Chapter 99

Fetal, Neonatal, and Pediatric Physiology

Samir K. Gadepalli and George B. Mychaliska

Key Points

1 Certain aspects of fetal and neonatal physiology differ markedly from adult physiology, whereas the

physiology of older children and adolescents approximates adult physiology.

2 During fetal life, the right ventricle provides about 65% of the fetal cardiac output and the left

ventricle ejecting the remaining 35%.

3 Prematurity and critical illness are both associated with persistent fetal circulation. Under these

conditions, the RV continues to contribute a large portion of the cardiac output and the postductal

saturations will be significantly lower than the preductal saturations.

4 Surfactant is a mixture of phospholipids, neutral lipids, and specific proteins that, by virtue of their

amphipathic nature, decrease surface tension, stabilize small alveoli, and improve overall alveolar

inflation.

5 The neonatal heart increases its cardiac output primarily through increases in heart rate.

6 The primary cause of neonatal bradycardia is hypoxia.

7 Ventricular septal defect (VSD) is the most common heart defect occurring in nearly a third of

neonates with congenital heart disease.

8 Patent ductus arteriosus: fluid restriction is the first line of therapy when appropriate with

indomethacin reserved for persistent cases to help stimulate closure.

9 An infant enduring water deprivation can only increase urine osmolality to 600 mOsm/kg, whereas

adults can concentrate to 1,200 mOsm/kg.

10 A term newborn grows at 25 to 30 g/d over the first 6 months, doubling their birth weight by 5

months, tripling it by 12 months.

11 The enteral nutrition of choice in neonates is breast milk even in the premature or very low–birthweight (<1,500 g) infant.

INTRODUCTION

An understanding of fetal, neonatal, and pediatric physiology is critical to understanding the

pathophysiology and treatment of fetal and pediatric surgical problems. As distinct from adult

physiology, fetal, neonatal, and pediatric physiology must account for varying degrees of growth and

maturation and for major physiologic transitions particularly from the prenatal to the postnatal period.

New insights into fetal and neonatal physiology coupled with technologic advances have led to

pioneering treatment approaches for congenital anomalies and the treatment of extreme prematurity.

1 First, although the old pediatric surgical adage “children are not small adults” still holds true, the

physiology of older children begins to approximate the physiology of adults. As such, this chapter

focuses primarily on the unique and distinguishing physiology of the fetus and neonate. Since

prematurity remains an unsolved problem, a section is also devoted to this cohort of neonates.

Second, the topic of physiology is broad and it was impossible to cover each organ system in depth.

We focused on critical topics that are necessary to the practice of pediatric surgery and touched on areas

that are innovative and promising.

Third, where applicable, we intended to also make this resource practical to the practice of pediatric

surgery. Where applicable, we discuss specific pediatric surgical diseases to illustrate physiologic

principles. Similarly, some aspects of medical management as it relates to unique physiology are

discussed.

Finally, we acknowledge that our understanding of fetal, neonatal, and pediatric physiology is not

static and remains an exciting area of scientific inquiry. As our knowledge grows, we can not only

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better understand pathophysiology of pediatric diseases, but also develop effective medical and surgical

treatments.

Fetal Physiology

Fetal Morphogenesis

The human embryo begins as a single cell. During gestation, a fertilized egg divides and differentiates

into more than 200 different morphologically recognizable cell types. Development begins with the

fusion of the male and female gametes at fertilization. The earliest form of an embryo is called a

zygote. Initially, the diploid chromosome number is restored by fusion of the two haploid gametes from

each parent.

The zygote undergoes a series of mitotic divisions and by the 8- and 16-cell stage, the embryo is

called a blastocyst and consists of a clump of cells termed the inner cell mass, that are surrounded by a

layer of trophoblast cells. Subsequent differentiation of the trophoblast results in a double-layered

membrane which is a progenitor tissue of the chorion, the fetal portion of the placenta. Once the zona

pellucida is shed, the blastocyst attaches and implants within the uterine endometrium. At the beginning

of the third week of development, gastrulation ensues and is characterized by morphogenetic

movements resulting in a primitive streak. Some epiblast cells enter the streak, while others remain

