Core Concepts : Fetal Cardiac Physiology Adrian Dyer and Catherine Ikemba Neoreviews 2012;13;e583 DOI: 10.1542/neo.

13-10-e583

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Article

cardiovascular

Core Concepts: Fetal Cardiac Physiology

Adrian Dyer, MD, Catherine Ikemba, MD

Abstract
The fetal myocardium and circulation differ from that of the adult in many important ways. Postnatal circulation occurs in series with the right ventricle providing a full cardiac output to the pulmonary circulation and the left ventricle delivering that same cardiac output to the body (systemic circulation). In the fetus, however, there is a parallel circulation in which organs receive blood ow from both ventricles, and the ventricular output is described as combined. Due to this arrangement, the fetus has unique methods to adapt to intrauterine stressors on the cardiovascular system. There are several normal physiologic transitions that take place after birth which may be perturbed by a compromised hemodynamic state or the presence of congenital heart disease. The transition to an adult circulation is a dynamic process, of which the understanding is critical to the care of neonates.

Author Disclosure Drs Dyer and Ikemba have disclosed no nancial relationships relevant to this article. This commentary does not contain a discussion of an unapproved/ investigative use of a commercial product/ device.

Objectives

After completing this article, readers should be able to:

1. Describe the anatomy and physiology of the fetal cardiovascular system and how it differs from postnatal circulation. 2. Explain the physiologic changes of the fetal circulation that occur when confronted with stress. 3. Describe the physiology of common congenital heart disease in utero. 4. List the important steps in the cardiovascular transition from fetus to neonate. 5. Recognize the limitations of fetal echocardiography.

Fetal Myocardial Function and Cardiac Output

The structure of the fetal myocardium is anatomically and functionally different than the adult myocardium. To understand the differences in the way the fetus and adult increase their CO, the basic components of CO will be discussed briey. CO is the product of heart rate (HR) and stroke volume (SV). CO HR SV. The main determinants of SV (the effective amount of blood volume that is ejected with each heart beat) are preload, afterload, and contractility. Preload is the venous return to the heart or the blood volume that is available to be pumped by the ventricles. Afterload is the arterial pressure against which the heart has to contract. Contractility is the intrinsic ability of the myocardium to contract or the force that can be generated at any given muscle length. The FrankStarling principle states that CO increases with an increase in preload, or in other words, increase stretch of the muscle, up to a critical atrial pressure/length of the muscle ber (ie, up to a certain preload). Past this point, increases in preload do not augment CO and actually are detrimental, resulting in congestive heart failure. The adult myocardium follows the FrankStarling principle. Increase in preload is an important method for increasing contractility and thus CO in the adult. The fetal myocardium also follows the FrankStarling law but operates at the upper limit of the atrial pressure/SV curve (Fig 1). In other words, the fetus is unable to increase its CO by increasing preload/muscle ber length. There are a few theories as to why the fetus has a much lower preload
University of Texas Southwestern Medical Center, Dallas, TX.

Abbreviations
CO: DA: DV: HR: IVC: RV: SV: cardiac output ductus arteriosus ductus venosus heart rate inferior vena cava right ventricle stroke volume

