The ontogeny of organ systems has long provided information for clinical assessment of obstetric problems. The events of embryonic and fetal development have acquired even greater clinical significance as technology of fetal assessment has become more informative. In the past, developmental phenomena were important primarily for application to teratologic problems. With the proliferation of diagnostic modalities and with effective postnatal care of the smallest infants, “applied embryology” has become a major resource for fetal assessment. This chapter summarizes the development of organ systems most frequently involved in clinical problems of the fetus and newborn infant.

The First Week

After formation of the zygote, ongoing mitoses and cleavage result in the formation of a morula (mulberry).^1,2 After 3 days, the embryo consists of 6 to 12 cells called blastomeres. At 4 days, it consists of 16 to 32 cells. It enters the uterus at about the time it develops into a blastocyst. The blastocyst is composed of an internal cavity (blastocoele), an inner cell mass (embryoblast), and an outer cell mass (trophoblast). The trophoblast completely envelops both the inner cell mass and the blastocoele. Toward the end of the first week, implantation occurs and the zona pellucida (which covers the trophoblast) is dissolved. The trophoblast then invades endometrium and is partially embedded in it.

The Second Week

By the end of the second week, the blastocyst is completely embedded in the endometrium, and the mucosal defect that was created by initial entry is repaired. The outer cell mass (trophoblast) differentiates into an external layer, the syncytiotrophoblast, and an internal layer that rapidly multiplies, called the cytotrophoblast. The syncytiotrophoblast implements deep implantation by eroding maternal tissue as syncytiotrophoblastic lacunae are formed. As erosion proceeds, blood-filled sinusoids deep in the endometrium are invaded. The syncytiotrophoblastic lacunae then become continuous with endometrial sinusoids to form a network of channels that are filled with maternal blood. This is a primitive uteroplacental circulation. The inner cell mass (embryoblast) develops into a two-tiered structure, the embryonic disk, that is composed of an ectodermal layer, which will be the embryo's dorsal aspect, and an endodermal layer, which will be its ventral aspect. The ectoderm is part of the amnion wall and ultimately invests it completely. The endoderm lines the yolk sac. By the end of the second week, an extraembryonic mesoderm develops outside of the embryonic disk, and it lines the inner surface of the cytotrophoblast.

The Third Week

During the third week the primitive streak is evident with the primitive knot at its cephalic end. With the appearance of these structures, the embryo becomes polarized; cranial and caudal, right and left orientations now are discernible. The primitive streak is a midline thickening of rapidly multiplying ectodermal cells that invaginate ventrally into the bilaminar embryonic disk. The invaginating cells develop a third cell germ layer, the intraembryonic mesoderm. These mesodermal cells inject themselves between the ectodermal and endodermal layers, and they migrate laterally to join extraembryonic mesoderm. Intraembryonic mesoderm and extraembryonic mesoderm now are continuous; the embryonic disk is a three-layered structure. The primary chorionic villi (which formed during the first week within the cytrophoblast) acquire a mesenchymal core to become secondary chorionic villi. They in turn develop into tertiary villi when permeated by capillaries that have formed from mesenchyme. Chorionic villi proliferate rapidly during the third week to acquire adequate nutrition and oxygen from maternal tissue. Later, these early villi become the fetal chorionic villi that project into the placental intervillous space, bathed by circulating maternal blood.

The embryonic period is the time of beginning organogenesis. It also is the time of peak vulnerability to the injurious factors that cause major congenital anomalies.^1,2

At the beginning of the fourth, week the embryo is trilaminar and discoid, noticeably expanded at the cephalic end. The changing contour of the embryo is influenced by internal organ development and by a continuous folding process in the cephalocaudal and transverse dimensions. The expanded cephalic end is rendered prominent by rapid growth of the brain.

