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Cardiovascular adaptation to extra uterine life
SYMPOSIUM: CARDIOVASCULAR
Cardiovascular adaptation to extra uterine life
causes vasoconstriction by elevating intracellular calcium and stimulation of ETB causes vasodilatation, although a further complexity is added with a feedback loop. The hypoxic fetal condition also inhibits the production of vasodilating nitric oxide and prostaglandins.
Alice Lawford Robert MR Tulloh
Abnormal fetal development A number of maternal risk factors increase the likelihood of abnormal circulatory changes after birth. For example nonsteroidal anti-inflammatory medication use tends to lead to premature closure of the ductus arteriosus with resultant pulmonary hypertension after birth and use of selective serotonin reuptake inhibitors (SSRI) can lead to persistent pulmonary hypertension. Maternal lithium use can lead to the structural congenital cardiac abnormality of Ebstein anomaly. Maternal diabetes leads to an increased risk of congenital heart disease; ventricular septal defect and transposition of the great arteries and also to hypertrophic cardiomyopathy (Box 2).
Abstract The adaptation to extra uterine life is of interest because of its complexity and the ability to cause significant health concerns. In this article we describe the normal changes that occur and the commoner abnormalities that are due to failure of normal development and the effect of congenital cardiac disease. Abnormal development may occur as a result of problems with the mother, or with the fetus before birth. After birth it is essential to determine whether there is an underlying abnormality of the fetal pulmonary or cardiac development and to determine the best course of management of pulmonary hypertension or congenital cardiac disease. Causes of under-development, mal-development and mal-adaptation are described as are the causes of critical congenital heart disease. The methods of diagnosis and management are described to allow the neonatologist to successfully manage such newborns.
Antenatal diagnosis Antenatal examination of the fetal heart can lead to the diagnosis of up to 70% of children who will require surgery in the first 6 months of life. In developed countries this examination is now a routine part of the fetal anomaly scan that takes place between 18 and 20 weeks’ gestation. It is particularly important for fetuses that may be at an increased risk of CHD. These include those with suspected Down’s syndrome or whose mothers or elder siblings have had CHD. In cases where a cardiac abnormality is detected, a paediatric cardiologist should perform detailed fetal echocardiography. Early diagnosis of CHD allows counselling to be provided for the parents and for antenatal management to be planned for the baby. In a minority of cases, the parents may decide to terminate the pregnancy. In the case of neonates with critical CHD and duct-dependent lesions who are likely to need
Keywords critical congenital heart disease; fetal circulation; nitric oxide; persistent pulmonary hypertension; pulmonary hypertension; sildenafil
Fetal life Normal fetal circulation In fetal life, the placenta supplies oxygenated blood via the umbilical vein to the circulation, 50% enters the hepatic circulation and 50% bypasses the liver via the ductus venosus and flows into the inferior vena cava, and then the right atrium. From here it flows through the foramen ovale to the left ventricle and hence to the cerebral and coronary circulation. Relatively deoxygenated blood flows from the cerebral and upper limb circulations to the right atrium but directed through the tricuspid valve, from the right ventricle to the pulmonary artery. Only 15% enters the fetal lungs, these are filled with fluid and mainly bypassed in the circulation because of the high pulmonary vascular resistance, blood flowing instead via the arterial duct to the feet. Then umbilical arteries supply the placenta ready for gas exchange to take place (Box 1).
Fetal vascular structures that exist to direct blood flow
Control of fetal pulmonary vascular tone The pulmonary vascular tone is high in the fetus and maintained by the presence of fetal lung fluid, low oxygen tension, and vasoactive factors such as endothelin-1 (ET1), platelet activating factor (PAF), reactive oxygen species (ROS), and increased Rho A-Rho Kinase (RhoA-ROK) signalling. ET1 is the predominant Endothelin in the pulmonary vascular endothelial cells and binds to ETA and ETB receptors. Stimulation of ETA
Fetal structure
Function
Arterial duct
Connects pulmonary artery to the aorta and shunts blood right to left; diverting flow away from fetal lungs Opening between the two atria that directs blood flow returning to right atrium through the septal wall into the left atrium bypassing lungs Receives oxygenated blood from umbilical vein and directs it to the inferior vena cava and right atrium Carrying deoxygenated blood from the fetus to the placenta Carrying oxygenated blood from the placenta to the fetus
Foramen ovale
Ductus venosus
Umbilical arteries Umbilical vein
Alice Lawford MB ChB ST2 Bristol Royal Hospital for Children, Bristol, UK. Robert M R Tulloh DM FRCPCH is Professor and Consultant in the Department of Congenital Heart Disease, Bristol Royal Hospital for Children, Bristol, UK.
PAEDIATRICS AND CHILD HEALTH 25:1
BOX 1
1
Ó 2014 Elsevier Ltd. All rights reserved.
SYMPOSIUM: CARDIOVASCULAR
At birth with the first breath the lungs are filled with air and there is an abrupt increase in pulmonary blood flow, creating a shear stress with in the vessel wall. Shear stress and oxygenation stimulate endothelial nitric oxide synthase and up-regulate its expression. Oxygenation also inhibits the enzymatic activity of phosphodiesterase 5 (PDE5) that breaks down cyclic GMP in order to terminate its activity. This and other inhibitors of PDE5 therefore increase the effectiveness of endogenous nitric oxide to cause vasodilatation. Another pathway of pulmonary vasodilatation is through the production of prostaglandins by the endothelium. Oxygenation stimulates production of prostaglandin (mostly prostacyclin PGI2) from arachidonic acid with cyclooxygenase (COX) as the rate-limiting step. This causes vaso-relaxation but the decrease in PVR caused is less than that seen with NO. In addition to NO and PGI2, oxygenation results in pulmonary dilatation via activation of potassium channel and reduction in calcium channel activity in pulmonary artery smooth muscles. At the first breath, the decreased pulmonary vascular resistance (PVR) leads to increased pulmonary blood flow of deoxygenated blood from the right ventricle. This increased blood flow leads to a delivery of oxygen rich blood from pulmonary veins to the left atrium, with resultant closure of the foramen ovale as the septum primum rests against the septum secundum and separates the two atria. The high concentration of oxygen in the arterial blood along with a fall in prostaglandins causes constriction of the ductus arteriosus. The cardiac output nearly doubles corresponding to the marked rise in oxygen consumption. The blood supply from the placenta is interrupted, both via vasoconstriction and from clamping of the cord that results in an increase in systemic vascular resistance. The ductus venosus closes as the flow dwindles in the umbilical vein. The right and left sides of the heart are now connected in series rather than in parallel. Although initially rapid, these changes consolidate over the next 2e3 weeks. Functional closure of the ductus occurs in the first 60 hours of life in the majority of term babies, but anatomic closure may not occur until 2e3 weeks of age because of prematurity, acidosis, and hypoxia.