within the epiblast to become the embryonic ectoderm. At the primitive streak, sets of polarized

epithelial cells within the epiblast transform into nonpolarized free cells termed mesenchyme, the

second embryonic tissue. These events are mediated by adhesive molecules located on the cell surface as

well as expression of homeobox genes and other signaling molecules leading to patterning of axial and

nonaxial structures. The primitive streak provides a means by which subsets of epiblast cells can ingress

and be distributed to more ventral regions of the embryo as the endoderm and the mesoderm. The first

cells through the streak comes the endoderm followed by cells that form the notochord which defines

the axis of the embryo and plays a significant role in the nervous system. Due to cleavage and gassed

relation, population of cells in various stages of the termination, are brought together in new spatial

relationships, which permits new tissue interactions. Subsequent organogenesis results from these tissue

interactions. These interactions are mediated by a variety of signaling molecules such as growth factors,

secreted factors, and transcriptions factors, produced by cells and often concentrated in the extracellular

matrix. The embryology and physiology of select organ systems will now be described.

Lung Development

The respiratory system consists of elements of air conduction and exchange. The uptake of oxygen from

the environment and removal of carbon dioxide serves to maintain cellular aerobic metabolism and

acid–base balance. In order to effectively perform these processes, normal structural and cellular

development is essential. The respiratory system must develop through five phases: embryonic,

pseudoglandular, canalicular, saccular, and alveolar. The boundaries between these phases merge into

each other with overlap at any given time point between areas of the lung and vary temporally between

individuals.1

Embryonic Phase (3 to 7 Weeks). Lung growth begins around postconception (p.c.) day 25 or 26 with

the outgrowth of a small diverticulum from the ventral wall of the foregut called the primitive

respiratory diverticulum or lung bud. This extends in the ventral caudal direction into the surrounding

mesoderm, growing anterior and parallel to the primitive esophagus. Within a few days, the grove

between the diverticulum and the foregut closes with the only luminal attachment remaining at the site

of the future hypopharynx and larynx.2 By p.c. day 28, the respiratory diverticulum bifurcates into the

right and left primary bronchial buds. This is followed by a second round of branching occurring around

the fifth week p.c. yielding the secondary bronchial buds. Finally, the third branching takes place during

the sixth week p.c. producing 10 tertiary bronchi on the right and 8 on the left. The vascular

components of the respiratory system also begin to develop with the pulmonary arteries forming as

branches off the sixth aortic arch and the pulmonary veins emerging from the developing heart.

The primitive lung bud is lined by epithelium derived from endoderm which will become the

epithelium lining the airways and alveoli. The lung buds grow into the surrounding mesodermal cells

which will differentiate into the blood vessels, smooth muscle, cartilage, and other connective tissue.

Ectoderm will eventually give rise to the innervation of the lung.1

Pseudoglandular Phase (5 to 17 Weeks). The lung begins to take on a glandular appearance during

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this stage of development. The lung is composed of multiple epithelial tubules surrounded by extensive

regions of mesenchyme, giving a glandular appearance. Cellular proliferation rate increases during this

stage and by p.c. week 16, all bronchial divisions are completed with further growth occurring only by

elongation and widening of existing airways. The intrapulmonary arterial system develops branching in

parallel with the bronchial and bronchiolar tubules. The respiratory epithelium begins to differentiate

with cilia appearing in the proximal airways and cartilage begins to develop to support the airways.1

Concurrently, closure of the pleuroperitoneal folds is completed.

Canalicular Stage (16 to 26 Weeks). This stage is named due to the appearance of vascular canals or

capillaries and the increase in the interstitial compartments forming the air–blood barrier. The capillary

beds rapidly expand with condensation and thinning of the mesenchyme, starting the first critical step in

the formation of the gas exchange regions of the lung. The ingrowth of capillaries results in thinning in

one population of overlying epithelial cells, narrowing the air–blood interface and differentiating into

type I pneumocytes. In other overlying epithelial cells, lamellar bodies associated with surfactant

synthesis appear, identifying type II pneumocytes. The airways continue to develop with completion of

the airways through the level of the terminal bronchioles with their associated acinus. Branching of the

distal airspaces continues until there are a total of 23 subdivisions.