Organ systems are the result of specific differentiation of each germ layer. Development of ectoderm culminates in mature organs that can perceive environmental circumstances and initiate reactions to them. Thus, the ectoderm evolves into the central and peripheral nervous systems, the special sensory organs (eye, ear, and nose), as well as the skin and its appendages. Development of mesoderm gives rise to bone, connective tissue, muscle, the cardiovascular system, blood cells, most of the urogenital system, and the adrenal glands. Early, the mesoderm forms somites, which are fundamental to body structure and contour. They appear in pairs as localized blocks of proliferated mesodermal cells on each side of the primitive neural tube. The first pair appears in the cephalic region at about the 20th day; during the ensuing few days, additional pairs of somites appear in caudal sequence. Somites impart the fundamental segmentation that characterizes a mature body. Each somite gives rise to a myotome, a sclerotome, and a dermatome. The myotome becomes muscle tissue; the sclerotome becomes cartilage and bone of the vertebrae; and the dermatome differentiates into subcutaneous tissue throughout the body. Development of endoderm produces epithelium of the respiratory and gastrointestinal tracts, and the urinary bladder. Endoderm also is the forerunner of tonsils, thyroid, parathyroids, liver, pancreas, and thymus.

Organ systems thus begin differentiation from germ layers of the trilaminar embryonic disk. During this period, the embryo is at peak vulnerability to disrupted differentiation and, therefore, to the formation of major congenital anomalies.

The fetal period begins 9 weeks after fertilization and continues to term.^1,2,3,4 The gross malformations that result from embryonic injury occur rarely during the fetal period. Rates of fetal growth vary according to the dimension involved.³ From the 9th through the 20th weeks, crown-rump length increases approximately fourfold; from the 20th week to term, the crown-rump length is only doubled, increasing by about 1 cm weekly. From the 9th to the 20th week, fetal weight increases approximately 60-fold, and from the 20th week to term, the increase is about 5-fold. The rate of weight gain is diminished, but the gain in absolute weight (in grams) is greatest during the last trimester, when normal fetal weight increases by an average of 2000 g. Daily weight gain in grams is relatively constant during the second trimester; it increases during the third trimester; a few weeks before birth it declines significantly.

Embryonic and fetal growth rates vary considerably between different organ systems and at various stages of gestation. Embryonic growth and early fetal growth are characterized by an increase in cell number (hyperplasia) and, therefore, in tissue deoxyribonucleic acid content. Later, both the size and number of cells are increased, resulting in an enhanced content of protein, ribonucleic acid, and deoxyribonucleic acid. This phase of combined cellular hyperplasia and hypertrophy continues postnatally according to schedules that vary from one organ to another. Mixed growth persists in muscle, for example, throughout adolescence, in brain through the second year of postnatal life, and in lung for 8 years after birth. The final stage of growth is mostly hypertrophic; that is, cells acquire cytoplasm, thus increasing the content of protein and ribonucleic acid.

As the fetus matures, body composition changes. Both the total water content and the extracellular water content diminish as intracellular water content increases. This trend continues after birth into adolescence. Furthermore, body protein and fat increase proportionately. Adipose tissue first appears in significant quantities during the third trimester and continues to accumulate long after birth, often in undesired quantity in adulthood. As fetal and postnatal growth proceed, there is less water, more lipid, and more protein per gram of body weight.

At the onset of the fetal period, the head accounts for half the fetal length, but its relative size diminishes, and at term it is one fourth of the body length. This trend continues to maturity.

Changes in several fetal external characteristics are noteworthy. The face becomes more infantile in appearance; the eyes, at first on the lateral aspect of the face, migrate to their mature ventral location. At 10 weeks, the eyes are closed; at 26 weeks, they are partly open and eyelashes are discernible. At approximately 28 weeks, the eyes are wide open. The ears, low set at an early stage, come to occupy their ultimate position on the head. They first stand out from the head at 16 weeks. The limbs lengthen; the external genitalia become grossly discernible at 12 weeks. Intestinal loops are within the proximal portion of the umbilical cord until the 10th or 11th weeks; they then migrate into the abdomen. Lanugo and scalp hair are identifiable at 20 weeks; lanugo mostly disappears by 36 weeks. The rapid deposition of subcutaneous fat during the last trimester contributes significantly to a cylindrical body contour, although head circumference slightly exceeds that of the chest and abdomen.