Maternal causes of congenital heart disease Maternal disorders Rubella infection Systemic lupus (SLE) Diabetes mellitus Maternal drug use Warfarin therapy Fetal alcohol syndrome Chromosomal abnormality Down’s syndrome (trisomy 21) Edward syndrome (trisomy 18) Patau syndrome (trisomy 13) Turner syndrome (45XO) Chromosome 22q11.2 deletion Williams syndrome (7q11.23 microdeletion) Noonan syndrome (PTPN11 mutation and others)
Peripheral stenosis, PDA Complete heart block (anti-Ro and anti-La antibody)
Pulmonary valve stenosis, PDA ASD, VSD, tetralogy of Fallot Atrio-ventricular septal defect, VSD Complex CHD Complex CHD Aortic valve stenosis, coarctation of the aorta Aortic arch anomalies, tetralogy of Fallot, common arterial trunk Supravalvular aortic stenosis, peripheral pulmonary artery stenosis Hypertrophic cardiomyopathy, atrial septal defect, pulmonary valve stenosis
ASD, atrial septal defect; CHD, congenital heart disease; PDA, persistent ductus arteriosus; VSD, ventricular septal defect.
BOX 2
treatment within the first 2 days of life, parents may be offered the option of delivery at or close to the cardiac centre. Abnormal circulatory changes at birth Congenital heart disease: the closure of a patent duct in critical congenital heart disease can precipitate rapid clinical deterioration, i.e. severe metabolic acidosis, seizures, shock, collapse and cardiac arrest. Congenital heart disease (CHD) is the most common congenital disorder in newborns. It occurs when there is failure of normal cardiac development or persistence of the fetal circulation after birth. The incidence is reported at 8 per 1000 live births. 25% of those with CHD have critical CHD requiring life saving surgery or catheter based intervention in the first year of life. The challenge is detecting for which neonates this is. Cases are increasingly being detected antenatally with routine screening as imaging modalities enhance. However many are missed and not symptomatic until shortly after birth and even after discharge from the birth hospitalisation. A normal neonatal examination does not exclude life threatening cardiac malformation, especially those with ductal dependent lesions, where pulmonary or systemic circulation is supplied solely by flow through the duct.
Changes that occur at birth Normal circulatory changes at birth The most dramatic physiological events related to birth are the switch from placenta to the lung as the organ of gas exchange. This is a highly co-ordinated process reliant on cortisol and vasoactive catecholamine to facilitate the transition (Figure 1). Fetal breathing movements generate trans-pulmonary pressures of up to 30 cm of water, demonstrating that they are capable aerating the lungs after birth. Activation of chemoreceptors by an increase in arterial carbon dioxide and physical stimuli such as light, heat and handling, trigger the onset of regular inspiratory efforts. Hypoxia increasingly stimulates respiratory drive in the newborn due a change in oxygen sensitivity, which increases in the weeks after birth. The trans-pulmonary pressure gradients generated during inspiration are likely to be primarily responsible for the rapid clearance of airway liquid immediately after birth allowing further expansion of the alveoli and a further reduction in the pulmonary vascular resistance.
PAEDIATRICS AND CHILD HEALTH 25:1
2
Ó 2014 Elsevier Ltd. All rights reserved.
SYMPOSIUM: CARDIOVASCULAR
Figure 1 Fetal and Neonatal Circulation e The fetal circulation is specifically adapted to efficiently exchange gases, nutrients, and wastes through placental circulation. Upon birth, the shunts (foramen ovale, ductus arteriosus, and ductus venosus) close and the placental circulation is disrupted, producing the series circulation of blood through the lungs, left atrium, left ventricle, systemic circulation, right heart, and back to the lungs. Copyright 2014 Elsevier Inc. All rights reserved. www.netterimages.com. F. Netter M.D.
In infants with a critical cardiac lesion, the risk of morbidity and mortality increases when there is a delay in diagnosis and timely referral to a tertiary centre with expertise in treating these conditions. CHD may also present at any time from birth to adult life, it is thus important that paediatricians are alert to it as a potential diagnosis, the need for early assessment and potential urgency for intervention. It is helpful to consider duct-dependent
PAEDIATRICS AND CHILD HEALTH 25:1
lesions as being either duct-dependent systemic (Box 3) or ductdependent pulmonary circulations (Box 4). Typically these present as the duct closes on the second day of life. Common mixing problems may present even earlier (Box 5). Duct dependent systemic circulation: with early discharge from hospital in many healthcare settings these lesions are typically
3
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SYMPOSIUM: CARDIOVASCULAR
undetected prior to discharge from hospital as the arterial duct initially remains patent. They usually present on day 2 of life as the duct closes. These babies have decreased peripheral perfusion as outflow from the left side of the heart is critically obstructed. They become collapsed secondary to cardiogenic shock with a metabolic acidosis, severe hypoxaemia, decreased pulses and resultant end organ damage. Neonates may also present with heart failure (tachypnoea, tachycardia, respiratory distress, hepatomegaly, sweating, and cardiomegaly) in the first week of life. Heart failure at this time is almost never due to left to right shunt, but almost always due to an obstructed systemic circulation.
