Approximate Gestational Age	Development
Embryonic Period
Day 26	Lung emerges as outpouching of primitive foregut
Week 4	Mainstem bronchi formed
Week 5	Lobar bronchi formed; pulmonary arteries and veins emerge
Week 6	Segmental bronchi formed
Pseudoglandular Period
Week 7	Diaphragm complete
Week 8	Heart formation complete
Week 10	Cilia, mucous glands, and goblet cells appear
Week 12	Smooth muscle present in large bronchi
Week 16	Conducting airways completed; respiratory bronchiole near completion
Canalicular Period
Week 17	Formation of terminal bronchioles
Week 22	Pulmonary capillary development begins
Week 23	Type I and type II cells and immature surfactant present
Weeks 24-26	Fetus potentially capable of gas exchange
Saccular Period
Weeks 26-28	Development of saccules (primitive alveoli)
Week 35	Mature surfactant present
Week 36	Early alveoli development
Alveolar Period
Weeks 36-40	Rapid alveolar development; efficient alveolar capillary membrane present
Birth–2 years	Alveoli continue to increase in number and size paralleled by arterial development

The embryo consists of three primary germ layers from which all tissues, organs, and organ systems arise (Figure 16-1). The endoderm is the innermost germ layer, the mesoderm is the middle layer, and the ectoderm is the outermost layer. Table 16-2 lists the structures that arise from each of the three germ layers. The epithelium of the respiratory tract originates from the endoderm, whereas supporting structures such as connective tissue and muscle arise from the mesoderm.

TABLE 16-2

Structures Arising from the Three Embryonic Layers

Ectoderm	Mesoderm	Endoderm
Central nervous system Peripheral nervous system Sensory epithelia Glandular tissues Epidermal tissues Teeth	Cardiovascular system Connective tissue Bone, cartilage, muscle Kidney and spleen tissue Reproductive tissues Serous linings	Epithelial tissue Respiratory, digestive, and urinary systems Large glands: tonsils, thyroid, thymus Auditory structures

Figure 16-1 Schematic drawing shows the lung bud that emerges as an outpouching of the primitive foregut eventually forming the lung. The three primary germ layers from which all tissues and organs originate are also illustrated. (From Moore KL, Persaud TVN: *The developing human: clinically oriented embryology,* ed 7, Philadelphia, 2003, Saunders.)

Embryonic Period

The embryonic period begins approximately 26 days after conception.1–4 During this period, the lung begins to emerge as an outpouching of the primitive foregut (see Figure 16-1). This outpouching elongates and separates into two bronchial buds and the trachea. The right lung bud parallels the esophagus and branches further into three additional buds. The left lung bud is directed more laterally and divides into two additional buds. Thus, the asymmetry of the main bronchi present in the adult is established. The right and left lung buds continue to grow and branch into segmental and subsegmental bronchi.

By the end of the embryonic period (near the sixth week of gestation), the major bronchi are formed, consisting of 10 right branches and 9 left branches (Figure 16-2).^1–4 During this time, the pulmonary arteries and veins emerge from the developing heart. The diaphragm also develops during this stage and is formed by about the seventh gestational week.^1–4 The diaphragm separates abdominal contents from the thorax. Failure of the diaphragm to form completely can result in congenital diaphragmatic hernia, allowing abdominal organs to enter the pleural cavity and compress the lungs and possibly lead to severe underdevelopment, or hypoplasia, of the lung.

Figure 16-2 Stages of development of the bronchial buds and lung. *28 days,* Formation of the trachea and bronchial buds. *35 days,* Secondary bronchi that branch into segmental bronchi are formed. *42 days,* Beginning of pseudoglandular period; the lung takes on the appearance of a gland. *56 days,* Branching of the tracheobronchial tree that forms the conducting airways. (From Moore KL, Persaud TVN: *The developing human: clinically oriented embryology,* ed 7, Philadelphia, 2003, Saunders.)

