The transition from intrauterine life to extrauterine existence encompasses significant cardiorespiratory adaptations. These include rapid lung aeration and increase in pulmonary blood flow (PBF). Perinatal asphyxia and fetal growth restriction can severely hamper this transition. Hypoxia is the common denominator in these 2 disease states, with the former characterized by acute insult and the latter by utero-placental insufficiency and a chronic hypoxemic state. Both may manifest as hemodynamic instability. In this review, we emphasize the role of physiologic-based cord clamping in supplementing PBF during transition. The critical role of lung aeration in initiating pulmonary gas exchange and increasing PBF is discussed. Physiologic studies in animal models have enabled greater understanding of the mechanisms and effects of various therapies on transitional circulation. With data from sheep models, we elaborate instrumentation for monitoring of cardiovascular and pulmonary physiology and discuss the combined effect of chest compressions and adrenaline in improving transition at birth. Lastly, physiologic adaptation influencing management in human neonatal cohorts with respect to cardiac and vascular impairments in hypoxic-ischemic encephalopathy and growth restriction is discussed. Impairments in right ventricular function and vascular mechanics hold the key to prognostication and understanding of therapeutic rationale in these critically ill cohorts. The right ventricle and pulmonary circulation seem to be especially affected and may be explored as therapeutic targets. The role of comprehensive assessments using targeted neonatal echocardiography as a longitudinal, reliable, and easily accessible tool, enabling precision medicine facilitating physiologically appropriate treatment choices, is discussed.

Specific physiologic and structural adaptations allow the fetus to survive and thrive in the intrauterine hypoxic environment. These include secretion of fluid by the respiratory epithelial lining, distension of airways with fluid resulting in an expanded lung, right ventricular (RV) dominance, and pulmonary-to-systemic shunting through shunts (ductal and foramen ovale). The differential vascular resistance ratio favors the pulmonary over systemic and as a result, only 8% to 10% of total cardiac output passes through the high-resistance pulmonary circuit. Combined cardiac output at ∼30 weeks’ gestational age increases to 25% indicating gradual in utero adaptation toward extrauterine existence.1  At its most basic, although the partial pressure of oxygen in the placenta is low, it still maintains adequate oxygen delivery to the tissues (aided by the presence of fetal hemoglobin).2,3  Alterations in humoral mediators play important roles. These changes include a reduction of the vasoconstrictor thromboxanes, greater synthesis of nitric oxide (through endothelial nitric oxide synthase stimulation), and lower pulmonary vascular resistance (PVR).4  Increased secretion of vasodilatory prostaglandins (Prostaglandin I2 and Prostaglandin E2), a surge in catecholamines (consequent increased cardiac contractility and heart rate), and cortisol secretion (important for surfactant maturation) enables this transition.5 

In this narrative review, we discuss recent advances in physiologic appreciation of the postnatal transition and resuscitation; specifically, we elaborate the specific role of animal studies in facilitating greater understanding of disease pathophysiology and the specific contributory role of cardiovascular performance in perinatal diseases states. Although a myriad of illnesses could affect cardiorespiratory transition, in this review, we focus on perinatal asphyxia and fetal growth restriction (FGR) because hypoxia is a hallmark characteristic of both. Whereas perinatal asphyxia represents acute hypoxia, FGR is an example of a “chronic” hypoxic adaptive state but with acute and chronic cardiorespiratory effects. Immediate neonatal circulation in asphyxiated infants is influenced by events leading to asphyxia (such as placental abruption–related blood loss or meconium aspiration), hypoxic-ischemic encephalopathy (HIE), and the treatment (therapeutic hypothermia [TH]). FGR deliveries are unique because the adaptive events like ventricular hypertrophy (followed by dilatation and globular cardiac shape) and thickened vasculature characterize important survival adaptations during fetal life. Postnatally, these translate into an inability to increase left ventricular (LV) stroke volume in the first week of life, potentially heightening the risk of circulatory instability.6 

Birth is perhaps the greatest physiologic adaptation that humans undertake to successfully transition from fetal to neonatal life. Although most newborns make this transition with apparent ease that belies the enormity of the challenge, specifically, 1 in 5 Australian newborns (includes both preterm and term) requires assistance immediately after birth to help them breathe.7  The inability to breathe spontaneously at birth increases the risk of death and disability.

The transition to newborn life requires 2 major physiologic adaptations: (1) clearance of airway liquid to enable pulmonary gas exchange and (2) the circulation must transition from a fetal into a newborn phenotype. Aeration of the lung, whether it occurs via breathing or positive-pressure ventilation, triggers these physiologic adaptations by stimulating a ∼30-fold increase in pulmonary blood flow (PBF). During fetal life, PBF is low, with most RV output bypassing the lungs and flowing through the ductus arteriosus (fetal shunt) into the descending aorta.8  Because fetal PBF is low, it contributes little to LV venous return, which is different to adult circulation in which PBF contributes 100% of the LV venous return. Instead, in the fetus, it is largely derived from umbilical venous flow, which flows via the foramen ovale into the left atrium.8  Because venous return (preload) is a major determinant of ventricular output, the umbilical circulation not only provides oxygen for the fetus but it also maintains cardiac output.

At birth, umbilical cord clamping (UCC) separates the infant from its oxygen supply (the placenta) and abolishes umbilical venous return. This sudden loss in right-heart venous return leads to blunting of the Frank-Starling relationship and impairs RV performance. This causes cardiac output to decrease by ∼50% and remain low until the infant aerates its lungs which in turn stimulates a rapid increase in PBF.8  This large increase in PBF restores LV venous return, thereby maintaining cardiac output. Thus, lung aeration is essential for both pulmonary gas exchange and restoring cardiac output. The timing of UCC in and of itself has a profound impact on the transition at birth. In many studies, researchers have demonstrated benefits of delaying UCC in preterm and term infants,911  but most have examined delayed UCC for a specific period (>1 minute after delivery) without reference to the infant’s changing physiology at birth. Aeration of the lung before UCC, either through spontaneous breathing or respiratory support, allows PBF to increase before umbilical venous return is lost through UCC. As a result, the supply of venous return for the left ventricle immediately switches from umbilical to pulmonary venous return without any diminution in supply or cardiac output.12  We have termed this physiologic-based cord clamping because the timing of UCC is based on the newborn’s physiology, with successful transition indicated by increased PBF, rather than a set time.13  Studies in both preterm and near-term lambs as well as preterm human infants have revealed that allowing lung aeration before UCC maintains a stable cardiac output, blood pressure (BP), and cerebral perfusion and oxygenation.12,1418  Possible benefits include protection of the newborn brain from fluctuations in BP and flow as well as preventing hypoxia, both major determinants of perinatal brain injury.

Pregnancy or perinatal complications affect a large proportion of infants. An understanding of how these can affect the normal cardiorespiratory transition at birth is critical before applying treatment recommendations. The results obtained in animal studies, with verification in human clinical trials, can potentially influence the management of healthy newborn infants worldwide.

Preclinical animal experiments provide an opportunity to appraise complex physiologic responses, revealing pathophysiological processes in response to fetal or neonatal compromise. Because of the invasive nature of these assessments, these would be difficult to perform in humans. In the sheep experimental model, perinatal compromise is induced by total occlusion of the umbilical cord and both discrete and whole-body changes monitored invasively and recorded in real time. Pressure and resistance changes within the systemic and pulmonary circulations provide key information and timing on the onset of respiration as well as movement of blood through the ductus arteriosus, ductus venosus, and the foramen ovale. Logistic challenges in the maintenance of recordings during the birthing process have resulted in most studies delivering sheep offspring via cesarean delivery. Large animal (sheep) models of fetal compromise allow comprehensive examination of the most common complications that may affect birth transition. This is, however, associated with higher costs, larger research teams, and the need for substantial equipment for translatable data acquisition. Experiment specific instrumentation, intervention, and outcomes studied in sheep models are described in Table 1.