Duct-dependent pulmonary circulation Duct-dependent pulmonary circulation (‘sick’ in first few days of life) C Transposition of great arteries (failure of mixing e common) C Critical pulmonary stenosis (less common) C Tetralogy of Fallot (more often not duct-dependent) C Pulmonary atresia with or without VSD (rare) C Tricuspid atresia with pulmonary atresia (rare) Box 4
babies from collapsing as the duct closes. A full discussion about the diagnosis and management of such conditions is beyond the scope of this article. It is however important to emphasize that there is little to lose by starting a prostaglandin infusion in a baby that is unwell and heart disease is suspected. Even though prostaglandin is not beneficial in total anomalous pulmonary venous connection, neither will any harm be caused. In this condition, all the pulmonary veins have an abnormal connection to the heart causing the neonate to be cyanosed and sometimes collapsed, the treatment is therefore urgent surgical operation. As already discussed, infants with critical CHD may present suddenly with serious life threatening clinical findings that require immediate intervention. Nevertheless, it is often difficult to differentiate CHD from pulmonary disease, sepsis or metabolic conditions when presented with a critically ill newborn. Below we provide a structure for the immediate approach to the sick newborn with possible CHD in the first few days of life (Box 6).
Duct-dependent pulmonary circulation: these are critically obstructed right heart lesions and occur when the arterial duct is the only route of pulmonary blood flow. These neonates will usually present in the first 2 days of life with progressive cyanosis, hypoxia, tachypnoea, acidosis and eventual collapse. Severity often depends on the degree of mixing which can occur between the systemic and pulmonary circulations through coexisting defects, atrial septal defect/foramen ovale, or ventricular septal defect. As these communications become smaller, the more cyanosed and unwell the baby will become. Some will persist due to abnormal connections from the aorta to the pulmonary circulation (collaterals or MAPCAs [major aortopulmonary collateral arteries]). Common mixing lesions: in the common mixing lesions, desaturated blood shunts from the right to the left side of the heart or with abnormal mixing of systemic and pulmonary venous return. These conditions present at birth with cyanosis due to high PVR and an initial right to left shunt. As the pulmonary vascular resistance falls, heart failure often becomes clinically evident after the first week of life as the amount of left to right shunt increases. In total anomalous pulmonary venous connection (TAPVC) the severity of symptoms and time of presentation depends upon the degree of obstruction of pulmonary venous return.
Persistent ductus arteriosus Problems can be seen after the neonatal period when fetal structures remain patent in an otherwise structurally normal neonate, such as the persistent ductus arteriosus (PDA). Ductal patency is common in preterm babies and becomes problematic in infants if still persistent at 6 weeks of age since spontaneous closure after this time is then rare. As the pulmonary vascular resistance lowers after birth, blood shunts from left to right through a PDA. If the PDA is large this can lead to heart failure, poor growth and even pulmonary haemorrhage. Clinically babies will have full or bounding pulses, a continuous murmur, and a hyperdynamic precordium. In preterm asymptomatic neonates, observation is all that is required as the majority close spontaneously. In symptomatic neonates with heart failure and/or ventilator dependence;
Management of duct-dependent circulations In those conditions with duct-dependent left (systemic) or right (pulmonary) circulation obstruction, a prostaglandin infusion is important to ensure survival. Prostaglandins E1 and E2 will both maintain patency and even dilate the arterial duct up to about 2 weeks of life; allowing maintenance of systemic and pulmonary blood flow in such neonates. In many babies, there is antenatal diagnosis of critical CHD, allowing elective and planned commencement of prostaglandin soon after birth, preventing the
Non-duct-dependent lesions Non-duct-dependent lesions, common mixing C Tetralogy of Fallot (common, may also be duct-dependent) C Total anomalous pulmonary venous connection, TAPVC (less common) C Complete atrio-ventricular septal defect (less common) C Truncus arteriosus (rare) C Tricuspid atresia without pulmonary atresia C Ebstein anomaly (rare, severe forms can be duct-dependent)
Duct-dependent systemic circulation Duct-dependent systemic circulation (‘sick’ in first few days of life) C Coarctation of the aorta C Interrupted aortic arch C Critical aortic stenosis C Hypoplastic left heart syndrome Box 3
PAEDIATRICS AND CHILD HEALTH 25:1
Box 5
4
Ó 2014 Elsevier Ltd. All rights reserved.
SYMPOSIUM: CARDIOVASCULAR
In all of these, the pulmonary arteries fail to dilate normally, leading to high pulmonary vascular resistance (PVR), right to left shunt at the foramen ovale and the arterial duct and the resulting acidosis and hypoxaemia exacerbates the high PVR leading to a deteriorating cycle until intervention occurs.
General management of suspected critical congenital heart disease Resuscitation C Airway, breathing, circulation C Give oxygen until the diagnosis is made C Consider ventilator support if there are signs of respiratory failure C Consider inotropic medication if shocked C Consider prostaglandin infusion
Management of PPHN Clearly it is important to rule out critical congenital heart disease before embarking on treatment of PPHN. This can realistically only be undertaken by means of expert echocardiography as described above, although the hyperoxia test and the use of oxygen saturation measurement in the hand and foot have their part to play. Most importantly it is essential to rule out totally anomalous pulmonary venous connection that can present very similarly and often is mis-diagnosed as PPHN and vice-versa. Good ventilation is the key to good management. Oxygen is the most important therapy, usually necessitating intubation of the neonate. Maintenance of mild alkalosis and a low carbon dioxide level allows the endogenous nitric oxide to be more effective. Magnesium sulphate, usually as a bolus dose of 200 mg/Kg is an additional therapy that enhances the production of endogenous nitric oxide. Care has to be observed, since this can also impair ventricular function and inotropic infusion is required to increase the cardiac output. The logical inotrope would be a phosphodiesterase type 3 inhibitor such as milrinone due to its lusitropic and inodilating effect. However, a small dose of sympathomimetic vasopressor may be required to maintain an adequate blood pressure for organ perfusion. Inevitably inhaled nitric oxide is the next supplemental therapy to be considered, although care should be taken to ensure that the above therapies are commenced first. Low dose (3e20 ppm) nitric oxide is usually sufficient and can be started when the oxygen index is greater than 25. Evidence is also increasing that advanced pulmonary vasodilators may be effective such as phosphodiesterase inhibitors (such as sildenafil) or endothelin receptor antagonists (such as Bosentan). Prostacyclin (PGI2) is known to be effective in severe cases (either inhaled or intravenous) but again, caution should be exercised in order to avoid severe hypotension. The treatment of last resort is Extracorporeal membrane oxygenation (ECMO). This is complex, expensive and associated with long-term neurological morbidity. For a full review of PPHN management a longer text needs to be consulted.