The dorsal portion of the foregut evolves into the esophagus. The formation of the tracheoesophageal septum separates the esophagus from the trachea (Figure 16-3). Teratogens (agents that disturb fetal development, such as drugs, infection, or chemicals) can produce congenital anomalies and may cause injury to the embryo during this stage of development, such as tracheoesophageal fistula (an abnormal opening between the trachea and the esophagus), choanal atresia (occlusion of the passageway between the nose and the pharynx), and pulmonary hypoplasia (underdevelopment of the lung).

Figure 16-3 Developmental stages of the tracheoesophageal septum. **A-C,** Lateral views showing the outpouching of the foregut into the esophagus and laryngotracheal tube. **D-F,** The formation of the tracheoesophageal septum showing its separation into the laryngotracheal tube and esophagus. (From Moore KL, Persaud TVN: *The developing human: clinically oriented embryology,* ed 7, Philadelphia, 2003, Saunders.)

Pseudoglandular Period

The pseudoglandular period begins about the sixth week and continues into the sixteenth week of gestation.1–3 The lung resembles a gland at this stage, giving rise to the name pseudoglandular. Branching and division of the tracheobronchial tree continue to occur asymmetrically and dichotomously (branching into two parts) forming the conducting airways. By the end of this period, the formation of respiratory bronchioles is nearly complete. Cilia, mucous glands, and goblet cells begin to appear in the epithelial lining at approximately 10 weeks’ gestation.^1–4 Absence or dysfunction of cilia can impair mucous transport and lead to chronic respiratory infections (see Chapter 1). Smooth muscle, which originates from the mesoderm, also appears during this stage and is present in the large bronchi by the twelfth week. Any event that alters the development of smooth muscle, cartilage, or vascular structures during this stage can lead to pulmonary disorders in infancy. A fetus born prematurely during this period is unable to survive.

Canalicular Period

The third stage of development, or the canalicular period, begins at approximately 17 weeks and continues through 26 weeks’ gestation.1–4 During this stage, the terminal bronchioles subdivide further to form the basic structure of the acinus, or gas-exchanging unit.^1–4 Capillaries begin to establish a network around the alveoli allowing for limited gas exchange by 22 weeks.^1–4 At approximately 23 weeks’ gestation, type I and type II alveolar cells begin to differentiate. Type I cells are important in the development of the alveolar capillary membrane, whereas type II cells are involved in surfactant production. By the end of the canalicular stage, some thin-walled primitive alveoli have developed, and the lung tissue is well vascularized. A fetus born prematurely at the end of this stage (approximately 24 to 26 weeks’ gestation) is potentially capable of air breathing and may survive with intensive medical care. The immature respiratory system often requires mechanical ventilatory assistance or surfactant replacement therapy or both. (See Chapter 3 for further discussion of surfactant replacement therapy.)

CONCEPT QUESTION 16-1

What problems would you expect in a premature infant born at 24 weeks of gestation?

Saccular Period

The saccular period begins around 26 weeks of gestation.1–4 During this stage of development, the terminal airways continue to widen and form cylindrical structures called saccules. These saccules subdivide to form subsaccules, which eventually develop into alveoli. By the end of this stage, the blood-air barrier is established allowing for adequate gas exchange for the fetus if it is born prematurely. Alveolar cells continue to differentiate into type I and type II cells, with type II cells synthesizing pulmonary surfactant. Surfactant is a complex mixture of phospholipids and proteins that lines the inner walls of the alveoli and offsets surface tension forces at the air-liquid interface of the alveoli (see Chapter 3). Surfactant production begins at approximately 20 weeks’ gestation and is present in only small amounts in infants born prematurely. The production of surfactant increases during gestation and reaches adequate levels to support air breathing during the last two weeks of pregnancy. Mature surfactant contains the phospholipid phosphatidylglycerol (PG), which is required for normal surfactant function. PG first appears at about 35 weeks of gestation and increases to peak levels at term.^1–3 Immature surfactant has insufficient PG and is easily inhibited by hypoxia, hypothermia, and acidosis. Thus, premature infants, especially infants born before 35 weeks’ gestation, are susceptible to developing respiratory distress syndrome (RDS) because of surfactant deficiency. Maternal administration of prenatal corticosteroids, which induce surfactant production, and the administration of exogenous surfactant directly into the newborn lungs after birth can decrease the severity of RDS and the need for mechanical ventilation.