TABLE 1

Representative Samples of Preclinical Studies in Sheep to Assess Transition to Ex Utero Life

ReferenceSpeciesModel%GA Induction%GA TransitionInstrumentationComments
Asphyxia       
 23 Sheep Decreased BP ∼22 mm Hg 93 93 CA catheter, CA blood flow Benefits of model: Sheep models allow for instrumentation of the fetus before the birth transition for monitoring of both cardiovascular and pulmonary physiology. 
 22 Sheep Decreased BP to ∼20 mm Hg 93 93 CA or FA catheter, JV catheter 
 25 Sheep Decreased BP ∼20 mm Hg 93 93 CA catheter, CA blood flow 
 26 Sheep Decreased BP ∼20 mm Hg 93 93 CA and JV catheters; CA and PA blood flow 
 21 Sheep Decreased BP to ∼25 mm Hg 93 93 CA catheter, CA blood flow Main outcomes are to demonstrate that the environment of the fetus at the time of asphyxia (ie, in amniotic fluid versus air) can have dramatic influence on the cardiovascular outcomes and reveal that further preclinical asphyxia studies are required to inform resuscitation guidelines. Sustained inflations improved transition alone and in combination with oxygen. The combination of chest compressions and adrenaline improves transition at birth. 
 24 Sheep Decreased BP ∼20 mm Hg 93 93 CA catheter, CA blood flow 
 27 Sheep Cardiac arrest for 5 min 93 93 CA and JV catheter, CA and PA blood flow 
 28 Sheep Cardiac arrest for 5 min 93 93 CA and JV catheter, CA and PA blood flow 
FGR       
 36 Sheep Single umbilical artery ligation 69 85 BA and JV catheter; CA and PA blood flow Benefits of model: The SUAL model produces placental insufficiency and asymmetric FGR and can be induced as early- or late-onset FGR. The size of the fetal and neonatal lambs allows fetal monitoring and neonatal use of the same equipment used in NICUs. 
 37 Sheep Single umbilical artery ligation 69 85 BA and JV catheter; CA and PA blood flow Main outcomes: FGR lambs have lower LV output and carotid blood flow and increased systemic BP in the first min of life. The respiratory requirements of the FGR lambs are comparable with human infants posttransition, and they share similar cardiovascular adaptations. 
 38 Sheep Single umbilical artery ligation 69 85 BA and JV catheter; CA and PA blood flow 
ReferenceSpeciesModel%GA Induction%GA TransitionInstrumentationComments
Asphyxia       
 23 Sheep Decreased BP ∼22 mm Hg 93 93 CA catheter, CA blood flow Benefits of model: Sheep models allow for instrumentation of the fetus before the birth transition for monitoring of both cardiovascular and pulmonary physiology. 
 22 Sheep Decreased BP to ∼20 mm Hg 93 93 CA or FA catheter, JV catheter 
 25 Sheep Decreased BP ∼20 mm Hg 93 93 CA catheter, CA blood flow 
 26 Sheep Decreased BP ∼20 mm Hg 93 93 CA and JV catheters; CA and PA blood flow 
 21 Sheep Decreased BP to ∼25 mm Hg 93 93 CA catheter, CA blood flow Main outcomes are to demonstrate that the environment of the fetus at the time of asphyxia (ie, in amniotic fluid versus air) can have dramatic influence on the cardiovascular outcomes and reveal that further preclinical asphyxia studies are required to inform resuscitation guidelines. Sustained inflations improved transition alone and in combination with oxygen. The combination of chest compressions and adrenaline improves transition at birth. 
 24 Sheep Decreased BP ∼20 mm Hg 93 93 CA catheter, CA blood flow 
 27 Sheep Cardiac arrest for 5 min 93 93 CA and JV catheter, CA and PA blood flow 
 28 Sheep Cardiac arrest for 5 min 93 93 CA and JV catheter, CA and PA blood flow 
FGR       
 36 Sheep Single umbilical artery ligation 69 85 BA and JV catheter; CA and PA blood flow Benefits of model: The SUAL model produces placental insufficiency and asymmetric FGR and can be induced as early- or late-onset FGR. The size of the fetal and neonatal lambs allows fetal monitoring and neonatal use of the same equipment used in NICUs. 
 37 Sheep Single umbilical artery ligation 69 85 BA and JV catheter; CA and PA blood flow Main outcomes: FGR lambs have lower LV output and carotid blood flow and increased systemic BP in the first min of life. The respiratory requirements of the FGR lambs are comparable with human infants posttransition, and they share similar cardiovascular adaptations. 
 38 Sheep Single umbilical artery ligation 69 85 BA and JV catheter; CA and PA blood flow 

BA, brachial artery; CA, carotid artery; GA, gestational age; JV, jugular vein; PA, pulmonary artery; SUAL, single umbilical artery ligation; —, not applicable.

Acute, severe fetal hypoxia causes an adaptive cardiovascular response that aims to preserve blood flow to the brain and heart at the expense of nonessential organs.19  This results in an acidotic, hypoxic, and unresponsive newborn unable to successfully undertake independent transition. In the sheep model, asphyxia is commonly initiated by occluding the umbilical cord until systemic arterial pressure falls to ∼20 to 25 mm Hg,2026  although some studies begin once the fetus is in full cardiac arrest.27  The heart rate response may be either decreased or increased depending on whether the fetus remained in utero or ex utero, respectively, during the asphyxia event.21,22  Cardiovascular and pulmonary responses are monitored in these experiments, with particular interest in highlighting the complex interplay between systems and organs.

Lamb studies have permitted concurrent monitoring of changes in pulmonary, femoral, and carotid artery blood flows during asphyxia and transition and have revealed that immediate UCC followed by ventilation caused a rebound tachycardia and hypertension that may be harmful to the brain. In contrast, physiologic-based cord clamping, in which cord clamping is delayed until the onset of ventilation, restored cardiac output and oxygenation in a manner similar to immediate cord clamping but was more protective for the neonatal brain by avoiding the rebound hypertension.15 

Animal models also aid understanding of the effects of various resuscitation measures on body systems. A study in asphyxiated lambs revealed a significant relationship between expired or end-tidal carbon dioxide and the return of spontaneous circulation,27  with the latter being an important physiologic milestone for recovery of asphyxiated newborns. In further studies on resuscitation of near-term asphyxiated lambs, researchers found that an initial sustained inflation in combination with chest compressions and oxygen improved transition at birth.23,26,28  Sustained inflation delivered immediately at birth, however, may have neuropathological implications. It was shown to be associated with a compromise of the blood-brain barrier and potential brain injury in near-term asphyxiated lambs.24  These findings highlight the delicate balance between lung recruitment, intrathoracic pressure, and the adequacy of cardiac output. Although room air is the gas mixture of choice for initiation of resuscitation, current guidelines recommend empirical use of 100% inspired oxygen during chest compressions. Data from a lamb experimental model of asphyxia would suggest otherwise; specifically, no difference in carotid or PBF was noted, and the changes in Pao2 and cerebral oxygen delivery were similar in animals resuscitated with either 21% or 100% oxygen.29  Essentially, effective return of spontaneous circulation must be balanced with the risk of neuropathology. Further research is needed to appraise the role of sustained inflation and/or high oxygen use during transition in terms of potential brain injury versus benefits to cardiorespiratory transition. Hemodynamic changes during recovery after severe asphyxia in near-term lambs are summarized in Fig 1. We compared BP recovery after severe asphyxia in 2 near-term lambs that underwent either immediate cord clamping before advanced resuscitation (Fig 1A) or physiologic-based cord clamping (advanced resuscitation with an intact umbilical cord).30  These studies have greatly advanced the understanding of the impact of birth asphyxia on transition and are referenced in European31  and American32  resuscitation guidelines.