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reserve and limited ability to increase its CO. The rst explanation is due to the immaturity of the fetal myocardium. There is a higher percentage of noncontractile proteins in the fetal myocardium, up to 60%, compared with 30% in the adult. The result is a stiffer, noncompliant myocardium. This is demonstrated by the normal Doppler ow signals across the atrioventricular valves in the fetal heart obtained on a fetal echocardiogram. In normal older children and adults, there is predominately early passive lling of the ventricles during ventricular diastole (larger E wave) and only a small amount of lling with atrial systole (small A wave) (Fig 2). In contrast, the fetus relies on atrial systole (atrial kick) for its preload instead of only pas- Figure 2. Normal Doppler inow across the tricuspid valve in an adult. Note the prominent E wave representing ventricular diastole and smaller A wave representing atrial systole (see sive lling during diastole (ie, a small text for details). E wave and large A wave are normal in the fetus but signies diastolic dysfunction in a child) (Fig 3). When there is diastolic dysfuncability to use calcium. This can also explain the sensitivity tion (or tachycardia) in the fetus, the atrioventricular inow of neonates to calcium-channel blockers and the improveis single peak during atrial contraction (Fig 4). ment in CO with calcium infusions in critically ill neonates. In addition, the fetal myocardium handles calcium inefThe other explanation is that the noncompliant fetal myociently compared with the adult myocardium. The sarcocardium is secondary to the extrinsic constraints on the fetal plasmic reticulum is immature, resulting in a decreased myocardium by the chest wall, pericardium, and uid-lled lungs. The implication is that to improve CO in the fetus, the predominant mechanism is to increase HR. Adrenergic innervation of the fetus is also immature, thus HR is predominately dictated by cholinergic inuences. This can explain the progressive decrease in HR that occurs as gestation progresses, as well as the bradycardic response to hypoxia that occurs in the fetus. In contrast, the older infants response to hypoxia is typically tachycardia. Cortisol and thyroid hormone are important for the maturity of the fetal myocardium and adrenergic response. In the sheep model, it has been shown that thyroid hormone is important in late gestation for both the developFigure 1. FrankStarling Law in the fetus versus mature ment of the b-adrenoreceptors and the maturity of the myocardium (see text for details). Increase in ventricular stroke myosin chains in the ventricular myocardium.
volume (SV) as atrial pressure rises with increasing preload. The fetal heart cannot increase its SV beyond a small incremental increase in atrial pressure, with peak SV occurring at w4 or 5 mm Hg. The mature adult heart can continue to increase its SV as preload increases up to atrial pressure 16 to 18 mm Hg. (Reprinted with permission from Rychik J. Fetal cardiovascular physiology. Pediatr Cardiol. 2004;25:201209.)

Anatomy of the Fetal Circulation

Ductus Venosus
The placenta functions as the major organ for gas exchange in the fetus (Figs 5 and 6). Oxygenated blood

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of fetal stress. In fact, the Doppler ow signal of the DV is very useful in the overall assessment of fetal well being and is part of the Huhta cardiovascular prole score, which is described below.

Right Ventricle
The remaining deoxygenated blood from the IVC, right hepatic vein, and superior vena cava is directed across the tricuspid valve to the RV. The normal tricuspid valve apparatus is extremely competent in fetal life. Any degree of regurgitation is abnormal and is a useful indicator of either abnormal morphology of the valve, right ventricular dysfunction, or downstream obstruction.
Figure 3. Normal Doppler inow across the tricuspid valve in the fetus. Note the prominent A wave (ie, atrial systole) and smaller E wave (ie, ventricular diastole) (see text for details).

Ductus Arteriosus

travels to the fetus via the umbilical vein. The umbilical vein enters the fetal abdomen and travels toward the liver. A portion of this blood perfuses the left lobe of the liver. The rest bypasses the liver via the ductus venosus (DV), connecting the left branch of the portal vein to the common hepatic vein where it joins the inferior vena cava (IVC). In the IVC, the hepatic and systemic venous blood runs with the DV blood; however, the blood coursing through the DV accelerates to pass through this narrow (0.52 mm) structure. This kinetic energy is transmitted into the IVC and right atrium and preferentially propels the oxygenated blood from the DV across the foramen ovale into the left atrium (streaming effect). Oxygenated blood from the left hepatic vein, which is conveniently positioned under the Eustachian valve, is also directed across the foramen ovale into the left atrium. The importance of this is that highly oxygenated blood is preferentially supplied to the organs with the highest oxygen demand: the brain and myocardium (via the coronary circulation).