Alveolar Period

The final period of lung development, the alveolar period, begins at approximately 36 weeks’ gestation and extends through infancy and childhood.1–4 During this stage, alveoli continue to develop and mature at a rapid rate, and pulmonary surfactant production increases. The full-term fetus has developed numerous alveoli with mature surfactant, creating an efficient alveolar capillary gas-exchange membrane. Although the lungs are completely developed, they do not take on a respiratory function until the moment of birth.

The lung at birth is not a miniature adult lung; it continues to develop and grow well into childhood. During the first years of life, alveoli develop rapidly paralleled by the expansion of the pulmonary capillary bed. As body weight increases, alveolar development increases proportionally, matched by an increase in the lungs’ oxygen uptake. At birth, approximately 50 million alveoli are present; by age 8 years, this number has increased to about 300 million alveoli.1–3 This explains why children who sustain lung injury during the neonatal period (birth to 28 days) can seemingly “outgrow” their lung disease. Alveolar development is usually complete by age 8; from this time on, alveoli increase in size until thoracic growth is complete.^1–4 Collateral pathways such as the canals of Lambert and pores of Kohn are poorly developed in young children. Consequently, children less than 10 years of age are more likely to develop airway obstruction and atelectasis than older children.⁵

Factors Affecting Fetal Development

Fetal Lung Fluid

The fetal lung has no respiratory function before birth; it is a secretory organ that produces approximately 250 to 350 mL of fluid per day.⁴ Fetal lung fluid is present by the sixth week of gestation and is derived from alveolar epithelium secretions. Most of the fluid produced remains in the lung; however, some is swallowed, and some is emitted into the amniotic fluid during periodic opening of the larynx when the fetus makes breathing movements. Lung fluid is constantly produced and plays a significant role in determining the size and shape of the developing air space. The composition of fetal lung fluid differs from the composition of amniotic fluid. Fetal lung fluid is higher in sodium and chloride concentrations; lower in pH; and lower in bicarbonate, potassium, and protein concentrations.⁴ Lung fluid also contains components of pulmonary surfactant and other fluids from alveolar epithelial cells; its presence in amniotic fluid aids the clinician in determining the degree of lung maturity.

CLINICAL FOCUS 16-1 Respiratory Distress Syndrome and Surfactant Therapy

An infant girl with an estimated gestational age of 30 weeks was delivered with Apgar scores of 5 and 7 at 1 minute and 5 minutes (see Clinical Focus 16-4). Over the next hour, the infant’s respiratory status began to deteriorate, with the infant exhibiting nasal flaring, expiratory grunting, and intercostal retractions. Arterial blood gas results on an F_IO₂ of 0.60 via oxygen hood results were as follows:

pH = 7.26

PaCO₂ = 50 mm Hg

PaO₂ = 40 mm Hg

A chest x-ray revealed findings consistent with RDS: bilateral ground-glass appearance and decreased lung volumes. The infant was intubated and placed on mechanical ventilation, and exogenous surfactant was delivered. Arterial blood gas results after surfactant administration were as follows:

pH = 7.36

PaCO₂ = 37 mm Hg

PaO₂ = 78 mm Hg on an F_IO₂ of 0.80

A few days later, the infant was extubated and placed on F_IO₂ of 0.30 via oxygen hood.