FIGURE 1

Comparison of BP recovery after severe asphyxia in near-term lambs. The mean BP is measured at end asphyxia (A) after return of cardiac output (R) and for 25 minutes after birth in asphyxiated lambs undergoing immediate cord clamping (A) or physiologic-based cord clamping (C). The dotted line indicates the time of UCC. The yellow shaded region indicates normal BP. Note the significant overshoot in BP in (A). This occurs because immediate cord clamping removes the low-resistance placenta (B), forcing blood to flow through a high-resistance systemic circulation resulting in a significant increase in BP. In contrast, delaying UCC for 10 minutes after return of cardiac output leaves the low-resistance placenta in the circulation (D), allowing blood to continue to flow through the low-resistance placenta, preventing a large increase in BP.

FIGURE 1

Comparison of BP recovery after severe asphyxia in near-term lambs. The mean BP is measured at end asphyxia (A) after return of cardiac output (R) and for 25 minutes after birth in asphyxiated lambs undergoing immediate cord clamping (A) or physiologic-based cord clamping (C). The dotted line indicates the time of UCC. The yellow shaded region indicates normal BP. Note the significant overshoot in BP in (A). This occurs because immediate cord clamping removes the low-resistance placenta (B), forcing blood to flow through a high-resistance systemic circulation resulting in a significant increase in BP. In contrast, delaying UCC for 10 minutes after return of cardiac output leaves the low-resistance placenta in the circulation (D), allowing blood to continue to flow through the low-resistance placenta, preventing a large increase in BP.

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Medications are required in a proportion of newborn infants as part of resuscitation. Successful transition of an asphyxiated newborn improves with a combination of chest compressions and resuscitation medications, which augments coronary artery perfusion by inducing systemic vasoconstriction. Experiments on a well-established ovine model of perinatal asphyxia cardiac arrest closely mimicking the newborn infant provide important information that can guide future clinical trials.33  The vasopressor effects of epinephrine are critical for the restoration of spontaneous circulation as revealed by an increase in carotid arterial pressure and flow in asphyxiated near-term lambs.25  There is some evidence that vasopressin has promise as a resuscitation vasopressor in a neonatal porcine model of postnatal asphyxia (improved survival, lower postresuscitation troponin, less hemodynamic compromise after cardiac arrest).34,35  Because these investigations were conducted in piglets that had already undergone transition, further studies are required to determine their potential during the transition at birth. The dichotomous effects of the actions of vasopressin on V1 receptors, which induce vasoconstriction through calcium channels and potential favorable pulmonary vasodilator properties through nitric oxide pathways, make it suitable for the transitioning newborn. Especially, the potential for vasopressin to assist the rapid increase in cardiovascular function by increasing total peripheral resistance and diastolic pressures, but without increasing PVR, is worthy of further investigation.

The common mode of inducing FGR in animal models is single umbilical artery ligation at either 60% or 70% of ovine gestation. This results in early- or late-onset placental insufficiency and FGR.36  In a series of preclinical studies, researchers have investigated the unique challenges facing human growth-restricted fetuses via instrumentation at 80% gestation to record central and PBF and pressure changes during the transition. Data from FGR preterm lambs reveal that they have reduced LV output and reduced cerebral blood flow but higher systemic vascular resistance at birth.3739  Preterm lambs also have a significantly altered cardiorespiratory response to surfactant.40  A more rapid improvement in compliance and tidal volume was observed in lambs appropriate for gestational age (AGA) (compared with FGR lambs) was noted.40  Data from lamb and rat models also reveal that chronic placental insufficiency alters perinatal pulmonary vasoreactivity and arterial structural vascular composition, preventing a fall in PVR at birth.41,42  In Sprague Dawley rats exposed to hypobaric hypoxia, hemodynamic and structural effects on pulmonary circulation were studied.43  Chronic hypoxemia induced muscularization of “resistance vessels” by way of proliferation of vascular smooth muscle.

Experiments on animal models may be helpful to accumulate preclinical evidence for potential therapies. In recent studies using sheep models, oxidate stress and deficiencies in the nitric oxide pathway have been targeted as key mechanisms underlying the cardiovascular and potentially respiratory morbidities seen in FGR.37,44,45  Inhaled nitric oxide has been investigated in preclinical models to improve cardiovascular function in the first hours of life with success.37  Although authors of additional studies have demonstrated benefits of antioxidants such as melatonin to improve cardiovascular function,46  it has not been investigated during the transition period. Hung et al47  recently examined whether daily administration of melatonin mitigates the pulmonary hypertension and vascular remodeling in chronically hypoxic rats. With the data, it was noted that melatonin treatment significantly attenuated pulmonary pressures, thickness of the pulmonary arteriolar wall, and oxidative and inflammatory markers in the hypoxic animals. In addition, a marked increase in the endothelial nitric oxide synthase phosphorylation in the lung was noted.47  Although these preliminary data suggest biological plausibility of its effects on pulmonary circulation, its effects on human transitional circulation are yet unexplored.

Birth is characterized by a rapid transition from a high-resistance–low-compliance fetal pulmonary circuit to one that is low-resistance high-compliance. In utero and perinatal events may hamper this orderly transition. In this section, we address common pathologies that influence perinatal transition in human neonates in which acute or chronic hypoxemia plays an important role.

HIE affects ∼1 to 2 infants per 1000 live births.48  TH is standard management on the basis of several randomized trials, which have revealed lower mortality and lower neurodevelopmental impairment in survivors.49  Despite these remarkable advances, brain injury still occurs in ∼50% infants with HIE.49  Cardiovascular dysfunction (evidence of transient myocardial ischemia or hypotension requiring an inotrope for >24 hours) is commonly noted during the first 72 hours after birth.50  The incidence of hemodynamic instability ranged from 33% to 77% in infants receiving TH, compared with 25% to 83% in controls.51,52  Specific contributors to hemodynamic instability may include primary cardiac dysfunction, pulmonary hypertension, circulatory inadequacy (in case of abruption being the underlying cause), or impaired adrenal gland performance.53  Heart rate augmentation is the primary compensatory mechanism in neonates, with subsequent enhancement in myocardial performance based on the force-frequency relationship. Therefore, a low baseline resting heart rate in HIE makes assessment of circulatory inadequacy difficult. Traditional appraisal of hemodynamically stability has been focused on arterial pressure thresholds; however, given the variance in physiologic modulators in the setting of HIE, defining the “need” to treat and selection of the physiologically most appropriate therapy may require broader consideration. For example, assessment of volume status may be difficult because poor urine output, elevated lactate levels, and delayed capillary refill may reflect a state of hemodynamic disturbance, severity of HIE or the biological consequences of TH, and lower core body temperature. A nonjudicious approach to fluid resuscitation, outside of the setting of true hypovolemia, should be avoided because of the increased risk of subclinical heart dysfunction from which heart failure may ensue. Giesinger et al52  summarized the interrelationship between contributors to ischemic injury resulting from initial insult, TH, reperfusion injury on rewarming, and the impact of HIE on cerebral perfusion. Because tissue oxygenation depends on organ blood flow and oxygen content of the blood, complemented by the tissue’s ability to extract oxygen, comprehensive appreciation of the physiologic contributors to adverse cardiovascular health is essential.