Saccular Stage (24 to 38 weeks). During this stage, the terminal clusters of acinar tubules and buds

dilate and expand into transitory alveolar saccules and ducts with a marked reduction of the

surrounding mesenchymal tissue. By 24 weeks, there is a sufficiently thin alveolar-capillary membrane

distance to participate in gas exchange (0.6 μm) with the efficacy of exchange being determined beyond

this point by the total surface area available for exchange. By the end of this stage, three additional

generations of alveolar ducts have formed and the conducting airways have developed mucous and

ciliated cells. Overall, cell proliferation slows and ultrastructural cytodifferentiation occurs. The saccules

consist of smooth-walled airspaces and a thick interstitial space. Type II epithelial cells continue to

mature and there is an increase in surfactant synthesis, but overall levels remain low.

Alveolar Stage (36 Weeks to 2 Years). This is the final stage of lung development and is characterized

by the formation of secondary alveolar septa which divide the terminal ducts and saccules into true

alveolar ducts and alveoli. There is maturation of the alveolar-capillary membrane, which increases the

surface area for gas exchange. As the terminal saccule restructures during this stage, the double

capillary network fuse becoming a single capillary network with each capillary being simultaneously

exposed to at least two alveoli. The barrier to gas exchange thins to a few nanometers. Type I and type

II cells increase in number, but only type II cells are proliferating actively suggesting that type I cells

are derived from type II cells.

Physiologic Control of Fetal Lung Growth

While the fetus and neonate proceed through the phases of lung growth and development, physical

factors play an important role in directing and assisting in this process. While not all factors affecting

this process are well understood, the role of fetal lung fluid (FLF) and mechanical distension appear to

play critical roles. During fetal life, the lung produces a unique fluid, FLF that is a result of net

transepithelial chloride and sodium flux and is produced within the lungs and leaves via the trachea.3 As

the fluid moves from the lung toward the oropharynx, it is either swallowed or enters the surrounding

amniotic fluid. Throughout gestation, the volume of FLF increases with studies in ovine animals

demonstrating FLF volume of 35 to 45 mL/kg which is significantly higher than functional residual

capacity (FRC) postbirth (25 to 30 mL/kg).4 This keeps the airway distended in order to stimulate

growth.

The volume of FLF is primarily regulated by the resistance to lung liquid efflux through the upper

airways and by fetal breathing movements (FBM) which include the associated diaphragmatic activity

and the volume is largely independent of production. When there is no FBM (apnea), the

transpulmonary pressure is usually 1 to 2 mm Hg above the amniotic sac pressure due to the elastic

recoil of the chest wall. Lung fluid efflux is prevented by high resistance of the upper airways which

prevent FLF loss and maintains an approximately 2 mm Hg distending pressure and fetal lung

expansion.5 During periods of FBM, the larynx actively dilates to decrease the resistance to FLF efflux

allowing fluid to leave at an increased rate. To compensate during periods of FBM, rhythmic contraction

of the diaphragm slows the loss of lung fluid and helps to maintain lung expansion during periods of

low upper airway resistance demonstrating that FBM serve to maintain lung expansion and promote

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lung growth. Sustained reduction of fetal lung expansion can slow the structural development of both

the vascular bed and alveolar epithelial cell phenotypes. On the other hand, prolonged overexpansion of

the fetal lungs via tracheal occlusion is a potent stimulator for fetal lung growth and tissue remodeling.6

Additionally, it has been observed that fetal airways undergo peristaltic contractions similar to the

gut which move intraluminal contents distally and cause expansion of end buds which also likely play a

role in fetal lung growth and expansion.7 Postnatal formation of significant numbers of alveoli continues

to occur for the first 1.5 to 3 years after birth with the lung growth continuing for another 15 to 18

years when the chest wall stops growing.