History and examination C Aetiological factors (family history CHD, chromosomal abnormalities, maternal illnesses/infections/medications/substance use) C Symptoms of heart failure (poor feeding, sweating, respiratory distress, weight gain) and examination for signs of heart disease (cyanosis, heart failure, collapse, murmur) Initial investigations C Pulse oximetry e pre and post ductal saturations (significant if more than 3% difference) C Blood gas (assesses hypoxaemia, hyperoxia test, metabolic acidosis, and lactate) C Blood tests (blood count, coagulation screen, chromosomes) C Chest radiogram (to exclude respiratory disease) C ECG (rarely of much use in the neonate) C Hyperoxia test e (to differentiate between cardiac and respiratory causes of cyanosis) (Place the baby in 100% oxygen for 10 minutes and then take an arterial blood gas. If the cause of cyanosis is non-cardiac, then the PaO2 should be greater than 20 KPa.) C Echocardiogram Treatment C Consider antibiotics if there is suspicion of sepsis C Urgent discussion with cardiologist C Stabilization and transfer to a specialist cardiac centre Box 6
oxygenation should be optimized, fluids restricted and heart failure treated. Pharmacological or surgical closure should be considered.
Failure to adapt normally to extra uterine life Summary
In some babies there is a failure for the pulmonary vascular resistance to fall normally (persistent pulmonary hypertension of the newborn, PPHN). The incidence is about 1/1000 live births, and is related to lung under-development, mal-development and/ or mal-adaptation. Under-development occurs when the lungs are prevented from developing normally, for example in cases of oligohydramnios or diaphragmatic hernia. Mal-development describes a failure of the normal physiological processes described above which result in a gradual fall in pulmonary vascular resistance. This lead possible to idiopathic PPHN. Several genetic causes, such as FOXF1 mutation causing alveolar capillary dysplasia have now been described. Mal-adaptation occurs when the normal adaptation is prevented from occurring, such as with meconium aspiration or neonatal respiratory distress syndrome.
PAEDIATRICS AND CHILD HEALTH 25:1
The transition from a fetus to a newborn is the most complex physiologic adaptation that occurs in human experience. Knowledge of this process is key to understanding the physiology of early neonatal management and possible CHD. Early diagnosis with detection of PPHN or neonatal CHD remains challenging as prenatal screening does not reliably detect all cases. Timely identification of neonates with PPHN or critical CHD during the first few days, appropriate management and transfer to a specialist unit significantly reduces mortality. Paediatricians must be alert and aware of these critical presentations within the first few days of life as cardiovascular adaptation fails. Simple initial interventions may be life saving. We have discussed the physiology of neonatal cardiovascular adaptation to extra uterine
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Ó 2014 Elsevier Ltd. All rights reserved.
SYMPOSIUM: CARDIOVASCULAR
Singh A. Ewer AKPulse oximetry screening for critical congenital heart defects: a UK national survey. Lancet 2013; 381: 535. Tulloh R. Cardiac disorders. In: Lissauer T, Clayden T, eds. Illustrated textbook of paediatrics. 4th edn. China: Mosby, ISBN 9780723435655; 2011; 301e18. Vargo L. Cardiovascular assessment. In: Rait C, Rait SG, eds. Physical assessment of the newborn a comprehensive approach to the art of physical examination. 3rd edn. Santa Rosa, CA: NICU Ink, ISBN 1887571094; 2003; 81e95.
life and provided a brief overview of early presentations of CHD and the immediate management. A FURTHER READING Abu-Harb M, Wyllie J, Hey E, Richmond S, Wren C. Presentation of obstructive left heart malformations in infancy. Arch Dis Child Fetal Neonatal Ed 1994; 71: F179e83. Bali S, Tulloh R. Assessing the newborn circulation: what to look out for. Cure Care J Neonatal Intensive Care Oct 11, 2013. Carlgren LE, Ericson A, K€ allen B. Monitoring of congenital cardiac defects. Pediatr Cardiol 1987; 8: 247e56. Gao Y, Raj JU. Regulation of the pulmonary circulation in the fetus and newborn. Physiol Rev 2010; 90: 1291e335. http://dx.doi.org/10.1152/ physrev.00032.2009. Hoffman JL, Kaplan S. The incidence of congenital heart disease. J Am Coll Cardiol 2002; 39: 1890e900. Mahle W, Koppel R. Screening with pulse oximetry for congenital heart disease. Lancet 2011; 378: 749e50. http://dx.doi.org/10.1016/ S0140-6736(11)61032-5. online. Mellander M. Diagnosis and management of life-threatening cardiac malformations in the newborn. Seminars Neonatal Med 2013; 18: 302e10, http://dx.doi.org/10.1016/j.siny.2013.04.007. Mellander M, Sunnegardh J. Failure to diagnose critical heart malformations in newborns before discharge- an increasing problem? Acta Paediatr 2006; 95: 407e13. Pradat P, Francannet C, Harris JA, Robert E. The epidemiology of cardiovascular defects part 1: a study based on data from three large registries of congenital malformations. Pediatr Cardiol 2003; 24: 195e221. Puthiyachirakkal M, Mhanna M. Pathophysiology, management, and outcome of persistent pulmonary hypertension of the newborn: a clinical review. Front Pediatr 2013; 1: 23. PMCID: PMC3864198.
PAEDIATRICS AND CHILD HEALTH 25:1
Practice points C
C C C
C C
C C
C C
6
Knowledge of the concepts involved in the transition from fetal to neonatal life is valuable in understanding abnormalities in adaptation when underlying cardiac defects are present CHD is common, yet easily missed antenatally and postnatally Duct dependant conditions usually present at 2 days of life Timely prostaglandin infusion can re-open the duct up to 2 weeks of life and prevent development of shock, severe hypoxaemia, acidosis and resultant end organ damage Discuss cases of suspected CHD with a cardiologist Ensure good mechanical ventilation for early management of PPHN Exclude a critical CHD before diagnosis of PPHN Nitric oxide, sildenafil, endothelin receptor antagonist, prostacyclin might be used to treat PPHN Do not forget possible differential diagnoses Prompt diagnosis and subsequent transfer and intervention are essential to reduce the mortality associated with CHD
Ó 2014 Elsevier Ltd. All rights reserved.