In the ninth week, erythropoiesis is active primarily in the liver; at 12 weeks, the spleen also is active. Bone marrow becomes the major site of blood cell production during the last trimester, although the liver continues some activity as late as the first postnatal week. Urine formation begins between the 9th and 12th weeks, when it is first voided into amniotic fluid. The urinary contribution to the volume of amniotic fluid increases throughout pregnancy. Although fetal movements occur earlier, they are not perceived by the mother before 16 to 17 weeks. Brown fat is first deposited at 20 weeks. It is the primary site of heat generation in utero and for several weeks following birth. The uterus is completely shaped by 18 weeks, and the vagina begins canalization. Descent of the testes begins at 20 weeks and is complete at term.

The Lungs

The fundamental mission of the lungs is gas exchange, which must be initiated immediately after birth.^1,2,5,6 Intact survival is in jeopardy if breathing is delayed for even minutes. In contrast, delayed onset of function in other organs (except for the brain stem) poses no such immediate threat to survival.

In the neonate, lung disorders fall into three broad categories: incomplete development (prematurity), improper development (congenital anomalies), and disrupted function (meconium aspiration, pulmonary vasospasm, or infection). Prediction of the capacity to breathe and assessment of postnatal disorders in any of these three categories require an understanding of the changes that characterize growth and maturation of the lung.

Lung development occurs in four progressive phases: the embryonic, pseudoglandular, canalicular, and terminal sac (alveolar) periods. During the embryonic period (22 to 26 days), a ventral endodermal diverticulum evaginates from the embryonic foregut. This anlage gives rise to lining epithelium of the entire respiratory tract, including the alveoli. The lung bud originates from the segment of gut destined to be the esophagus. Persistence of a connection between the two primitive structures (lung bud and foregut) results in one of several types of tracheoesophageal fistulas. At 26 to 28 days, the lung bud divides into two structures; each will be a mature lung. Subsequent growth of the two lung buds progresses into surrounding mesenchyme. The mesenchyme differentiates into cartilage, muscle, connective tissue, lymphatics, and blood vessels. The growth of each lung bud continues caudally and laterally into the pleural space, carrying with it the surrounding mesenchyme. Successive generations of airways, each diminishing in diameter peripherally, continue to branch during growth.

The pseudoglandular period begins at about 4 weeks and continues to the 16th week. During this period, the branching of airways and blood vessels has established the mature pattern. The airways divide actively until the 16th week, and by this time the number of airway generations is approximately equal to those of the adult. In essence, the lung is composed of proximal conducting airways and distal respiratory airways (alveolar surface), where gas is exchanged between air and blood. At 16 weeks, the number of conducting airways per segment is almost equal to that of adults, and they end blindly. They are lined with endodermal epithelium that later will line the respiratory airways and alveoli as well. The conducting airways are preacinar generations of tubules; under the light microscope, they have the appearance of an acinar gland.