The majority of the blood that is pumped by the RV across the pulmonary valve into the main pulmonary artery is directed across the ductus arteriosus (DA). The DA is a wide muscular vessel that bypasses the pulmonary circulation and instead connects the pulmonary arterial trunk to the descending aorta. In utero, the DA remains open due to the hypoxic fetal environment, nitric oxide, and high circulating levels of prostaglandins. The direction of ow in the DA is dictated by the balance between the resistances of the pulmonary vascular and placental beds. A majority of blood passing through the DA returns to the placenta for gas exchange, whereas the remainder perfuses the lower body.

Ductus Arteriosus and Fetal Congenital Heart Disease

In the case of critical pulmonary valve stenosis or pulmonary atresia, there is very little to no blood ow from the RV into the branch pulmonary arteries. Therefore, pulmonary perfusion relies on reversal of the direction of blood ow in the DA from normal right-to-left to left-to-right ow. Postnatally, if this ductus is not kept open with prostaglandin, these infants become profoundly cyanotic.

Ductus Venosus Under Fetal Stress

The DV is under tonic adrenergic control and responds to nitric oxide and prostaglandins. It can dilate or constrict depending on systemic inuences. For example, in fetal hypoxemia in sheep, the diameter of the DV can increase by 60%. Therefore, the DV seems to be important in cases

Foramen Ovale
In utero, the mean right atrial pressure is slightly higher than the left atrial pressure (45 mm Hg versus 23 mm Hg). This gradient promotes the normal right-to-left
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body, and placenta. The aortic isthmus is the segment between the origin of the left subclavian artery and the aortic end of the DA. Normally, the left ventricle causes forward ow in the isthmus. The RV may, under some conditions, pump blood retrograde in the isthmus via the DA. The direction of blood ow in this region depends on the relative contractility of the left ventricle and RV, as well as the downstream resistances of the upper body versus the placenta. Under normal anatomic and physiologic circumstances, the low resistance of the placenta results in forward ow in the aortic isthmus during systole and diastole.

Aortic Isthmus and Fetal Congenital Heart Disease

Figure 4. Abnormal Doppler inow across the tricuspid valve in a fetus with hydrops fetalis. Note the single peak inow signal wave (see text for details).

blood ow of oxygenated blood across the foramen ovale in the fetus and provides the majority of left ventricular preload. Around 28 to 30 weeks gestation, the amount of blood crossing the foramen decreases. At the same time, pulmonary blood ow, provided by the right atrium and ventricle, increases. Thus there is increased pulmonary venous return to the left atrium, which keeps left ventricular preload fairly constant and as it prepares for a postnatal circulation.

Left Atrium and Left Ventricle

Pulmonary venous return is added to the DV and left hepatic venous blood in the left atrium. Based on sheep studies, it was initially thought that only a trivial fraction of the right ventricular output (<10%) went to the lungs, and therefore, pulmonary venous return contributed trivially to left ventricular preload. Human fetal studies have revealed that a higher proportion of right ventricular output goes to the pulmonary circulation (13%25%), especially after 32 weeks gestation. From the left atrium, this highly oxygenated blood is pumped by the left ventricle to the coronary and cerebral circulations (ie, the organs with the highest oxygen demands).

This region demonstrates the amazing adaptability of the fetal circulation. In the case of decreased effective left ventricular output (ie, hypoplastic left heart syndrome or critical aortic stenosis), the ow in the aortic isthmus and often the entire transverse arch, is retrograde and supplied from the RV via the DA. This ensures cerebral perfusion and allows for continued development of the brain in fetuses with left-sided obstructive lesions. However, these patients are at risk for developmental delay, and there is suspicion that the abnormal, retrograde ow in the isthmus may contribute. Obstructive left-sided heart disease is also an example of the important exibility of the fetal system due to the fetal circulation being in parallel (interdependent). If the output of one ventricle falls, the other ventricle increases its output to compensate, and therefore, may grow larger in comparison. In fetuses with hypoplastic left heart syndrome, for example, the RV is dilated and hypertrophied.