Cardiovascular adaptation to extra uterine life
causes vasoconstriction by elevating intracellular calcium and stimulation of ETB causes vasodilatation, although a further complexity is added with a feedback loop. The hypoxic fetal condition also inhibits the production of vasodilating nitric oxide and prostaglandins.
Alice Lawford Robert MR Tulloh
Abnormal fetal development A number of maternal risk factors increase the likelihood of abnormal circulatory changes after birth. For example nonsteroidal anti-inflammatory medication use tends to lead to premature closure of the ductus arteriosus with resultant pulmonary hypertension after birth and use of selective serotonin reuptake inhibitors (SSRI) can lead to persistent pulmonary hypertension. Maternal lithium use can lead to the structural congenital cardiac abnormality of Ebstein anomaly. Maternal diabetes leads to an increased risk of congenital heart disease; ventricular septal defect and transposition of the great arteries and also to hypertrophic cardiomyopathy (Box 2).
Abstract The adaptation to extra uterine life is of interest because of its complexity and the ability to cause significant health concerns. In this article we describe the normal changes that occur and the commoner abnormalities that are due to failure of normal development and the effect of congenital cardiac disease. Abnormal development may occur as a result of problems with the mother, or with the fetus before birth. After birth it is essential to determine whether there is an underlying abnormality of the fetal pulmonary or cardiac development and to determine the best course of management of pulmonary hypertension or congenital cardiac disease. Causes of under-development, mal-development and mal-adaptation are described as are the causes of critical congenital heart disease. The methods of diagnosis and management are described to allow the neonatologist to successfully manage such newborns.
Antenatal diagnosis Antenatal examination of the fetal heart can lead to the diagnosis of up to 70% of children who will require surgery in the first 6 months of life. In developed countries this examination is now a routine part of the fetal anomaly scan that takes place between 18 and 20 weeks’ gestation. It is particularly important for fetuses that may be at an increased risk of CHD. These include those with suspected Down’s syndrome or whose mothers or elder siblings have had CHD. In cases where a cardiac abnormality is detected, a paediatric cardiologist should perform detailed fetal echocardiography. Early diagnosis of CHD allows counselling to be provided for the parents and for antenatal management to be planned for the baby. In a minority of cases, the parents may decide to terminate the pregnancy. In the case of neonates with critical CHD and duct-dependent lesions who are likely to need
Keywords critical congenital heart disease; fetal circulation; nitric oxide; persistent pulmonary hypertension; pulmonary hypertension; sildenafil
Fetal life Normal fetal circulation In fetal life, the placenta supplies oxygenated blood via the umbilical vein to the circulation, 50% enters the hepatic circulation and 50% bypasses the liver via the ductus venosus and flows into the inferior vena cava, and then the right atrium. From here it flows through the foramen ovale to the left ventricle and hence to the cerebral and coronary circulation. Relatively deoxygenated blood flows from the cerebral and upper limb circulations to the right atrium but directed through the tricuspid valve, from the right ventricle to the pulmonary artery. Only 15% enters the fetal lungs, these are filled with fluid and mainly bypassed in the circulation because of the high pulmonary vascular resistance, blood flowing instead via the arterial duct to the feet. Then umbilical arteries supply the placenta ready for gas exchange to take place (Box 1).
Fetal vascular structures that exist to direct blood flow
Control of fetal pulmonary vascular tone The pulmonary vascular tone is high in the fetus and maintained by the presence of fetal lung fluid, low oxygen tension, and vasoactive factors such as endothelin-1 (ET1), platelet activating factor (PAF), reactive oxygen species (ROS), and increased Rho A-Rho Kinase (RhoA-ROK) signalling. ET1 is the predominant Endothelin in the pulmonary vascular endothelial cells and binds to ETA and ETB receptors. Stimulation of ETA
Fetal structure
Function
Arterial duct
Connects pulmonary artery to the aorta and shunts blood right to left; diverting flow away from fetal lungs Opening between the two atria that directs blood flow returning to right atrium through the septal wall into the left atrium bypassing lungs Receives oxygenated blood from umbilical vein and directs it to the inferior vena cava and right atrium Carrying deoxygenated blood from the fetus to the placenta Carrying oxygenated blood from the placenta to the fetus
Foramen ovale
Ductus venosus
Umbilical arteries Umbilical vein
Alice Lawford MB ChB ST2 Bristol Royal Hospital for Children, Bristol, UK. Robert M R Tulloh DM FRCPCH is Professor and Consultant in the Department of Congenital Heart Disease, Bristol Royal Hospital for Children, Bristol, UK.
PAEDIATRICS AND CHILD HEALTH 25:1
BOX 1
1
Ó 2014 Elsevier Ltd. All rights reserved.