The canalicular period unfolds during the 16th to the 24th gestational weeks. During this interval, blood vessels proliferate profusely from mesenchyme around terminal segments of tubules, which were formed during the pseudoglandular period. The blood vessels proliferate adjacent to tubular cuboidal epithelium while additional branches of the airway develop to establish the respiratory (alveolar) gas exchange surface. Multiple shallow outpouchings form along the walls of these newly extended respiratory bronchioles; these are primitive alveolar structures. Bronchioles now terminate in multiple saccules, lined by flat epithelium that is enveloped by proliferating capillaries. At about 22 weeks, a small surface area can accommodate gas exchange between air and blood. Interstitial tissue is interposed between airways; it constitutes a large proportion of the total tissue mass. The connective tissue is responsible for poor lung compliance because even if the airways were more mature, poor compliance would preclude adequate lung expansion for air intake. At this stage of maturation, some terminal airway cells contain cytoplasmic lamellar substance that is precursor to active surfactant. The small quantity that can be generated is insufficient for airway stability. By the end of the canalicular period (22 to 24 weeks), the average fetus weighs approximately 500 to 600 g. The number of intracellular lamellar bodies increases; cells now are recognizable as type II alveolar cells. The surface area for gas exchange is remarkably enlarged as a result of extensive capillary invasion. Extrauterine survival at 22 weeks cannot be anticipated, but some infants can be maintained by appropriate mechanical ventilatory support. The terminal sac or alveolar period begins with the 25th gestational week. During this interval, development of the respiratory portion of the airway involves an increased number of respiratory bronchioles and saccules. All are lined by flattened epithelium. The surface area for gas exchange is now sufficient to accommodate extrauterine breathing. Thus, at 22 to 23 weeks if liveborn, some infants can breathe successfully but only with appropriate mechanical support. At this age, their weights are approximately 500 to 600 g. The respiratory bronchiolar segment of the airway, which is distal to the last conducting tubule, is highly vascularized, whereas its epithelial lining has become remarkably attenuated at the points of capillary contact. The air spaces are primitive alveoli. The airways terminate in groups of saccules that still are widely separated by an abundant connective tissue. Although the terminal airways are marginally functional for gas exchange, they still are immature. The primitive alveoli are considerably more shallow than mature ones. Direct airway-capillary contact still is limited. The large quantity of interstitial connective tissue impairs compliance. Further, it poses a barrier to gas exchange where capillaries have not become apposed to airways.

At 27 to 28 weeks, the fetus weighs 900 to 1000 g. More capillaries now contact walls of alveolar sacs, which themselves are increased in number. The alveolar sacs constitute most of the cross-sectional area of the lung; previously, the bronchioles were more prominent. Connective tissue spaces between terminal units remain relatively extensive; lung compliance still is poor. The expansive connective tissue space probably accounts for the ease with which fluid accumulates in the lung postnatally because in the premature infant, the lung is a veritable sump. Furthermore, because the connective tissue space is large, it accommodates a considerable volume of extra-alveolar air (interstitial emphysema) in infants whose alveoli rupture from high pressures generated by mechanical ventilatory support. At lower gestational ages, extra-alveolar air likely remains in the interstitial space rather than bursting through the hilum or visceral pleura to form a pneumothorax, as is more usual in infants over 32 weeks.

At 28 to 29 weeks, the average fetus weighs 1000 to 1100 g. Further differentiation occurs at the distal ends of airways; terminal saccules are more copiously lined with mature type II cells from which surfactant is released. More capillaries are in direct contact with alveoli. At this stage of development, most infants can be sustained with mechanical ventilatory support. From 30 to 33 weeks, new alveolar units are rapidly generated. Interstitial tissue still is extensive; alveolar walls are thicker than they will be at term. Saccules still are shallow. At 34 to 36 weeks, most pulmonary growth is in the alveoli. The need for ventilatory support is more related to dysfunction from perinatal misadventure than to immature development. If unstressed, the neonate ventilates independently. Congenital malformations are best understood with knowledge of pulmonary development. Agenesis of the lung and tracheal stenosis are the result of maldevelopment of the primitive lung bud. Tracheoesophageal fistulas of various types probably originate from early branching of the lung bud. Defective deposition of bronchiolar cartilage from embryonic mesenchyme causes a syndrome of deficient cartilaginous rings in which bronchi collapse for lack of supporting cartilage. Congenital lung cysts are detachments of respiratory bronchioles, alveolar ducts, and sacs from the proximal airways with which they should be continuous. The cysts are enlarged progressively by trapped fluid that is secreted by cells in respiratory bronchioles.

The fetal lungs are metabolically active even though they have no ventilatory function. Blood vessels are narrow, and alveoli are filled with lung fluid that differs in origin and composition from amniotic fluid. Lung fluid, derived from cells in the airway, is less viscous, and it contains lower protein concentrations than amniotic fluid and plasma. Diminished viscosity presumably facilitates postnatal evacuation during the first breaths.