Given the above complexities, targeted neonatal echocardiography may aid in ascertaining the incidence, severity, and nature of hemodynamic impairments. Commonly studied conventional echocardiography parameters are depicted in Table 2.48,5456  Tissue Doppler imaging and speckle-tracking echocardiography are newer modalities, which provide quantitative measures of myocardial velocities and regional myocardial function, respectively.5759  Historically, echocardiography research in HIE has been focused exclusively on lower cardiac output,48,55,60,61  presumed secondary to impaired LV systolic performance, oftentimes with maintained systolic BP.48  As the dominant ventricle prenatally, the right ventricle may be at a greater risk because of its dominant role in transitional circulation and increased vulnerability to coronary artery hypoperfusion.55,61,62  Hypoxia and acidosis contribute to significant pulmonary hypertension. In clinical trials of TH, ∼20% of asphyxiated infants in the control group and 25% in the hypothermia group were diagnosed with pulmonary hypertension.63  Combined with cardiac dysfunction, the frequent coexistence of pulmonary hypertension (and the side effect of increased PVR related to TH) causes poor PBF, ventilation-perfusion mismatch, and lower systemic preload, further reducing systemic output.64  HIE, whether in and of itself or compounded by the biological effects of TH (vasoconstriction and increased viscosity), may also hamper myocardial perfusion, evidenced by low coronary flow and raised cardiac troponin. This clinical phenotype has been associated with low cardiac output.55,61  Because metabolic demands are low, the aforementioned changes may simply reflect cardiac adaptation to the original insult and the ongoing therapeutics. Data characterizing the relationship between myocardial dysfunction and adverse neurodevelopmental outcomes are emerging. In the largest prospective observational study, Giesinger et al65  conducted longitudinal echocardiography as part of comprehensive multimodal neurohemodynamic evaluation in 53 infants with HIE who were administered TH. Both severity of cardiovascular illness and severity of neurologic insult were higher in neonates with adverse outcome. Of note, RV dysfunction (and not pulmonary hypertension or LV performance) was independently associated with an increased risk of mortality or abnormal MRI, after adjustment for both illness severity and magnitude of encephalopathy according to Sarnat staging. These findings were confirmed in a study of 33 infants with HIE who were administered TH; specifically, echocardiography in the first 6 hours (before initiation of TH) noted impaired RV function. Longitudinal echocardiography noted improved function between the cooling and the rewarming phases.66 

TABLE 2

Summary of Conventional Echocardiographic Parameters Used in Infants With HIE

VariableViewComment
Heart function   
 Fractional shortening (%) and ejection fraction (%) Two-dimensional, parasternal long axis or short axis Assesses LV systolic function 
May be affected by septal deviation 
 mVCFc (circumferences) Two-dimensional, parasternal long axis or short axis and apical 5-chamber view Assesses LV systolic function 
   Load independent 
 Fractional area change (%) Two-dimensional, apical RV 3-chamber view Assesses global RV contractility 
 TAPSE (mm) m-mode, apical 4-chamber view Assesses longitudinal RV contractility 
 Myocardial performance index PW, apical 4-chamber view Combined measure of systolic and diastolic intervals 
 Transmitral E/A ratio PW, apical 4-chamber view Assess LV diastolic function and compliance 
 Isovolumic relaxation time (ms) PW, apical 4-chamber view Assess LV diastolic function and compliance 
Pulmonary hypertension   
 TPV/RVETc PW, oblique parasternal PA view Surrogate of PVR 
 Lower ratio = higher PVR 
 Tricuspid regurgitation (m/s) CW, apical 4 chamber Pulmonary hypertension (4TRVmax2 + 5) 
 Ductal shunt PW, high parasternal view Percent of time in cardiac cycle shunting right to left 
  >30% is significant 
Cardiac output/systemic blood flow   
 Biventricular cardiac output (mL/kg per min) PW, oblique parasternal PA view and apical 5-chamber view Stroke volume × heart rate 
 Superior vena caval flow (mL/kg per min) PW, subcostal Surrogate of cerebral blood flowa 
 Pulmonary venous flow (cm/s or cm) Left atrial, crab view Peak velocity/velocity time integral 
  Need lower color scale to visualize flow 
 Middle cerebral artery resistive index PW, temporal view (Peak systolic velocity − end diastolic velocity)/peak systolic velocity 
 LV end diastolic volume (mm3Two-dimensional, parasternal long axis or short axis Volume status 
  Subjective, needing further quantification by other methods 
 IVC distensibility (mm) Two-dimensional, subcostal sagittal Volume status 
  Subjective, needing further quantification by other methods 
VariableViewComment
Heart function   
 Fractional shortening (%) and ejection fraction (%) Two-dimensional, parasternal long axis or short axis Assesses LV systolic function 
May be affected by septal deviation 
 mVCFc (circumferences) Two-dimensional, parasternal long axis or short axis and apical 5-chamber view Assesses LV systolic function 
   Load independent 
 Fractional area change (%) Two-dimensional, apical RV 3-chamber view Assesses global RV contractility 
 TAPSE (mm) m-mode, apical 4-chamber view Assesses longitudinal RV contractility 
 Myocardial performance index PW, apical 4-chamber view Combined measure of systolic and diastolic intervals 
 Transmitral E/A ratio PW, apical 4-chamber view Assess LV diastolic function and compliance 
 Isovolumic relaxation time (ms) PW, apical 4-chamber view Assess LV diastolic function and compliance 
Pulmonary hypertension   
 TPV/RVETc PW, oblique parasternal PA view Surrogate of PVR 
 Lower ratio = higher PVR 
 Tricuspid regurgitation (m/s) CW, apical 4 chamber Pulmonary hypertension (4TRVmax2 + 5) 
 Ductal shunt PW, high parasternal view Percent of time in cardiac cycle shunting right to left 
  >30% is significant 
Cardiac output/systemic blood flow   
 Biventricular cardiac output (mL/kg per min) PW, oblique parasternal PA view and apical 5-chamber view Stroke volume × heart rate 
 Superior vena caval flow (mL/kg per min) PW, subcostal Surrogate of cerebral blood flowa 
 Pulmonary venous flow (cm/s or cm) Left atrial, crab view Peak velocity/velocity time integral 
  Need lower color scale to visualize flow 
 Middle cerebral artery resistive index PW, temporal view (Peak systolic velocity − end diastolic velocity)/peak systolic velocity 
 LV end diastolic volume (mm3Two-dimensional, parasternal long axis or short axis Volume status 
  Subjective, needing further quantification by other methods 
 IVC distensibility (mm) Two-dimensional, subcostal sagittal Volume status 
  Subjective, needing further quantification by other methods 

CW, continuous wave; IVC, inferior vena cava; m-mode, motion mode; mVCFc, mean velocity of circumferential fiber shortening; PA, pulmonary artery; PW, pulse wave; RVETc, heart rate corrected right ventricular ejection time; TAPSE, tricuspid annular plane systolic excursion; TPV, time to peak velocity; TRVmax2, maximal velocity of tricuspid regurgitation.

a

Represents only a portion of venous return to the heart.

Although the relationship between cardiovascular and neurologic illness severity and outcomes is still inadequately understood, clinicians feel a compulsion to treat presumed low BP or low cardiac output state. Infants with HIE who develop hemodynamic instability are commonly administered inotropes on the basis of arterial pressure thresholds derived from small population studies in which BP is generally measured by noninvasive methods.67,68  Multicenter prospective cohort studies, powered to account for sex, racial, gestational, and birth weight variabilities, are better guides to normative values. The optimal thresholds for BP, cardiac output, and cerebral blood flow during the precooling period, after initiation of induced hypothermia and after rewarming, are unknown. Rapid increases in arterial pressure (and cerebral perfusion in a pressure-passive system) after initiation of inotropes or vasopressor drugs may theoretically increase the risk of reperfusion brain injury because it is unclear how much cerebral blood flow is optimal at different phases of the hypoxia-ischemia or reperfusion phases. In addition, nonjudicious use of vasoconstrictors may be detrimental to patients with heart dysfunction because they augment afterload, leading to lower cardiac output. Enhanced diagnostic precision, intermittent delineation of ambient physiology and frequent assessments of cerebral and/or cardiovascular hemodynamics may enhance choice (and need for) of cardiotropes. Targeted neonatal echocardiography reasonably provides the optimum diagnostic and longitudinal monitoring tool to delineate precise pathophysiology and refine therapeutic interventions in high-risk populations.6971  Jain et al69  noted the value of targeted neonatal echocardiography in predicting cardiorespiratory instability after duct ligation. Low LV output at 1 hour postoperation was a sensitive predictor of systemic hypotension and the need for inotropes. Targeted neonatal echocardiography revealed an independent association between impaired RV performance (but not LV systolic performance) and the combined outcome of death and/or abnormal MRI in asphyxiated infants. The data indicated the importance of pulmonary circulation (and the right ventricle) as a potential therapeutic target.65  In another study on asphyxiated infants, targeted neonatal echocardiography was used to delineate how cardiac function evolved from the precooling phase, through 72 hours of TH, and then rewarming phase.66  In essence, the facility helps in the assessment of pathophysiology in critical disease states.