SYMPOSIUM: CARDIOVASCULAR
At birth with the first breath the lungs are filled with air and there is an abrupt increase in pulmonary blood flow, creating a shear stress with in the vessel wall. Shear stress and oxygenation stimulate endothelial nitric oxide synthase and up-regulate its expression. Oxygenation also inhibits the enzymatic activity of phosphodiesterase 5 (PDE5) that breaks down cyclic GMP in order to terminate its activity. This and other inhibitors of PDE5 therefore increase the effectiveness of endogenous nitric oxide to cause vasodilatation. Another pathway of pulmonary vasodilatation is through the production of prostaglandins by the endothelium. Oxygenation stimulates production of prostaglandin (mostly prostacyclin PGI2) from arachidonic acid with cyclooxygenase (COX) as the rate-limiting step. This causes vaso-relaxation but the decrease in PVR caused is less than that seen with NO. In addition to NO and PGI2, oxygenation results in pulmonary dilatation via activation of potassium channel and reduction in calcium channel activity in pulmonary artery smooth muscles. At the first breath, the decreased pulmonary vascular resistance (PVR) leads to increased pulmonary blood flow of deoxygenated blood from the right ventricle. This increased blood flow leads to a delivery of oxygen rich blood from pulmonary veins to the left atrium, with resultant closure of the foramen ovale as the septum primum rests against the septum secundum and separates the two atria. The high concentration of oxygen in the arterial blood along with a fall in prostaglandins causes constriction of the ductus arteriosus. The cardiac output nearly doubles corresponding to the marked rise in oxygen consumption. The blood supply from the placenta is interrupted, both via vasoconstriction and from clamping of the cord that results in an increase in systemic vascular resistance. The ductus venosus closes as the flow dwindles in the umbilical vein. The right and left sides of the heart are now connected in series rather than in parallel. Although initially rapid, these changes consolidate over the next 2e3 weeks. Functional closure of the ductus occurs in the first 60 hours of life in the majority of term babies, but anatomic closure may not occur until 2e3 weeks of age because of prematurity, acidosis, and hypoxia.
Maternal causes of congenital heart disease Maternal disorders Rubella infection Systemic lupus (SLE) Diabetes mellitus Maternal drug use Warfarin therapy Fetal alcohol syndrome Chromosomal abnormality Down’s syndrome (trisomy 21) Edward syndrome (trisomy 18) Patau syndrome (trisomy 13) Turner syndrome (45XO) Chromosome 22q11.2 deletion Williams syndrome (7q11.23 microdeletion) Noonan syndrome (PTPN11 mutation and others)
Peripheral stenosis, PDA Complete heart block (anti-Ro and anti-La antibody)
Pulmonary valve stenosis, PDA ASD, VSD, tetralogy of Fallot Atrio-ventricular septal defect, VSD Complex CHD Complex CHD Aortic valve stenosis, coarctation of the aorta Aortic arch anomalies, tetralogy of Fallot, common arterial trunk Supravalvular aortic stenosis, peripheral pulmonary artery stenosis Hypertrophic cardiomyopathy, atrial septal defect, pulmonary valve stenosis
ASD, atrial septal defect; CHD, congenital heart disease; PDA, persistent ductus arteriosus; VSD, ventricular septal defect.
BOX 2
treatment within the first 2 days of life, parents may be offered the option of delivery at or close to the cardiac centre. Abnormal circulatory changes at birth Congenital heart disease: the closure of a patent duct in critical congenital heart disease can precipitate rapid clinical deterioration, i.e. severe metabolic acidosis, seizures, shock, collapse and cardiac arrest. Congenital heart disease (CHD) is the most common congenital disorder in newborns. It occurs when there is failure of normal cardiac development or persistence of the fetal circulation after birth. The incidence is reported at 8 per 1000 live births. 25% of those with CHD have critical CHD requiring life saving surgery or catheter based intervention in the first year of life. The challenge is detecting for which neonates this is. Cases are increasingly being detected antenatally with routine screening as imaging modalities enhance. However many are missed and not symptomatic until shortly after birth and even after discharge from the birth hospitalisation. A normal neonatal examination does not exclude life threatening cardiac malformation, especially those with ductal dependent lesions, where pulmonary or systemic circulation is supplied solely by flow through the duct.
Changes that occur at birth Normal circulatory changes at birth The most dramatic physiological events related to birth are the switch from placenta to the lung as the organ of gas exchange. This is a highly co-ordinated process reliant on cortisol and vasoactive catecholamine to facilitate the transition (Figure 1). Fetal breathing movements generate trans-pulmonary pressures of up to 30 cm of water, demonstrating that they are capable aerating the lungs after birth. Activation of chemoreceptors by an increase in arterial carbon dioxide and physical stimuli such as light, heat and handling, trigger the onset of regular inspiratory efforts. Hypoxia increasingly stimulates respiratory drive in the newborn due a change in oxygen sensitivity, which increases in the weeks after birth. The trans-pulmonary pressure gradients generated during inspiration are likely to be primarily responsible for the rapid clearance of airway liquid immediately after birth allowing further expansion of the alveoli and a further reduction in the pulmonary vascular resistance.
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Figure 1 Fetal and Neonatal Circulation e The fetal circulation is specifically adapted to efficiently exchange gases, nutrients, and wastes through placental circulation. Upon birth, the shunts (foramen ovale, ductus arteriosus, and ductus venosus) close and the placental circulation is disrupted, producing the series circulation of blood through the lungs, left atrium, left ventricle, systemic circulation, right heart, and back to the lungs. Copyright 2014 Elsevier Inc. All rights reserved. www.netterimages.com. F. Netter M.D.
In infants with a critical cardiac lesion, the risk of morbidity and mortality increases when there is a delay in diagnosis and timely referral to a tertiary centre with expertise in treating these conditions. CHD may also present at any time from birth to adult life, it is thus important that paediatricians are alert to it as a potential diagnosis, the need for early assessment and potential urgency for intervention. It is helpful to consider duct-dependent
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lesions as being either duct-dependent systemic (Box 3) or ductdependent pulmonary circulations (Box 4). Typically these present as the duct closes on the second day of life. Common mixing problems may present even earlier (Box 5). Duct dependent systemic circulation: with early discharge from hospital in many healthcare settings these lesions are typically
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undetected prior to discharge from hospital as the arterial duct initially remains patent. They usually present on day 2 of life as the duct closes. These babies have decreased peripheral perfusion as outflow from the left side of the heart is critically obstructed. They become collapsed secondary to cardiogenic shock with a metabolic acidosis, severe hypoxaemia, decreased pulses and resultant end organ damage. Neonates may also present with heart failure (tachypnoea, tachycardia, respiratory distress, hepatomegaly, sweating, and cardiomegaly) in the first week of life. Heart failure at this time is almost never due to left to right shunt, but almost always due to an obstructed systemic circulation.