Postnatally, the chest diameter increases rapidly, largely because of new alveoli and respiratory bronchioles. Alveolarization is rapid from late fetal to neonatal stages. The process may be complete by 1 year after birth. At term, estimates of the number of alveoli vary from 50 million to 150 million. At 3 months, there are 77 million, and in the adult, 200 million to 600 million alveoli. At term, the alveolar sacs are 50 μm in diameter compared with 100 to 200 μm in older children and 200 to 300 μm in adults. The adult surface area for gas exchange is about 20 times greater than that of the neonate, which is close to the relative increment of adult over neonatal body weight.

Heart

The first sign of cardiac development appears at 18 or 19 days, when a few mesenchymal cells begin differentiation into angiogenic clusters.^1,2,7,8,9 The cells are first located on the lateral sides of the embryo, but as they proliferate, they spread in a cephalic direction to form a primitive plexus of small vessels anterior to the neural plate. These small vessels constitute the cardiogenic area. With simultaneous growth of the central nervous system in a cephalic direction, the cardiogenic area occupies a position that is caudal to the developing brain. Within the cardiogenic area, two longitudinal strands of cells are formed. They canalize to become the first cardiac structures. These are endocardial heart tubes, which fuse to form the single primary heart tube. Fusion begins at the cranial end of the endocardial tubes and progresses caudally. Surrounding the fused primary heart tube is a mass of thickened mesenchyme called the myoepicardial mantle, which differentiates into mature myocardium and visceral pericardium.

Continued growth of the straight primary heart tube causes looping and segmentation. Looping occurs as the heart tube is bent on itself to form a U-shaped structure and then an S-shaped one as the looping process continues. Segmentation gives rise to several dilations along the tube, each demarcated by intervening constrictions. From the venous to the arterial end, blood flows through the following dilatations and constrictions: (1) the dilated sinus venosus and primitive atrium, (2) the constriction of the atrioventricular canal, (3) the dilated primitive ventricle, and (4) a constriction that delineates the primitive ventricle from (5) the bulbus cordis. The bulbus gradually narrows without constriction to become the truncus arteriosus. As the primitive heart grows and bends more acutely, the atrium and the sinus venosus together assume positions dorsal to the ventricle, bulbus cordis, and truncus arteriosus. The sinus venosus becomes cornuate with the appearance of two lateral extensions, the right and left horns of the sinus venosus. As these changes occur, the bending tube anchors to the septum transversum at the sinus venosus (caudal end), and to the aortic sac at the truncus venosus (cranial end). The aortic sac gives rise to the sixth aortic arches.

During the fifth week, a ridge begins to project from the wall into the lumen of the truncus arteriosus and bulbus cordis. When the process is complete, the ridges form a continuous single spiral septum that runs through the truncus and bulbus. This is the aorticopulmonary septum; it divides both the bulbus and truncus into two generally parallel channels. The two channels of the truncus arteriosus become the roots and proximal portions of the aorta and pulmonary artery. The split bulbus becomes the right and left ventricular outflow tracts. The sinus venosus initially is a single chamber that opens into the wall of the right atrium. The subsequently formed left horn forms the mature coronary sinus; the right horn becomes incorporated into the wall of the right atrium.

The four cardiac chambers develop between the fourth and seventh weeks. The common atrium is divided by growth of the septum primum and, later, of the septum secundum. The septum primum grows from the roof of the common atrium toward the endocardial cushion. The ostium primum is a gap between the septum's leading edge and the endocardial cushion; the ostium is obliterated gradually as the septum grows toward and fuses with the endocardial cushion. Several perforations appear at the dorsal aspect of the septum primum; they coalesce to form the foramen secundum. About a week later, the septum secundum is generated as crescentic membrane that emanates from the atrial wall and grows parallel and immediately to the right of the septum primum. As it grows it obliterates the foramen secundum, but because of incomplete septal growth, another aperture, called the foramen ovale, appears. A window thus persists between the two atria, and it is not obliterated until the first breaths are taken soon after birth (see later).