Aortic Isthmus During Fetal Stress

The direction of ow in this region also may be retrograde in a fetus with signicant left ventricular dysfunction. This is another example of the adaptability of the fetal circulation and the ability to autoregulate. To preserve cerebral perfusion in the developing brain, the cerebral resistance decreases and promotes retrograde blood ow from the RV.

Aortic Isthmus
A trivial portion of the left ventricular CO traverses the distal aortic arch to get to the descending aorta, lower
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Fetal Cardiovascular System Under Stress

As discussed above, the afterload on a ventricle can be thought of as the pressure that it has to overcome to open

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Figure 6. Fetal circulation (see text for details). Diagram of

Figure 5. Venous ow in the fetus. Diagram showing venous ow patterns in the fetal lamb. Umbilical venous blood is distributed to the left lobe of the liver, through the ductus venosus (DV), and to the right lobe of the liver. Portal venous blood passes almost exclusively to the right lobe, but a small proportion enters the DV. DV and left hepatic venous blood preferentially pass through the foramen ovale, whereas right hepatic venous and distal inferior vena caval blood are preferentially directed through the tricuspid valve. Superior vena caval blood almost all passes through the tricuspid valve. SVC[superior vena cava; LHV[left hepatic vein; RHV[right hepatic vein. (Reprinted with permission from Rudolph AM. Hepatic and ductus venosus blood ows during fetal life. Hepatology. 1983;3:254258.)

the circulation in the normal fetus, showing the patterns of blood ow and the oxygen saturations in the main vessels. Note the higher oxygen saturation in the ascending aorta compared with the descending aorta and the lower saturation in the pulmonary artery. The oxygen saturations shown are derived from fetal lambs in utero. (Reprinted with permission from Rudolph AM. Aortopulmonary transposition in the fetus: speculation on pathophysiology and therapy. Pediatr Res. 2007;61[3]:375380.)

either the aortic or pulmonary valve. In the fetus, the combined afterload of the left ventricle (brain, upper body, and aortic isthmus, which is narrowed even in the absence of a coarctation) is higher than the right ventricular afterload (low resistance DA and placenta in addition to the higher resistance lower body and lung). The end result is a higher output of the RV compared with the left (twice as much in fetal sheep). In the human fetus, the brain is bigger, has a larger vascular surface area, and therefore offers less resistance, allowing the left ventricular output to be more than in sheep but still less than the RV. During stressful situations, autoregulation of blood ow occurs, which alters the afterload of a particular organ thus

preserving blood ow to those organs with the highest oxygen demand. For example, in fetuses with congenital heart disease consisting of a single ventricle that involves intracardiac mixing and lower oxygen content to the brain, the relative cerebral hypoxemia stimulates a decrease in cerebral vascular resistance resulting in increased diastolic blood ow to the brain. The brain sparing effect may also be seen in the case of maternal hypoxia or impaired placental gas exchange in which there is decreased fetal oxygen content but preservation of blood ow. The fetus is able to maintain CO by redirecting ow to the organs with the highest oxygen demands, such as the myocardium, adrenal glands, and brain, at the expense of the gastrointestinal tract, kidneys, lungs, and periphery. Another interesting example of the interplay between afterload and preload in the fetal cardiovascular system is displayed in the right ventricular response to stressors. As mentioned earlier, the RV provides more CO than the left ventricle, is larger, and has more wall stress (per Laplaces law: wall stress is directly proportional to transmural pressure and radius but inversely related to wall thickness). Alterations in preload or afterload affect both ventricles, but the RV is more sensitive to changes. It
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responds with more profound hypertrophy, dilation, and/ or dysfunction. Therefore, Doppler assessment of tricuspid inow, evidence of tricuspid regurgitation, and IVC and DV signals are sensitive indicators of fetal distress. Doppler assessment has been incorporated in the semiquantitative scoring system developed by Dr James Huhta and colleagues that has been shown to be predictive of perinatal outcome in congenital heart disease and fetal hydrops. This cardiovascular prole score includes ve categories: presence/severity of hydrops, umbilical venous and DV Doppler pattern, heart size, cardiac function, and umbilical arterial Doppler pattern. Each component is worth two points; thus a normal score is 10. Along with the biophysical prole, the cardiovascular prole score can be used to predict a fetus outcome, with a lower score indicating worse outcomes. For example, in a hydropic fetus, a cardiovascular prole score of six or less is associated with higher perinatal mortality.