Duct-dependent pulmonary circulation Duct-dependent pulmonary circulation (‘sick’ in first few days of life) C Transposition of great arteries (failure of mixing e common) C Critical pulmonary stenosis (less common) C Tetralogy of Fallot (more often not duct-dependent) C Pulmonary atresia with or without VSD (rare) C Tricuspid atresia with pulmonary atresia (rare) Box 4
babies from collapsing as the duct closes. A full discussion about the diagnosis and management of such conditions is beyond the scope of this article. It is however important to emphasize that there is little to lose by starting a prostaglandin infusion in a baby that is unwell and heart disease is suspected. Even though prostaglandin is not beneficial in total anomalous pulmonary venous connection, neither will any harm be caused. In this condition, all the pulmonary veins have an abnormal connection to the heart causing the neonate to be cyanosed and sometimes collapsed, the treatment is therefore urgent surgical operation. As already discussed, infants with critical CHD may present suddenly with serious life threatening clinical findings that require immediate intervention. Nevertheless, it is often difficult to differentiate CHD from pulmonary disease, sepsis or metabolic conditions when presented with a critically ill newborn. Below we provide a structure for the immediate approach to the sick newborn with possible CHD in the first few days of life (Box 6).
Duct-dependent pulmonary circulation: these are critically obstructed right heart lesions and occur when the arterial duct is the only route of pulmonary blood flow. These neonates will usually present in the first 2 days of life with progressive cyanosis, hypoxia, tachypnoea, acidosis and eventual collapse. Severity often depends on the degree of mixing which can occur between the systemic and pulmonary circulations through coexisting defects, atrial septal defect/foramen ovale, or ventricular septal defect. As these communications become smaller, the more cyanosed and unwell the baby will become. Some will persist due to abnormal connections from the aorta to the pulmonary circulation (collaterals or MAPCAs [major aortopulmonary collateral arteries]). Common mixing lesions: in the common mixing lesions, desaturated blood shunts from the right to the left side of the heart or with abnormal mixing of systemic and pulmonary venous return. These conditions present at birth with cyanosis due to high PVR and an initial right to left shunt. As the pulmonary vascular resistance falls, heart failure often becomes clinically evident after the first week of life as the amount of left to right shunt increases. In total anomalous pulmonary venous connection (TAPVC) the severity of symptoms and time of presentation depends upon the degree of obstruction of pulmonary venous return.
Persistent ductus arteriosus Problems can be seen after the neonatal period when fetal structures remain patent in an otherwise structurally normal neonate, such as the persistent ductus arteriosus (PDA). Ductal patency is common in preterm babies and becomes problematic in infants if still persistent at 6 weeks of age since spontaneous closure after this time is then rare. As the pulmonary vascular resistance lowers after birth, blood shunts from left to right through a PDA. If the PDA is large this can lead to heart failure, poor growth and even pulmonary haemorrhage. Clinically babies will have full or bounding pulses, a continuous murmur, and a hyperdynamic precordium. In preterm asymptomatic neonates, observation is all that is required as the majority close spontaneously. In symptomatic neonates with heart failure and/or ventilator dependence;
Management of duct-dependent circulations In those conditions with duct-dependent left (systemic) or right (pulmonary) circulation obstruction, a prostaglandin infusion is important to ensure survival. Prostaglandins E1 and E2 will both maintain patency and even dilate the arterial duct up to about 2 weeks of life; allowing maintenance of systemic and pulmonary blood flow in such neonates. In many babies, there is antenatal diagnosis of critical CHD, allowing elective and planned commencement of prostaglandin soon after birth, preventing the
Non-duct-dependent lesions Non-duct-dependent lesions, common mixing C Tetralogy of Fallot (common, may also be duct-dependent) C Total anomalous pulmonary venous connection, TAPVC (less common) C Complete atrio-ventricular septal defect (less common) C Truncus arteriosus (rare) C Tricuspid atresia without pulmonary atresia C Ebstein anomaly (rare, severe forms can be duct-dependent)
Duct-dependent systemic circulation Duct-dependent systemic circulation (‘sick’ in first few days of life) C Coarctation of the aorta C Interrupted aortic arch C Critical aortic stenosis C Hypoplastic left heart syndrome Box 3
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Box 5
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In all of these, the pulmonary arteries fail to dilate normally, leading to high pulmonary vascular resistance (PVR), right to left shunt at the foramen ovale and the arterial duct and the resulting acidosis and hypoxaemia exacerbates the high PVR leading to a deteriorating cycle until intervention occurs.
General management of suspected critical congenital heart disease Resuscitation C Airway, breathing, circulation C Give oxygen until the diagnosis is made C Consider ventilator support if there are signs of respiratory failure C Consider inotropic medication if shocked C Consider prostaglandin infusion
Management of PPHN Clearly it is important to rule out critical congenital heart disease before embarking on treatment of PPHN. This can realistically only be undertaken by means of expert echocardiography as described above, although the hyperoxia test and the use of oxygen saturation measurement in the hand and foot have their part to play. Most importantly it is essential to rule out totally anomalous pulmonary venous connection that can present very similarly and often is mis-diagnosed as PPHN and vice-versa. Good ventilation is the key to good management. Oxygen is the most important therapy, usually necessitating intubation of the neonate. Maintenance of mild alkalosis and a low carbon dioxide level allows the endogenous nitric oxide to be more effective. Magnesium sulphate, usually as a bolus dose of 200 mg/Kg is an additional therapy that enhances the production of endogenous nitric oxide. Care has to be observed, since this can also impair ventricular function and inotropic infusion is required to increase the cardiac output. The logical inotrope would be a phosphodiesterase type 3 inhibitor such as milrinone due to its lusitropic and inodilating effect. However, a small dose of sympathomimetic vasopressor may be required to maintain an adequate blood pressure for organ perfusion. Inevitably inhaled nitric oxide is the next supplemental therapy to be considered, although care should be taken to ensure that the above therapies are commenced first. Low dose (3e20 ppm) nitric oxide is usually sufficient and can be started when the oxygen index is greater than 25. Evidence is also increasing that advanced pulmonary vasodilators may be effective such as phosphodiesterase inhibitors (such as sildenafil) or endothelin receptor antagonists (such as Bosentan). Prostacyclin (PGI2) is known to be effective in severe cases (either inhaled or intravenous) but again, caution should be exercised in order to avoid severe hypotension. The treatment of last resort is Extracorporeal membrane oxygenation (ECMO). This is complex, expensive and associated with long-term neurological morbidity. For a full review of PPHN management a longer text needs to be consulted.