FGR is defined as a birth weight <10th percentile for gestation and sex with reversed or absent antenatal Doppler recordings.72  Premature birth complicated by FGR exacerbates perinatal morbidity and mortality.7375  Fetal programming initiates changes in physiology, metabolism, and structure (cardiac hypertrophy, increased sympathetic [and reduced parasympathetic activity] and reduced nephron endowment), which can affect transitional circulation.76  The causes of FGR are varied, but they are most often associated with placental insufficiency, resulting in an inadequate supply of oxygen and nutrients to the developing fetus.

In a cohort of FGR infants, placental vascular disease (histologic maternal and fetal vascular malperfusion and accelerated villous maturation) was an early clue of this maladaptation.77,78  Cord blood level of α-klotho (an antiaging protein produced by the placenta) is decreased in FGR infants and may be relevant in vascular-mediated accelerated placental aging.79  Other mediators and the putative clinical effects of a stiff vasculature are summarized elsewhere.80  This indicates vasculature as an affected organ; vascular ultrasound of fetal and neonatal vasculature has noted thickened systemic arteries.81,82  Recent data using high-resolution ultrasound reveal that pulmonary vasculature is similarly affected.80  FGR neonates also have a thicker pulmonary artery wall, reduced pulsatility, and greater RV myocardial performance index (indicating poor performance), compared with appropriately grown infants.80  In a cohort of preterm infants assessed in the initial 24 hours of life, the baseline PVR was higher in FGR infants compared with gestation-matched AGA infants.83  In response to surfactant replacement therapy, the cardiorespiratory transition (reduction in PVR and increase in PBF and reduction in fraction of inspired oxygen) was significantly impaired in FGR infants.83  In essence, this variable cardiorespiratory trajectory, being charted by in utero experiences, is relevant in perinatal transition as well as important pathogenic mechanisms for respiratory sequelae.8385  Abnormalities in antenatal Doppler recordings also have a close relationship with cardiovascular transition to extrauterine life, making them a useful monitoring parameter.86  Alongside the vascular changes, the heart itself is affected in FGR infants. Alterations in cardiac shape and function (hypertrophied [dilated in later gestation] cardiomyopathy like hearts) are noted on human fetal studies.87  Similar changes in cardiac geometry and systolic and diastolic dysfunction have been noted in preterm and term FGR neonates in the first few days of postnatal life as well.8890  Leipälä et al6  noted altered hemodynamic adaptation in preterm FGR infants compared with equally premature but AGA infants. An inability to increase cardiac output (despite a hypertrophied left ventricle) was noted, which could potentially increase the risk of circulatory failure during early adaptation.

Other than close monitoring and optimum timing of delivery, there is currently no disease-specific treatment of FGR. Although prevention, early diagnosis and close monitoring, and optimization of maternal nutrition are key, targets of intervention to improve FGR cardiovascular health must be tested in preclinical models to determine optimal timing and targets. Breastfeeding for >6 months improves cardiac geometry (less hypertrophy) and lower arterial thickness.91  Other targets include modulators of the renin-angiotensin system (decrease angiotensin II and increase angiotensin [1–7]) and antenatal melatonin (antagonizes oxidative injury and restores nitric oxide production).76  It is promising that the effects of melatonin on oxidative parameters in preterm respiratory distress syndrome and in those with chronic lung disease have shown beneficial effects.92,93  Whether it facilitates perinatal transition in human infants needs to be prospectively explored. In the immediate neonatal period, individualized management of FGR infants such as avoiding mechanical ventilation and administering surfactant through noninvasive means may be prospectively studied. Whether managing pulmonary vascular disease alters clinical outcomes should be studied prospectively.

The immediate transitional period after birth is characterized by major and interrelated changes in cardiopulmonary physiology that influence resuscitative and stabilization efforts. Optimization of lung recruitment positively affects the establishment of normal PBF and needs considering when determining the optimal timing of cord clamping. Infants with evidence of acute hypoxic-ischemic insult, during the birth process or immediately after birth, or infants with FGR secondary to chronic intrauterine hypoxia-ischemia are susceptible to abnormal cardiopulmonary adaptation, which may manifest as acute hemodynamic instability. Because of the limitations of routine clinical assessment, comprehensive targeted neonatal echocardiography is an essential longitudinal tool to enable enhanced diagnostic precision and facilitate more physiologically appropriate treatment choices. The relationship between hemodynamic disturbance and adverse neurologic outcomes warrants prospective investigation of at-risk phenotypes and novel treatment options.

Prof Sehgal conceptualized and designed the study and drafted the initial manuscript; Dr Allison, Prof Miller, Assoc Prof Polglase, Prof McNamara, and Prof Hooper drafted the initial manuscript; and all authors reviewed and revised the manuscript, approved the final manuscript as submitted, and agree to be accountable for all aspects of the work.

FUNDING: No external funding.