Discussion

RDS, a condition found primarily in premature infants, is characterized by respiratory failure after premature birth associated with severe atelectasis. The lack of adequate amounts of surfactant resulting in high surface tension is the major cause of alveolar collapse. To maintain alveolar ventilation, the infant must generate tremendous intrathoracic pressures with each breath, which results in increased work of breathing and eventually respiratory failure. A newborn with RDS presents with signs of respiratory distress at birth or within a few hours after birth. Diagnosis is made by clinical presentation (nasal flaring, expiratory grunting, and intercostal retraction), chest x-ray, and arterial blood gas results. The standard treatment for RDS is surfactant replacement therapy. (A premature infant born at 30 weeks is an automatic indication for prophylactic surfactant therapy.) Surfactant replacement therapy improves lung compliance by reducing surface tension, allowing alveoli to remain inflated. This improves arterial blood gas values and decreases the need for mechanical ventilation and oxygen delivery.

Although the presence of fetal lung fluid is essential for normal development of the lung, the switch from placental to pulmonary gas exchange at birth requires rapid removal of this fluid from the newborn lung. The production of lung fluid decreases shortly before term to approximately 65% of previous values. In addition, lung fluid is absorbed during labor so that only about 35% of the original lung fluid volume needs to be cleared during delivery.⁴ At the time of birth, the infant’s inspiratory effort generates an enormous amount of negative intrapulmonary pressure to fill the lungs with air. With the first few breaths, most fetal lung fluid is expelled; the remaining lung fluid is cleared by absorption through the pulmonary vasculature and lymphatic systems.

Fetal breathing movements begin at approximately 10 weeks of gestation and increase in strength and frequency as gestation progresses, increasing to a rate of 30 to 70 breathing efforts per minute during the last 10 weeks.⁴ This early respiratory activity contributes to the regulation of lung fluid and aids in the stretch of lung tissue, which influences lung growth. Fetal breathing movements appear to originate from the diaphragm and are thought to be necessary for training and developing the respiratory muscles so that they can generate enough force to overcome the surface tension of airless alveoli during the initial breath. The absence of lung fluid and breathing movements during fetal development results in an underdeveloped lung.²

CONCEPT QUESTION 16-2

What abnormality might occur in the absence of adequate amounts of fetal lung fluid?

Maternal-Fetal Gas Exchange

The placenta is a highly vascular gas-exchange organ, providing a circulatory link between mother and embryo; it is required for survival of the fetus. The fetus relies on maternal blood flow through the placenta for the exchange of nutrients and wastes, including oxygen delivery and carbon dioxide removal. The placenta separates the fetus from the endometrium (mucous membrane lining) of the uterus and consists of two compartments: (1) the fetal compartment, arising from the embryonic sac, and (2) the maternal compartment, derived from the endometrium. The placenta transports nutrients and wastes between mother and fetus through the umbilical cord. Abruptio placentae, or premature detachment of the placenta from the uterine wall, is a medical emergency and may result in life-threatening maternal hemorrhage and fetal asphyxia.

Shortly after the fertilized egg implants in the uterine wall, the placenta begins to develop with small finger-like projections invading the endometrial lining of the uterus. These projections, called chorionic villi, continue to branch further into the endometrium, creating irregular pockets around the villi called intervillous spaces (Figure 16-4). Maternal blood fills these spaces supplying oxygen and nutrients to the fetus. As the fetus matures, villi increase in number, expanding the surface area for gas exchange.

Figure 16-4 How the amnion enlarges, fills the chorionic cavity, and envelops the umbilical cord. Part of the umbilical vesicle is incorporated into the embryo as the primordial gut. A, At 3 weeks. B, At 4 weeks. C, At 10 weeks. D, At 20 weeks. E, Cutaway view of the placenta showing spiral arteries that supply maternal blood to the intervillous space and villus capillaries that supply oxygenated blood to the fetus through the umbilical vein (*red*). The umbilical arteries (*blue*) return deoxygenated blood from the fetus to the placenta. (**A-D,** From Moore KL: The developing human: clinically oriented embryology, ed 8, Philadelphia, 2008, Saunders; E, From Wilkins RL, et al, editors: *Fundamentals of respiratory care,* ed 8, St Louis, 2003, Mosby.)