History and examination C Aetiological factors (family history CHD, chromosomal abnormalities, maternal illnesses/infections/medications/substance use) C Symptoms of heart failure (poor feeding, sweating, respiratory distress, weight gain) and examination for signs of heart disease (cyanosis, heart failure, collapse, murmur) Initial investigations C Pulse oximetry e pre and post ductal saturations (significant if more than 3% difference) C Blood gas (assesses hypoxaemia, hyperoxia test, metabolic acidosis, and lactate) C Blood tests (blood count, coagulation screen, chromosomes) C Chest radiogram (to exclude respiratory disease) C ECG (rarely of much use in the neonate) C Hyperoxia test e (to differentiate between cardiac and respiratory causes of cyanosis) (Place the baby in 100% oxygen for 10 minutes and then take an arterial blood gas. If the cause of cyanosis is non-cardiac, then the PaO2 should be greater than 20 KPa.) C Echocardiogram Treatment C Consider antibiotics if there is suspicion of sepsis C Urgent discussion with cardiologist C Stabilization and transfer to a specialist cardiac centre Box 6
oxygenation should be optimized, fluids restricted and heart failure treated. Pharmacological or surgical closure should be considered.
Failure to adapt normally to extra uterine life Summary
In some babies there is a failure for the pulmonary vascular resistance to fall normally (persistent pulmonary hypertension of the newborn, PPHN). The incidence is about 1/1000 live births, and is related to lung under-development, mal-development and/ or mal-adaptation. Under-development occurs when the lungs are prevented from developing normally, for example in cases of oligohydramnios or diaphragmatic hernia. Mal-development describes a failure of the normal physiological processes described above which result in a gradual fall in pulmonary vascular resistance. This lead possible to idiopathic PPHN. Several genetic causes, such as FOXF1 mutation causing alveolar capillary dysplasia have now been described. Mal-adaptation occurs when the normal adaptation is prevented from occurring, such as with meconium aspiration or neonatal respiratory distress syndrome.
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The transition from a fetus to a newborn is the most complex physiologic adaptation that occurs in human experience. Knowledge of this process is key to understanding the physiology of early neonatal management and possible CHD. Early diagnosis with detection of PPHN or neonatal CHD remains challenging as prenatal screening does not reliably detect all cases. Timely identification of neonates with PPHN or critical CHD during the first few days, appropriate management and transfer to a specialist unit significantly reduces mortality. Paediatricians must be alert and aware of these critical presentations within the first few days of life as cardiovascular adaptation fails. Simple initial interventions may be life saving. We have discussed the physiology of neonatal cardiovascular adaptation to extra uterine
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Singh A. Ewer AKPulse oximetry screening for critical congenital heart defects: a UK national survey. Lancet 2013; 381: 535. Tulloh R. Cardiac disorders. In: Lissauer T, Clayden T, eds. Illustrated textbook of paediatrics. 4th edn. China: Mosby, ISBN 9780723435655; 2011; 301e18. Vargo L. Cardiovascular assessment. In: Rait C, Rait SG, eds. Physical assessment of the newborn a comprehensive approach to the art of physical examination. 3rd edn. Santa Rosa, CA: NICU Ink, ISBN 1887571094; 2003; 81e95.
life and provided a brief overview of early presentations of CHD and the immediate management. A FURTHER READING Abu-Harb M, Wyllie J, Hey E, Richmond S, Wren C. Presentation of obstructive left heart malformations in infancy. Arch Dis Child Fetal Neonatal Ed 1994; 71: F179e83. Bali S, Tulloh R. Assessing the newborn circulation: what to look out for. Cure Care J Neonatal Intensive Care Oct 11, 2013. Carlgren LE, Ericson A, K€ allen B. Monitoring of congenital cardiac defects. Pediatr Cardiol 1987; 8: 247e56. Gao Y, Raj JU. Regulation of the pulmonary circulation in the fetus and newborn. Physiol Rev 2010; 90: 1291e335. http://dx.doi.org/10.1152/ physrev.00032.2009. Hoffman JL, Kaplan S. The incidence of congenital heart disease. J Am Coll Cardiol 2002; 39: 1890e900. Mahle W, Koppel R. Screening with pulse oximetry for congenital heart disease. Lancet 2011; 378: 749e50. http://dx.doi.org/10.1016/ S0140-6736(11)61032-5. online. Mellander M. Diagnosis and management of life-threatening cardiac malformations in the newborn. Seminars Neonatal Med 2013; 18: 302e10, http://dx.doi.org/10.1016/j.siny.2013.04.007. Mellander M, Sunnegardh J. Failure to diagnose critical heart malformations in newborns before discharge- an increasing problem? Acta Paediatr 2006; 95: 407e13. Pradat P, Francannet C, Harris JA, Robert E. The epidemiology of cardiovascular defects part 1: a study based on data from three large registries of congenital malformations. Pediatr Cardiol 2003; 24: 195e221. Puthiyachirakkal M, Mhanna M. Pathophysiology, management, and outcome of persistent pulmonary hypertension of the newborn: a clinical review. Front Pediatr 2013; 1: 23. PMCID: PMC3864198.
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Practice points C
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Knowledge of the concepts involved in the transition from fetal to neonatal life is valuable in understanding abnormalities in adaptation when underlying cardiac defects are present CHD is common, yet easily missed antenatally and postnatally Duct dependant conditions usually present at 2 days of life Timely prostaglandin infusion can re-open the duct up to 2 weeks of life and prevent development of shock, severe hypoxaemia, acidosis and resultant end organ damage Discuss cases of suspected CHD with a cardiologist Ensure good mechanical ventilation for early management of PPHN Exclude a critical CHD before diagnosis of PPHN Nitric oxide, sildenafil, endothelin receptor antagonist, prostacyclin might be used to treat PPHN Do not forget possible differential diagnoses Prompt diagnosis and subsequent transfer and intervention are essential to reduce the mortality associated with CHD
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