As septation of the common atrium progresses, separation of atrium and ventricle progresses simultaneously. Endocardial cushions fuse to divide the single channel between the atrial and ventricular chambers (common atrioventricular canal) into two parallel passages: the right (tricuspid) and left (mitral) atrioventricular canals. The common ventricle becomes two chambers when the interventricular septum is complete. The septum consists of muscular and membranous portions. The muscular portion is formed first, deriving from three sources within the ventricles. The membranous part, arising from endocardial cushion tissue, completes the separation of left and right ventricles when it fuses with the muscular septum. The embryonic arches give rise to the mature major arteries of the thorax, head, and neck. The arches arise from the aortic sac, which is a cephalic continuation of the truncus arteriosus. The arches grow around the foregut from the aortic sac to join a pair of dorsal aortae. Although six arches develop, they are not present simultaneously. By the time the sixth arch is formed, the first two have disappeared.

The first two pairs of arches contribute to portions of arteries in the head and neck. The third pair of arches forms the common carotid and part of the internal carotid arteries. The left fourth arch becomes the mature aortic arch. The proximal ascending aorta is derived from the truncus arteriosus. The distal ascending aorta arises from the aortic sac. The right fourth aortic arch becomes the proximal segment of the right subclavian artery. The fifth pair of arches degenerates without giving rise to mature structures. The left sixth arch contributes to the proximal portion of the left pulmonary artery and to the entire ductus arteriosus. The right sixth arch becomes the proximal part of the right pulmonary artery.

The dorsal aortae, at first a pair of vessels that receive aortic arches from the ventrally placed aortic sac, contribute to several mature arterial structures. The left subclavian artery is derived from the left dorsal aorta, whereas the right subclavian arises from its counterpart on the right. Most of the left dorsal aorta becomes the distal section of the mature aortic arch and the descending aorta. On the right, the upper part of the dorsal aorta becomes the proximal portion of the right subclavian artery. The lower part of the right dorsal aorta degenerates.

Peristaltic contractions of the heart begin on the 22nd day, originating intrinsically in the muscle. Blood flow at first is to and fro, but becomes unidirectional by the end of the fourth week; contractions become coordinated. Although the primary function of circulating blood is the dissemination of oxygen and nutrition to all parts of the developing body, the circulatory pattern also must develop functional continuity with, and physical separation from, the maternal placental circulation.

The First Breath: Critical Endpoint of Pulmonary and Cardiovascular Development

Initiation of extrauterine breathing is a joint cardiovascular and pulmonary undertaking.^{5,10,11,12,13,14,15,16,17} Most publications describe the event in a context of pulmonary development, whereas discussion of circulatory changes at birth usually is considered separately in sections on cardiovascular development. The fact is that developmental cardiovascular and pulmonary functions are inextricable in the initiation of extrauterine breathing.

During intrauterine life, exchange of gases occurs across the placental membrane from one liquid medium to another. After birth, the exchange must occur across the alveolar membrane between air and liquid. Among the multiple adaptations that an infant must make at birth, the need to breathe air is the most urgent and critical. Four prerequisites must be satisfied to do so:

1. Initial respiratory movements must be stimulated.
   
2. Air must fill the airway; opposing forces must be overcome if lungs are to expand.
   
3. Some air must remain in alveoli at end-expiration (establishment of functional residual capacity [FRC]).
   
4. Pulmonary blood flow must increase and cardiac output must be redistributed.
   

The events that constitute initial respiration transpire simultaneously, and in normal circumstances they are established (if not completely) within seconds after birth.

INITIATION OF RESPIRATORY MOVEMENTS.