Maternal blood enters the intervillous space through the spiral arteries (see Figure 16-4). At this point, the diffusion of oxygen, carbon dioxide, and metabolic products occurs between maternal and fetal blood. After this exchange, maternal blood exits the intervillous spaces through venous channels. Oxygenated fetal blood leaves the chorionic villi via capillaries that merge into a single umbilical vein.

The placenta is not a very efficient gas-exchange organ. The PO₂ of maternal blood in the intervillous spaces is about 50 mm Hg, but blood leaving the placenta through the umbilical vein to oxygenate the fetus has a PO₂ value of only about 30 mm Hg. Fetal blood returning through the umbilical arteries to the placenta for reoxygenation has a PO₂ of only about 19 mm Hg.² The maximum PO₂ experienced by the fetus is about 30 mm Hg. The primary factor limiting oxygen transport to the fetus is blood flow. Any factor diminishing uterine or fetal blood flow results in fetal hypoxia and intrauterine growth retardation (IUGR). Severe reduction in fetal blood flow may result in fetal asphyxia and death. Table 16-3 shows normal blood gas values of the umbilical arteries and veins in a full-term fetus.

TABLE 16-3

Normal Blood Gas Values in a Term Fetus

	PO₂ (mm Hg)	PCO₂ (mm Hg)	pH
Umbilical artery	19	47	7.36
Umbilical vein	30	43	7.39

The umbilical cord connecting the placenta to the fetus contains one vein that delivers oxygenated blood to the fetus and two arteries that carry deoxygenated blood from the fetus back to the placenta. Placental circulation can be compared with the pulmonary circulation in postnatal life: The placenta functions similar to the lungs. The umbilical vein carries oxygenated blood from the placenta to the fetus just as the pulmonary veins carry oxygenated blood from the lungs to the left atrium. Umbilical arteries carry deoxygenated fetal blood back to the placenta for reoxygenation, just as the pulmonary artery carries deoxygenated blood from the body back to the lungs. See the section on fetal circulation later in this chapter for a complete description of fetal circulation.

A tough gelatinous material called Wharton’s jelly surrounds the umbilical vessels, which prevents the cord from kinking and occluding blood flow to the fetus (Figure 16-5). After birth, the umbilical vessels remain open for a short time, allowing vascular access for fluid infusion and blood sampling.

Figure 16-5 Cross-section view of the umbilical cord showing the umbilical vein, arteries, and Wharton’s jelly.

CONCEPT QUESTION 16-3

What maternal factors could adversely affect gas exchange in the fetus?

Fetal Hemoglobin

Fetal blood oxygen tension is low compared with values seen after birth. As stated previously, the most oxygenated fetal blood is found in the umbilical vein with a PO₂ of approximately 30 mm Hg. Nevertheless, fetal tissues are adequately oxygenated for the following reasons: (1) the unique blood flow through fetal circulation results in increased blood flow to vital organs (liver, heart, and brain); (2) the fetus has an increased number of red blood cells and hemoglobin compared with the adult; (3) and fetal hemoglobin (HbF) has an increased affinity for oxygen compared with adult hemoglobin.⁶

HbF is the predominant form of hemoglobin in the fetus at approximately eight weeks of gestation; HbF continues to increase until the third trimester when its concentration begins to decline gradually. At 24 weeks of gestation, HbF constitutes about 90% of the total hemoglobin, whereas at birth, HbF represents approximately 70% of the total hemoglobin.⁴ The production of HbF decreases rapidly after birth, and by 6 to 12 months of age, HbF has been replaced by adult hemoglobin (HbA).⁴

HbF has a greater affinity for oxygen than HbA. This increase in oxygen affinity is associated with a left shift of the fetal oxyhemoglobin dissociation curve (Figure 16-6), which means that oxygen binds more readily to HbF. The placental transfer of oxygen from maternal blood to fetal blood is thus facilitated, allowing the fetus to survive in a relatively hypoxic environment. Therefore, a PO₂ of 30 mm Hg in the fetus corresponds to a hemoglobin saturation of 75% to 80% (see Chapter 8

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