Fetal Circulation and Placental Gas Exchange

The umbilicoplacental circulation is critical for normal growth and development of the fetus. The

umbilical artery and vein are long and muscular and the placental vascular bed is high flow and low

resistance. Although the umbilical vessels are highly vasoactive, they remain nearly maximally dilated

during pregnancy. The umbilical arteries arise from the internal iliac arteries and curve along either side

of the bladder before entering the umbilical cord where they form a loose spiral around a single

umbilical vein. The umbilical arteries branch at the fetal surface of the placenta to form many radially

oriented chorionic arteries located on the surface of the chorionic plate. Veins within the villi merge

progressively to return blood from the placenta to the chorionic veins on the fetoplacental surface

entering a single umbilical vein. Venous blood is then returned to the fetal inferior vena cava through

the parallel arrangement of the ductus venosus and the hepatic vessels. The ductus venosus plays a

critical role in fetal circulation because it shunts highly oxygenated and nutrient-rich umbilical venous

blood to the brain and myocardium instead of the fetal liver. The percentage of umbilical blood flow

bypassing the hepatic circulation through the ductus venosus decreases from approximately 40% at

midgestation to 20% at term.8

The fetal circulation with intra- and extracardiac shunts permits the lungs to be bypassed and results

in the delivery of more highly oxygenated blood flow to the brain and heart. Due to the shunts, fetal

organs receive blood from both ventricles which forms a parallel circulation. The ductus venosus,

foramen ovale, and ductus arteriosus (DA) are the shunts required for fetal circulation. The first shunt

encountered is the ductus venosus, which shunts half of the blood away from the liver directly to the

heart. Highly oxygenated blood from the ductus venosus mixes with blood from the interior vena cava,

but preferential streaming directs blood with more oxygen across the foramen ovale into the left

atrium. As a result, highly oxygenated blood travels to the left ventricle and is ejected into the aorta,

thus feeding the coronary arteries and arteries to the brain. In contrast, the mostly deoxygenated blood

from the superior vena cava (SVC) tends to stream directly into and across the tricuspid valve into the

right ventricle, where it is then ejected out the pulmonary artery. Due to the high pulmonary vascular

resistance, the blood is shunted via the DA, entering the proximal descending aorta just past the left

subclavian artery at the end of the aortic arch. The shunted blood entering the descending aorta

perfuses the lower body and returns to the placenta via the umbilical arteries. Only 10% of the

combined cardiac output (CO) perfuses the lungs (Fig. 99-1).

2 Fetal CO is described as combined ventricular output or combined CO. The right ventricle ejects

against high-resistance lungs and lower body and low-resistance DA and placenta. The left ventricle

ejects against high-resistance brain, upper body, and aortic isthmus. Given a lower afterload, the right

ventricle provides about 65% of the fetal CO and the left ventricle ejecting the remaining 35%.

Umbilical blood flow gradually increases as the fetus grows. The umbilical blood flow during the

third trimester remains fairly constant at 110 to 125 mL/min/kg of fetal weight.9,10 Fetal biventricular

CO is approximately 450 mL/min/kg and remains fairly constant. Thus, umbilical blood flow represents

approximately 30% of fetal biventricular CO. The integrity of the placental circulation is essential to

fetal growth and development. Total uterine blood flow increases substantially during pregnancy, but

umbilicoplacental blood flow remains approximately 200 mL/min/kg of fetal weight throughout

gestation. Blood flow is mediated by a number of factors including ANG II, catecholamines, arginine

vasopressin (AVP), nitric oxide (NO), prostaglandins, estrogen, and progesterone. The placental has

many physiologic functions. Placental transfer, not just flow, is involved in determining fetal growth.

Idiopathic intrauterine growth restriction (IUGR) has been attributed to placental insufficiency due to

oxygen delivery, flow, and transfer of nutrients particularly amino acid transporters. In IUGR, fetuses

fail to achieve their full growth potential due to infection, drug abuse, maternal malnutrition, and

placental insufficiency. Umbilical blood flow is lower in growth-restricted fetuses.11

Fetal Cardiac Function and Oxygen Delivery

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The fetus has immature structure, function, and innervation of the heart. The fetal heart is less

compliant and thus shows a reduced ability to augment CO with changes in preload. The negative

increased afterload on CO is exaggerated in the fetal heart. The Frank–Starling mechanism seems to

remain the major regulator of CO in the fetus.

While fetal oxygen transport system is set up to provide optimal oxygen delivery and has the capacity

to adjust delivery to match demand in the setting of the intrauterine environment, this system can be

stressed as it adjusts to life outside the womb. The delivery of oxygen to tissues depends on the pressure

gradient between the blood and the mitochondria and varies with regional oxygen delivery, tissue

oxygen consumption and hemoglobin–oxygen affinity.