The precise roles of the various stimuli that bombard the infant to initiate respiratory movements after birth have not been clarified. Their separate effects are difficult to delineate. The identification of intrauterine respiratory movements suggests that extrauterine breathing is a continuation of fetal respiratory movements. The neonate may be well practiced by virtue of the fetal experience. If this experience explains the ease with which regular respirations are established after birth, additional explanation is required for the enhanced vigor with which the first extrauterine breaths are activated.

Asphyxia (low arterial PO₂, low pH, and high PCO₂) is a significant stimulant. It stimulates carotid and aortic chemoreceptors, and the medullary respiratory control center. These asphyxial changes are present at birth in most normal newborn infants, and they are potent activators of the first breath. In the moments before the onset of respiration, oxygen saturation is 9% to 96% in umbilical venous blood, whereas umbilical artery blood ranges from 0% to 67%. Yet, many of these transiently hypoxemic infants are vigorous even though oxygen saturations are below 10% in many of them. Some have no measurable oxygen, but they breathe spontaneously within seconds after delivery. The average PCO₂ at birth is elevated to 58 mm Hg, and the mean pH is depressed to 7.28 or lower. Presumably, these short periods of asphyxia are characteristic of normal birth. Metabolic acidosis is absent (normal buffer base); respiratory acidosis (high PCO₂ and diminished pH) is the rule. The first breath may be a deep inspiratory gasp, stimulated by hypoxia, that is not unlike gasps caused by asphyxia in utero. Conversely, protracted asphyxial episodes are another matter. Longer periods of hypoxemia lead to lactic acid accumulation and, therefore, metabolic acidosis in addition to respiratory acidosis. Short asphyxial episodes stimulate the first breath; prolonged asphyxial episodes depress it.

Cold stress is another important stimulus to the onset of breathing. Skin temperature falls in response to an abrupt exposure to room air. The baby leaves a warm fluid environment at 98.6°F and is thrust into a cool, dry one at 70° to 75°F in an air-conditioned delivery room. This sudden change in ambient temperature stimulates nerve endings (thermal receptors) in the skin, with subsequent transmission of impulses to the medullary respiratory center. This probably is an intense stimulus; the response is instantaneous. The rapid onset of breathing requires an instantaneous response. Lambs fail to breathe when delivered into a saline bath that is at normal body temperature. During the first few minutes after delivery, core temperature falls at a rate of approximately 0.2°F per minute; the decline in skin temperature is three times greater.

ENTRY OF AIR INTO THE LUNGS AND EXPANSION OF ALVEOLI.

Studies on the initiation of breathing indicate that normal respiratory efforts begin at 0.5 to 72 seconds after birth (mean, 18 seconds). Air enters the lungs as soon as intrathoracic pressure falls with descent of the diaphragm. Entry of air is opposed by surface tension forces at air-fluid interfaces and by viscous forces from lung fluid that fills the airway. These forces normally are overcome and the lungs are aerated immediately after birth. Lung fluid is not completely absorbed for 12 to 24 hours; within 2 hours after birth, 70% usually is evacuated. The significance of unopposed surface tension forces become apparent later in this discussion.

Transpulmonary pressures of 35 to 40 cm H₂O usually are required for the first inspiration, but opening pressures as high as 100 cm H₂O occasionally are necessary. Some investigators have found considerably lower transpulmonary pressure during initial breathing efforts. Negative thoracic pressure is mostly created by diaphragmatic descent. The role of chest recoil after delivery probably is insignificant. After the first inspiration, a larger positive intrathoracic pressure (mean, 70 cm H₂O) is generated during expiration. It is generated by closure of the glottis, either complete or partial, as the baby forces air out the airway. These are the moments in the delivery room when a welcome lusty cry is first heard. The high expiratory pressure thus created distributes air throughout the lung while promoting evacuation of fluid across alveolar membranes by providing a pressure gradient from airway to interstitium.

The entry of air into the lungs and the expansion of alveoli require a mechanism for minimizing or eliminating surface tension forces and a mechanism for evacuating lung fluid.

SURFACE TENSION AND SURFACTANT.

