth, this would appear as a placental transfusion. This concept may explain why delayed UCC is less effective in infants delivered by cesarean section without going through labor and why multiple sheep experiments, where the lambs are delivered by ce-sarean section, have not been able to detect any placental transfusion.
Recent studies in twins have shown that hemoglobin levels are significantly higher in the second born twin for the first 48 hours after birth if the infants are delivered vaginally, but not if the twins were delivered by cesarean section. This effect was first observed in monochorionic twins, leading to the theory that labor induced the net movement of blood from the first-born twin into the second-born twin via anastomoses in the placenta. However, as this effect was also present in dichorionic twins, it was suggested that earlier UCC in the first-born twin resulted in less placental blood transfusion compared with the second-born twin. However, it is also possible that second-born twins are exposed to less compression than the first-born twin during delivery, resulting in less blood loss into the placenta during labor. Whatever the explanation, these studies indicate that the effects of labor and vaginal delivery are major determinants for whether increased hemoglobin content is observed postnatally. In any event, the term “placental transfusion” during delayed UCC is likely to be misleading and the concept of “blood volume restoration” or “rebalancing of the circulation” is probably more accurate.
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