Oxygen is transported through the blood stream either dissolved in aqueous solution or bound to

hemoglobin. Arterial oxygen content can be calculated using the formula: arterial oxygen content =

(Hgb × 1.36 × SaO2

) + (0.0031 × PaO2

) where Hgb is hemoglobin concentration in grams, SaO2

is

the arterial saturation of hemoglobin, and PaO2

is the arterial partial pressure of oxygen. If hemoglobin

is 100% saturated then 1g of hemoglobin can deliver 1.36 mL of oxygen. The actual amount of oxygen

carried by hemoglobin is variable and is defined by the hemoglobin disassociation curve (Fig. 99-2).

Normally, hemoglobin is close to 100% saturated, however, the sigmoidal nature of the curve ensures

that the hemoglobin saturation remains high even at low PaO2

. The hemoglobin disassociation curve is

not static and hemoglobin’s affinity for oxygen can be influenced by a number of factors. Hemoglobin

has an increased affinity for oxygen with a left shift of the oxygen disassociation curve in alkalosis,

hypothermia, decreased 2,3 diphosphoglycerate (DPG) or fetal hemoglobin. Hemoglobin’s affinity for

oxygen decreases in the setting of acidosis, hyperthermia, or increased 2,3 DPG. This facilitates

unloading of oxygen at lower flow to the peripheral tissues.

Fetal hemoglobin (HgbF) plays an important role in the transport and unloading of oxygen in the

fetal and neonatal periods. Human hemoglobin consists of three basic chain structures which include the

alpha chain, beta chain, and gamma chain which make hemoglobin A (HgbA) of (α2β2) and hemoglobin

F (HgbF) (α2γ2). The beta and gamma chains differ from each other by a few amino acid residues. The

fetal hemoglobin has a significantly higher affinity for oxygen which favors uptake of hemoglobin

across the placenta. Near term there is a period of accelerated erythropoiesis during which HgbA

synthesis predominates with a gradual orderly, and not completely understood, transition in synthesis

from γ to β hemoglobin chains.12

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Figure 99-1. Fetal circulation. (From Rosdahl CB, Kowalski MT, eds. Textbook of Basic Nursing. Philadelphia, PA: Wolters Kluwer

Health; 2012.)

Transition to Postnatal Life

3 One of the most critical and fascinating periods in human physiology is the changes which occur,

usually in a matter of minutes, which allows a human to transition from surviving in the uterine

environment to the external environment. Around the time of birth, epithelial cells cease production of

lung fluid and begin to actively absorb it back into the fetal circulation. This process is facilitated by

active sodium transport which is stimulated by thyroid hormone, glucocorticoids, and epinephrine.1

During the first breaths, pulmonary arterial pO2

increase and pCO2 decrease resulting in pulmonary

vascular dilation, decreased pulmonary vascular resistance, and constriction of the DA. Although

pulmonary vascular resistance decreases dramatically at birth, pulmonary artery pressure, pulmonary

blood flow, and pulmonary vascular resistance decrease gradually over the first few weeks of life. The

increased pulmonary blood flow results in an increase in left atrial pressure and as a result, the flap-like

foramen ovale closes in response to higher left atrial pressures relative to right atrial pressure. The RV

compliance gradually increases as well, and the resultant change in the differences in ventricular

compliance allows the flap of the foramen ovale to gradually close over in the first few days to week of

life, minimizing mixing, so that the outputs of the left and right ventricles become equivalent. The DA

closes in the first 24 to 48 hours of life as a result of changes in direction of flow, contractile elements,

an increase in pO2

, a drop in PGE synthesized by the placenta, and other humoral factors. Removal of

the placenta results in a decrease in circulating prostaglandin levels and increasing pO2

levels are a

stimulus for ductal closure. When the foramen ovale or DA does not close, they are referred as patent

foramen ovale (PFO) and patent ductus arteriosus (PDA). Certain clinical conditions may contribute to

the persistence of fetal circulation or to the reappearance of fetal shunts under stress. Prematurity and

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