AGA

appropriate for gestational age

BP

blood pressure

FGR

fetal growth restriction

HIE

hypoxic-ischemic encephalopathy

LV

left ventricular

PBF

pulmonary blood flow

PVR

pulmonary vascular resistance

RV

right ventricular

TH

therapeutic hypothermia

UCC

umbilical cord clamping

1
Berhrsin
J
,
Gibson
A
.
Cardiovascular system adaptation at birth
.
Paediatr Child Health
.
2011
;
21
(
1
):
1
6
2
Di Tommaso
M
,
Seravalli
V
,
Martini
I
,
La Torre
P
,
Dani
C
.
Blood gas values in clamped and unclamped umbilical cord at birth
.
Early Hum Dev
.
2014
;
90
(
9
):
523
525
3
Kotaska
K
,
Urinovska
R
,
Klapkova
E
,
Prusa
R
,
Rob
L
,
Binder
T
.
Re-evaluation of cord blood arterial and venous reference ranges for pH, pO(2), pCO(2), according to spontaneous or cesarean delivery
.
J Clin Lab Anal
.
2010
;
24
(
5
):
300
304
4
Reynolds
P
.
Fetal to neonatal transition – how does it take place?
Surgery
.
2013
;
31
:
106
109
5
Cavaliere
TA
.
From fetus to neonate: a sensational journey
.
Newborn Infant Nurs Rev
.
2016
;
16
(
2
):
43
47
6
Leipälä
JA
,
Boldt
T
,
Turpeinen
U
,
Vuolteenaho
O
,
Fellman
V
.
Cardiac hypertrophy and altered hemodynamic adaptation in growth-restricted preterm infants
.
Pediatr Res
.
2003
;
53
(
6
):
989
993
7
Australian Institute of Health and Welfare
.
Australia’s Mothers and Babies 2015 - in Brief
.
Canberra, Australia
:
Australian Institute of Health and Welfare
;
2017
8
Rudolph
AM
.
Fetal and neonatal pulmonary circulation
.
Am Rev Respir Dis
.
1977
;
115
(
6 pt 2
):
11
18
9
Fogarty
M
,
Osborn
DA
,
Askie
L
, et al
.
Delayed vs early umbilical cord clamping for preterm infants: a systematic review and meta-analysis
.
Am J Obstet Gynecol
.
2018
;
218
:
1
18
10
Rabe
H
,
Gyte
GM
,
Díaz-Rossello
JL
,
Duley
L
.
Effect of timing of umbilical cord clamping and other strategies to influence placental transfusion at preterm birth on maternal and infant outcomes
.
Cochrane Database Syst Rev
.
2019
;
9
(
9
):
CD003248
11
Polglase
GR
,
Stark
M
.
Cord clamping in term and pre-term infants: how should clinicians proceed?
Med J Aust
.
2018
;
208
(
8
):
330
331
12
Bhatt
S
,
Alison
BJ
,
Wallace
EM
, et al
.
Delaying cord clamping until ventilation onset improves cardiovascular function at birth in preterm lambs
.
J Physiol
.
2013
;
591
(
8
):
2113
2126
13
Hooper
SB
,
Polglase
GR
,
te Pas
AB
.
A physiological approach to the timing of umbilical cord clamping at birth
.
Arch Dis Child Fetal Neonatal Ed
.
2015
;
100
(
4
):
F355
F360
14
Polglase
GR
,
Dawson
JA
,
Kluckow
M
, et al
.
Ventilation onset prior to umbilical cord clamping (physiological-based cord clamping) improves systemic and cerebral oxygenation in preterm lambs
.
PLoS One
.
2015
;
10
(
2
):
e0117504
15
Polglase
GR
,
Blank
DA
,
Barton
SK
, et al
.
Physiologically based cord clamping stabilises cardiac output and reduces cerebrovascular injury in asphyxiated near-term lambs
.
Arch Dis Child Fetal Neonatal Ed
.
2018
;
103
(
6
):
F530
F538
16
Blank
DA
,
Badurdeen
S
,
Omar F Kamlin
C
, et al
.
Baby-directed umbilical cord clamping: a feasibility study
.
Resuscitation
.
2018
;
131
:
1
7
17
Knol
R
,
Brouwer
E
,
van den Akker
T
, et al
.
Physiological-based cord clamping in very preterm infants - randomised controlled trial on effectiveness of stabilisation
.
Resuscitation
.
2020
;
147
:
26
33
18
Katheria
A
,
Poeltler
D
,
Durham
J
, et al
.
Neonatal resuscitation with an intact cord: a randomized clinical trial
.
J Pediatr
.
2016
;
178
:
75
80.e3
19
Giussani
DA
.
The fetal brain sparing response to hypoxia: physiological mechanisms
.
J Physiol
.
2016
;
594
(
5
):
1215
1230
20
Aridas
JD
,
Yawno
T
,
Sutherland
AE
, et al
.
Detecting brain injury in neonatal hypoxic ischemic encephalopathy: closing the gap between experimental and clinical research
.
Exp Neurol
.
2014
;
261
:
281
290
21
Ong
T
,
Sobotka
KS
,
Siew
ML
, et al
.
The cardiovascular response to birth asphyxia is altered by the surrounding environment
.
Arch Dis Child Fetal Neonatal Ed
.
2016
;
101
(
6
):
F540
F545
22
Sobotka
KS
,
Morley
C
,
Ong
T
, et al
.
Circulatory responses to asphyxia differ if the asphyxia occurs in utero or ex utero in near-term lambs
.
PLoS One
.
2014
;
9
(
11
):
e112264
23
Klingenberg
C
,
Sobotka
KS
,
Ong
T
, et al
.
Effect of sustained inflation duration; resuscitation of near-term asphyxiated lambs
.
Arch Dis Child Fetal Neonatal Ed
.
2013
;
98
(
3
):
F222
F227
24
Sobotka
KS
,
Hooper
SB
,
Crossley
KJ
, et al
.
Single sustained inflation followed by ventilation leads to rapid cardiorespiratory recovery but causes cerebral vascular leakage in asphyxiated near-term lambs
.
PLoS One
.
2016
;
11
(
1
):
e0146574
25
Sobotka
KS
,
Polglase
GR
,
Schmölzer
GM
,
Davis
PG
,
Klingenberg
C
,
Hooper
SB
.
Effects of chest compressions on cardiovascular and cerebral hemodynamics in asphyxiated near-term lambs
.
Pediatr Res
.
2015
;
78
(
4
):
395
400
26
Sobotka
KS
,
Ong
T
,
Polglase
GR
,
Crossley
KJ
,
Moss
TJ
,
Hooper
SB
.
The effect of oxygen content during an initial sustained inflation on heart rate in asphyxiated near-term lambs
.
Arch Dis Child Fetal Neonatal Ed
.
2015
;
100
(
4
):
F337
F343
27
Chandrasekharan
P
,
Vali
P
,
Rawat
M
, et al
.
Continuous capnography monitoring during resuscitation in a transitional large mammalian model of asphyxial cardiac arrest
.
Pediatr Res
.
2017
;
81
(
6
):
898
904
28
Vali
P
,
Chandrasekharan
P
,
Rawat
M
, et al
.
Continuous chest compressions during sustained inflations in a perinatal asphyxial cardiac arrest lamb model
.
Pediatr Crit Care Med
.
2017
;
18
(
8
):
e370
e377
29
Rawat
M
,
Chandrasekharan
P
,
Gugino
S
, et al
.
Oxygenation and hemodynamics during chest compressions in a lamb model of perinatal asphyxia induced cardiac arrest
.
Children (Basel)
.
2019
;
6
(
4
):
52
30
Polglase
GR
,
Schmölzer
GM
,
Roberts
CT
, et al
.
Cardiopulmonary resuscitation of asystolic newborn lambs prior to umbilical cord clamping; the timing of cord clamping matters!
.
Front Physiol
.
2020
;
11
:
902
31
Wyllie
J
,
Bruinenberg
J
,
Roehr
CC
,
Rüdiger
M
,
Trevisanuto
D
,
Urlesberger
B
.
European resuscitation council guidelines for resuscitation 2015: section 7. Resuscitation and support of transition of babies at birth
.
Resuscitation
.
2015
;
95
:
249
263
32
Wyckoff
MH
,
Aziz
K
,
Escobedo
MB
, et al
.
Part 13: neonatal resuscitation: 2015 American heart association guidelines update for cardiopulmonary resuscitation and emergency cardiovascular care
.