ventricle can then become dilated. If the offending agent is removed, as in short-term tocolysis with indomethacin, these fetuses usually improve. Patients who develop hydrops in response to acute ductal constriction typically have concomitant premature constriction of the foramen ovale, which inhibits the compensatory mechanism; combined CO is not able to be preserved and results in cardiac dysfunction.

Transitional Circulation
The neonatal myocardium rapidly increases SV after birth. There is both an increase in thyroid hormone production shortly before birth and a catecholaminergic surge around the time of birth.

Closure of the Foramen Ovale

At birth, the onset of respiration inates the lungs and drops the pulmonary vascular resistance. Clamping of the umbilical cord removes the low resistance placenta, and the systemic resistance increases at the same time. This changes the competing systemic and pulmonary vascular resistances reversing the direction of ow across the DA. The result is increased blood ow in the branch pulmonary arteries and lungs, instead of across the DA to the lower body, which now has a higher resistance. As more blood returns via the pulmonary veins to the left atrium and less blood returns to the right atrium due to clamping of the umbilical cord, left atrial pressure increases compared with the right, which closes the ap mechanism of the foramen ovale. Anatomic closure of the foramen ovale typically is complete by age 3 years, but in many adults a small shunt persists and is hemodynamically insignicant.

Clinical Correlation of Maladaptive Increase in Preload (Fetal Congestive Heart Failure)

Twin-twin transfusion is thought to be due to a placental vasculopathy that occurs in the presence of monochorionic twins. The result is a smaller donor twin and a larger recipient twin who is at risk for signicant cardiac dysfunction and hydrops. The donor twin is volume depleted and produces hormones in response. These include activation of the renin-angiotensin system (elevated levels of angiotensin II) and endothelin-1. These hormones adversely affect the vascular compliance of the donor cardiovascular system and predispose the donors to hypertension and atherosclerotic disease later in life. More acutely, the net result in the recipient twin is increased volume load and a progressive cardiomyopathy that leads to ventricular dilation, hypertrophy, and dysfunction. In addition, the hormones that are secreted in response to hypovolemia by the donor twin are passed to the recipient, which results in further volume retention, vasoconstriction, and ventricular hypertrophy in the recipient twin.

Closure of the Ductus Arteriosus

The DA functionally typically closes in 24 hours in a healthy full-term neonate. Closure is mediated by increased oxygen tension and a change in circulating prostaglandins. Anatomic closure takes longer and is replaced by the ligamentum arteriosum. This process involves thrombosis, brosis, and muscle contraction and is usually completed by 2 to 3 months in a normal, full-term infant. Closure of the DA may be delayed in preterm and/or hypoxic neonates.

Clinical Correlation of Maladaptive Increase in Afterload

Premature constriction of the DA occurs rarely and is due to either administration of prostaglandin synthesis inhibitors (ie, indomethacin, ibuprofen, aspirin, or any cyclooxygenase enzyme inhibitors), or rarely, naturally occurring constriction. The result is an acute increase in the afterload of the RV. This can cause signicant right ventricular dysfunction. The fetus compensates by increasing the amount of blood that is shunted right-to-left across the foramen ovale, thus preserving combined CO. The left
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Closure of the Ductus Venosus

Functional closure of the DV occurs soon after birth. There is decreased blood ow returning to the right atrium after the umbilical cord is clamped, which allows the DV to passively collapse. Anatomic closure may take up to 3 weeks after birth.