Circulation
.
2015
;
132
(
18
suppl 2
):
S543
S560
33
Vali
P
,
Sankaran
D
,
Rawat
M
,
Berkelhamer
S
,
Lakshminrusimha
S
.
Epinephrine in neonatal resuscitation
.
Children (Basel)
.
2019
;
6
(
4
):
E51
34
McNamara
PJ
,
Engelberts
D
,
Finelli
M
,
Adeli
K
,
Kavanagh
BP
.
Vasopressin improves survival compared with epinephrine in a neonatal piglet model of asphyxial cardiac arrest
.
Pediatr Res
.
2014
;
75
(
6
):
738
748
35
Prengel
AW
,
Linstedt
U
,
Zenz
M
,
Wenzel
V
.
Effects of combined administration of vasopressin, epinephrine, and norepinephrine during cardiopulmonary resuscitation in pigs
.
Crit Care Med
.
2005
;
33
(
11
):
2587
2591
36
Alves de Alencar Rocha
AK
,
Allison
BJ
,
Yawno
T
, et al
.
Early- versus late-onset fetal growth restriction differentially affects the development of the fetal sheep brain
.
Dev Neurosci
.
2017
;
39
(
1–4
):
141
155
37
Polglase
GR
,
Allison
BJ
,
Coia
E
, et al
.
Altered cardiovascular function at birth in growth-restricted preterm lambs
.
Pediatr Res
.
2016
;
80
(
4
):
538
546
38
Allison
BJ
,
Hooper
SB
,
Coia
E
, et al
.
Ventilation-induced lung injury is not exacerbated by growth restriction in preterm lambs
.
Am J Physiol Lung Cell Mol Physiol
.
2016
;
310
(
3
):
L213
L223
39
Malhotra
A
,
Castillo-Melendez
M
,
Allison
BJ
, et al
.
Neuropathology as a consequence of neonatal ventilation in premature growth-restricted lambs
.
Am J Physiol Regul Integr Comp Physiol
.
2018
;
315
(
6
):
R1183
R1194
40
Malhotra
A
,
Miller
SL
,
Jenkin
G
, et al
.
Fetal growth restriction is associated with an altered cardiopulmonary and cerebral hemodynamic response to surfactant therapy in preterm lambs
.
Pediatr Res
.
2019
;
86
(
1
):
47
54
41
Abman
SH
,
Shanley
PF
,
Accurso
FJ
.
Failure of postnatal adaptation of the pulmonary circulation after chronic intrauterine pulmonary hypertension in fetal lambs
.
J Clin Invest
.
1989
;
83
(
6
):
1849
1858
42
Goldberg
SJ
,
Levy
RA
,
Siassi
B
,
Betten
J
.
The effects of maternal hypoxia and hyperoxia upon the neonatal pulmonary vasculature
.
Pediatrics
.
1971
;
48
(
4
):
528
533
43
Rabinovitch
M
,
Gamble
W
,
Nadas
AS
,
Miettinen
OS
,
Reid
L
.
Rat pulmonary circulation after chronic hypoxia: hemodynamic and structural features
.
Am J Physiol
.
1979
;
236
(
6
):
H818
H827
44
Allison
BJ
,
Brain
KL
,
Niu
Y
, et al
.
Fetal in vivo continuous cardiovascular function during chronic hypoxia
.
J Physiol
.
2016
;
594
(
5
):
1247
1264
45
Brain
KL
,
Allison
BJ
,
Niu
Y
, et al
.
Induction of controlled hypoxic pregnancy in large mammalian species
.
Physiol Rep
.
2015
;
3
(
12
):
e12614
46
Tare
M
,
Parkington
HC
,
Wallace
EM
, et al
.
Maternal melatonin administration mitigates coronary stiffness and endothelial dysfunction, and improves heart resilience to insult in growth restricted lambs
.
J Physiol
.
2014
;
592
(
12
):
2695
2709
47
Hung
MW
,
Yeung
HM
,
Lau
CF
,
Poon
AMS
,
Tipoe
GL
,
Fung
ML
.
Melatonin attenuates pulmonary hypertension in chronically hypoxic rats
.
Int J Mol Sci
.
2017
;
18
(
6
):
1125
48
Gebauer
CM
,
Knuepfer
M
,
Robel-Tillig
E
,
Pulzer
F
,
Vogtmann
C
.
Hemodynamics among neonates with hypoxic-ischemic encephalopathy during whole-body hypothermia and passive rewarming
.
Pediatrics
.
2006
;
117
(
3
):
843
850
49
Jacobs
SE
,
Berg
M
,
Hunt
R
,
Tarnow-Mordi
WO
,
Inder
TE
,
Davis
PG
.
Cooling for newborns with hypoxic ischaemic encephalopathy
.
Cochrane Database Syst Rev
.
2013
;(
1
):
CD003311
50
Shah
P
,
Riphagen
S
,
Beyene
J
,
Perlman
M
.
Multiorgan dysfunction in infants with post-asphyxial hypoxic-ischaemic encephalopathy
.
Arch Dis Child Fetal Neonatal Ed
.
2004
;
89
(
2
):
F152
F155
51
Azzopardi
DV
,
Strohm
B
,
Edwards
AD
, et al.;
TOBY Study Group
.
Moderate hypothermia to treat perinatal asphyxial encephalopathy
.
N Engl J Med
.
2009
;
361
(
14
):
1349
1358
52
Giesinger
RE
,
Bailey
LJ
,
Deshpande
P
,
McNamara
PJ
.
Hypoxic-ischemic encephalopathy and therapeutic hypothermia: the hemodynamic perspective
.
J Pediatr
.
2017
;
180
:
22
30.e2
53
Fernandez
E
,
Schrader
R
,
Watterberg
K
.
Prevalence of low cortisol values in term and near-term infants with vasopressor-resistant hypotension
.
J Perinatol
.
2005
;
25
(
2
):
114
118
54
Kluckow
M
.
Functional echocardiography in assessment of the cardiovascular system in asphyxiated neonates
.
J Pediatr
.
2011
;
158
(
2
suppl
):
e13
e18
55
Sehgal
A
,
Wong
F
,
Mehta
S
.
Reduced cardiac output and its correlation with coronary blood flow and troponin in asphyxiated infants treated with therapeutic hypothermia
.
Eur J Pediatr
.
2012
;
171
(
10
):
1511
1517
56
Koestenberger
M
,
Avian
A
,
Cantinotti
M
,
Hansmann
G
;
European Pediatric Pulmonary Vascular Disease Network
.
Tricuspid annular plane systolic excursion (TAPSE) in pediatric pulmonary hypertension: integrating right ventricular ejection efficiency (RVEe) into advanced multi-parametric imaging
.
Int J Cardiol
.
2019
;
274
:
296
298
57
Nestaas
E
,
Støylen
A
,
Brunvand
L
,
Fugelseth
D
.
Longitudinal strain and strain rate by tissue Doppler are more sensitive indices than fractional shortening for assessing the reduced myocardial function in asphyxiated neonates
.
Cardiol Young
.
2011
;
21
(
1
):
1
7
58
Sehgal
A
,
Wong
F
,
Menahem
S
.
Speckle tracking derived strain in infants with severe perinatal asphyxia: a comparative case control study
.
Cardiovasc Ultrasound
.
2013
;
11
:
34
59
Czernik
C
,
Rhode
S
,
Helfer
S
,
Schmalisch
G
,
Bührer
C
.
Left ventricular longitudinal strain and strain rate measured by 2-D speckle tracking echocardiography in neonates during whole-body hypothermia
.
Ultrasound Med Biol
.
2013
;
39
(
8
):
1343
1349
60
Nestaas
E
,
Skranes
JH
,
Støylen
A
,
Brunvand
L
,
Fugelseth
D
.
The myocardial function during and after whole-body therapeutic hypothermia for hypoxic-ischemic encephalopathy, a cohort study
.
Early Hum Dev
.
2014
;
90
(
5
):
247
252
61
Costa
S
,
Zecca
E
,
De Rosa
G
, et al
.
Is serum troponin T a useful marker of myocardial damage in newborn infants with perinatal asphyxia?
Acta Paediatr
.
2007
;
96
(
2
):
181
184
62
VanLoozen
DH
,
Murdison
KA
,
Polimenakos
AC
.
Neonatal myocardial perfusion in right ventricle dependent coronary circulation: clinical surrogates and role of troponin-I in postoperative management following systemic-to-pulmonary shunt physiology
.
Pediatr Cardiol
.
2018
;
39
(
7
):
1496
1499
63
Shah
PS
,
Ohlsson
A
,
Perlman
M
.
Hypothermia to treat neonatal hypoxic ischemic encephalopathy: systematic review
.
Arch Pediatr Adolesc Med
.
2007
;
161
(
10
):
951
958
64
Benumof
JL
,
Wahrenbrock
EA
.
Dependency of hypoxic pulmonary vasoconstriction on temperature
.
J Appl Physiol
.
1977
;
42
(
1
):
56
58
65
Giesinger
RE
,
El Shahed
AI
,
Castaldo
MP
, et al
.
Impaired right ventricular performance is associated with adverse outcome after hypoxic ischemic encephalopathy
.
Am J Respir Crit Care Med
.
2019
;
200
(
10
):
1294
1305
66
Sehgal
A
,
Linduska
N
,
Huynh
C
.
Cardiac adaptation in asphyxiated infants treated with therapeutic hypothermia
.
J Neonatal Perinatal Med
.
2019
;
12
(
2
):
117
125
67
Kent
AL
,
Kecskes
Z
,
Shadbolt
B
,
Falk
MC
.
Normative blood pressure data in the early neonatal period
.
Pediatr Nephrol
.
2007
;
22
(
9
):
1335
1341
68
Satoh
M
,
Inoue
R
,
Tada
H
, et al
.
Reference values and associated factors for Japanese newborns’ blood pressure and pulse rate: the Babies’ and Their Parents’ Longitudinal Observation in Suzuki Memorial Hospital on Intrauterine Period (BOSHI) study
.
J Hypertens
.
2016
;
34
(
8
):
1578
1585
69
Jain
A
,
Sahni
M
,
El-Khuffash
A
,
Khadawardi
E
,
Sehgal
A
,
McNamara
PJ
.
Use of targeted neonatal echocardiography to prevent postoperative cardiorespiratory instability after patent ductus arteriosus ligation
.
J Pediatr
.
2012
;
160
(
4
):
584
589.e1
70
de Boode
WP
,
Singh
Y
,
Molnar
Z
, et al.;
European Special Interest Group “Neonatologist Performed Echocardiography” (NPE)
.
Application of Neonatologist Performed Echocardiography in the assessment and management of persistent pulmonary hypertension of the newborn
.
Pediatr Res
.
2018
;
84
(
suppl 1
):
68
77
71
Giesinger
RE
,
Stanford
AH
,
Rios
DR
, et al.;
United States Hemodynamics Collaborative
.
Targeted neonatal echocardiography in the United States of America: the contemporary perspective and challenges to implementation
.
Pediatr Res
.
2019
;
85
(
7
):
919
921
72
Lausman
A
,
Kingdom
J
;
Maternal Fetal Medicine Committee
.
Intrauterine growth restriction: screening, diagnosis, and management
.
J Obstet Gynaecol Can
.
2013
;
35
(
8
):
741
748
73
Garite
TJ
,
Clark
R
,
Thorp
JA
.
Intrauterine growth restriction increases morbidity and mortality among premature neonates
.
Am J Obstet Gynecol
.
2004
;
191
(
2
):
481
487
74
Rosenberg
A
.
The IUGR newborn
.
Semin Perinatol
.
2008
;
32
(
3
):
219
224
75
Sehgal
K
,
Sehgal
K
,
Tan
K
,
Sehgal
A
.
Impaired in-utero growth: an important risk factor for chronic lung disease [abstract]. Pediatric Academic Society
.
2019
;
E-PAS2019
:
442
76
Sehgal
A
,
Alexander
BT
,
Morrison
JL
,
South
AM
.
Fetal growth restriction and hypertension in the offspring: mechanistic links and therapeutic directions
.
J Pediatr
.
2020
;
224
:
115
123.e2
77
Sehgal
A
,
Murthi
P
,
Dahlstrom
JE
.
Vascular changes in fetal growth restriction: clinical relevance and future therapeutics
.
J Perinatol
.
2019
;
39
(
3
):
366
374
78
Sehgal
A
,
Dahlstrom
JE
,
Chan
Y
,
Allison
BJ
,
Miller
SL
,
Polglase
GR
.
Placental histopathology in preterm fetal growth restriction
.
J Paediatr Child Health
.
2019
;
55
(
5
):
582
587
79
Franklin
AD
,
Saqibuddin
J
,
Stephens
K
, et al
.
Cord blood alpha klotho is decreased in small for gestational age preterm infants with placental lesions of accelerated aging
.
Placenta
.
2019
;
87
:
1
7
80
Sehgal
A
,
Gwini
SM
,
Menahem
S
,
Allison
BJ
,
Miller
SL
,
Polglase
GR
.
Preterm growth restriction and bronchopulmonary dysplasia: the vascular hypothesis and related physiology
.
J Physiol
.
2019
;
597
(
4
):
1209
1220
81
Zanardo
V
,
Fanelli
T
,
Weiner
G
, et al
.
Intrauterine growth restriction is associated with persistent aortic wall thickening and glomerular proteinuria during infancy
.
Kidney Int
.
2011
;
80
(
1
):
119
123
82
Sehgal
A
,
Allison
BJ
,
Gwini
SM
,
Menahem
S
,
Miller
SL
,
Polglase
GR
.
Vascular aging and cardiac maladaptation in growth-restricted preterm infants
.
J Perinatol
.
2018
;
38
(
1
):
92
97
83
Sehgal
A
,
Bhatia
R
,
Roberts
CT
.
Cardiovascular response and sequelae after minimally invasive surfactant therapy in growth-restricted preterm infants
.
J Perinatol
.
2020
;
40
(
8
):
1178
1184
84
Bose
C
,
Van Marter
LJ
,
Laughon
M
, et al
;
Extremely Low Gestational Age Newborn Study Investigators
.
Fetal growth restriction and chronic lung disease among infants born before the 28th week of gestation
.
Pediatrics
.
2009
;
124
(
3
).
85
Keller
RL
,
Feng
R
,
DeMauro
SB
, et al.;
Prematurity and Respiratory Outcomes Program
.
Bronchopulmonary dysplasia and perinatal characteristics predict 1-year respiratory outcomes in newborns born at extremely low gestational age: a prospective cohort study
.
J Pediatr
.
2017
;
187
:
89
97.e3
86
Turan
S
,
Turan
OM
,
Salim
M
, et al
.
Cardiovascular transition to extrauterine life in growth-restricted neonates: relationship with prenatal Doppler findings
.
Fetal Diagn Ther
.
2013
;
33
(
2
):
103
109
87
Crispi
F
,
Hernandez-Andrade
E
,
Pelsers
MM
, et al
.
Cardiac dysfunction and cell damage across clinical stages of severity in growth-restricted fetuses
.
Am J Obstet Gynecol
.
2008
;
199
(
3
):
254.e1
-
254.e8
88
Sehgal
A
,
Allison
BJ
,
Gwini
SM
,
Miller
SL
,
Polglase
GR
.
Cardiac morphology and function in preterm growth restricted infants: relevance for clinical sequelae
.
J Pediatr
.
2017
;
188
:
128
134.e2
89
Sehgal
A
,
Doctor
T
,
Menahem
S
.
Cardiac function and arterial biophysical properties in small for gestational age infants: postnatal manifestations of fetal programming
.
J Pediatr
.
2013
;
163
(
5
):
1296
1300
90
Fouzas
S
,
Karatza
AA
,
Davlouros
PA
, et al
.
Neonatal cardiac dysfunction in intrauterine growth restriction
.
Pediatr Res
.
2014
;
75
(
5
):
651
657
91
Rodriguez-Lopez
M
,
Osorio
L
,
Acosta-Rojas
R
, et al
.
Influence of breastfeeding and postnatal nutrition on cardiovascular remodeling induced by fetal growth restriction
.
Pediatr Res
.
2016
;
79
(
1–1
):
100
106
92
Gitto
E
,
Reiter
RJ
,
Cordaro
SP
, et al
.
Oxidative and inflammatory parameters in respiratory distress syndrome of preterm newborns: beneficial effects of melatonin
.
Am J Perinatol
.
2004
;
21
(
4
):
209
216
93
Gitto
E
,
Reiter
RJ
,
Amodio
A
, et al
.
Early indicators of chronic lung disease in preterm infants with respiratory distress syndrome and their inhibition by melatonin
.
J Pineal Res
.
2004
;
36
(
4
):
250
255

Competing Interests

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

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