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Limitations of Fetal Echocardiography

Although fetal echocardiography is a powerful tool reported to identify 80% of signicant congenital heart disease, the unique features of fetal cardiovascular anatomy and physiology described earlier in this article lead to several important limitations to this test. There is a normal interatrial communication in the fetus, the foramen ovale, thus secundum atrial septal defects cannot be detected in utero. There is limited pulmonary blood ow to the lungs of a fetus, and there is limited pulmonary venous return such that pulmonary venous anatomy is often difcult to delineate. The aortic isthmus is normally small in the fetus, and coarctation of the aorta often does not manifest until the DA closes in postnatal life. Finally, the pressure differences between the right and left ventricle are small, thus a ventricular septal defect may not be detected in utero due to minimal shunting across such a defect. These limitations are important for the neonatologist to keep in mind when evaluating a newborn who may have had a fetal echocardiogram.

American Board of Pediatrics Neonatal-Perinatal Content Specications

Know the factors affecting and regulating myocardial performance and function in the fetus and newborn infant and during the transitional period. Know the factors affecting and regulating the systemic circulation in the fetus (including umbilical vessels) and newborn infant during the transitional period. Know the appropriate techniques to assess cardiovascular function in the fetus and newborn infant. Know the physiology of the ductus arteriosus.

Conclusions
The fetal cardiovascular system has the unique capability of allowing the fetus to develop normally but also adapt to stressors encountered in utero, including signicant congenital heart disease. Echocardiography is a powerful noninvasive tool to evaluate the overall health of the fetal cardiovascular system. Understanding fetal anatomy and the complex transitions that must take place to achieve normal adult cardiac physiology is helpful in caring for normal neonates, as well as infants with congenital heart disease.

Suggested Reading
Donofrio MT, Bremer YA, Schieken RM, et al. Autoregulation of cerebral blood ow in fetuses with congenital heart disease: the brain sparing effect. Pediatr Cardiol. 2003;24(5):436443 Falkensammer CB, Paul J, Huhta JC. Fetal congestive heart failure: correlation of Tei-index and Cardiovascular-score. J Perinat Med. 2001;29(5):390398

Faye-Petersen OM, Crombleholme TM. Twin-to-twin transfusion syndrome: Part I. Types and pathogenesis. NeoReviews. 2008;9 (9):e370e379 Friedman WF. The intrinsic physiologic properties of the developing heart. Prog Cardiovasc Dis. 1972;15(1):87111 Ho SW, Angelini A, Moscoso G. Developmental cardiac anatomy. In: Long WA, ed. Fetal and Neonatal Cardiology. Philadelphia, PA: WB Saunders Company; 1990:315 Huhta JC. Right ventricular function in the human fetus. J Perinat Med. 2001;29(5):381389 Kiserud T, Acharya G. The fetal circulation. [Review]Prenat Diagn. 2004;24(13):10491059 Kovalchin JP, Silverman NH. The impact of fetal echocardiography. Pediatr Cardiol. 2004;25(3):299306 Parellada J, Gest A. Fetal circulation and changes occurring at birth. In: Garson A Jr, Bricker JT, Fisher DJ, Neish SR, eds. The Science and Practice of Pediatric Cardiology, 2nd ed. Baltimore, MD: Williams and Wilkins; 1998:349358 Robinson JN, Simpson LL, Abuhamad AZ. Screening for fetal heart disease with ultrasound. Clin Obstet Gynecol. 2003;46(4):890896 Rudolph AM. Aortopulmonary transposition in the fetus: speculation on pathophysiology and therapy. Pediatr Res. 2007;61(3): 375380 Rudolph AM. Distribution and regulation of blood ow in the fetal and neonatal lamb. Circ Res. 1985;57(6):811821 Rudolph AM. Hepatic and ductus venosus blood ows during fetal life. Hepatology. 1983;3(2):254258 Rychik J. Fetal cardiovascular physiology. Pediatr Cardiol. 2004;25 (3):201209

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Core Concepts : Fetal Cardiac Physiology Adrian Dyer and Catherine Ikemba Neoreviews 2012;13;e583 DOI: 10.1542/neo.13-10-e583

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