Alveolar walls are largely liquid; they envelop air. Surface tension forces are activated when an air-liquid interface is created as air descends into the respiratory tract. Intermolecular attraction contracts the surface area of the liquid alveolar wall. In accordance with the LaPlace equation, the smaller the alveolus, the stronger are surface tension forces; they vary inversely with the square of the alveolar radius. The smaller the alveolus, the greater the tendency to collapse if surface forces are unopposed.

Pulmonary surfactant is composed of approximately 10 compounds. It consists predominantly of phosphatidylcholine (lecithin) and, to a lesser extent, of cholesterol, neutrolipids, or other phospholipids. Quantitatively, the major component is phosphatidylcholine. This is the compound most active in lowering surface tension. Another important component of surfactant is phosphatidylglycerol. The phosphatidylglycerol fraction of surfactant is considerably smaller than that of phosphatidylcholine, but interest in phosphatidylglycerol stems from a close correlation between its appearance and lung maturity.

Surfactant is synthesized in type II alveolar cells. It is stored for a long time before its discharge (by exocytosis) onto the alveolar membrane. At this site, it diminishes the collapsing effect of surface forces on the alveoli.

In the normal lung, surface tension is minimized or eliminated by surfactant. The substance appears in fetal lung at 22 to 24 weeks of gestation. Without surfactant, surface tension forces increase as alveoli deflate during expiration, ultimately resulting in collapse. In the presence of surfactant, surface tension forces diminish during deflation because surfactant molecules are compressed. In the compressed state, surfactant eliminates surface forces by obliterating the air-liquid interface. Conversely, the surfactant layer becomes attenuated during alveolar expansion. Molecules in the surfactant layer are separated from each other and an air-liquid interface develops momentarily. The influence of surfactant is thus least at peak inspiration. At this point, surface tension reinforces initiation of deflation in the intrinsically elastic lung.

When surfactant is diminished in lungs of premature infants, hyaline membrane disease (respiratory distress syndrome) evolves. Surfactant eases the initial opening of alveoli at relatively low pressures. It also prevents alveolar collapse from surface forces at end-expiration. Alveolar stability, once established, provides easy lung expansion at relatively low pressures during subsequent inspirations. It contributes to the evacuation of lung fluid by maintaining alveolar stability. Were the alveoli to collapse at end-expiration, fluid would remain in interstitial tissues and return to alveolar lumens in response to surface tension. Surfactant promotes capillary circulation by maintaining maximal alveolar diameter, thus dilating precapillary vessels.

LUNG FLUID.

At term, the fetal lung is filled with liquid of intrapulmonary origin. The volume of liquid is approximately equal to the FRC that is established soon after the onset of breathing (30 to 35 mL/kg). The fetal lung is therefore not collapsed, but rather it is distended with fluid until displaced by entry of air. Lung fluid maintains the patency of the developing airway. It appears early in gestation, and as it accumulates, recurrent periodic expulsion of small quantities from the lungs propels it to the posterior pharynx and thence into amniotic fluid. Because fetal lung fluid contains surfactant, this mechanism is the basis for determinations of surfactant levels in amniotic fluid. Lung fluid is generated at a steady rate throughout gestation; its formation diminishes considerably at term, during 48 hours preceding onset of labor. Fetal fluid is critical to normal lung development; in fetal lambs, its protracted drainage through a tracheal catheter is associated with pulmonary hypoplasia.

The pH, bicarbonate, and protein content of lung fluid are lower than those of amniotic fluid; its osmolality, sodium, and chloride concentrations are higher. Protein content of lung fluid also is considerably lower than that in plasma, thus providing an osmotic gradient that favors migration of fluid from alveoli and interstitium into blood capillaries.

Fetal lung fluid imposes a major force against the entry of air during the first breath. During descent through the birth canal, a strong thoracic squeeze on the fetal chest expels 30 to 35 mL of the fluid, which is approximately one third of its total volume in a 3.0-kg neonate. Expulsion of lung fluid often is observable during delivery as the head extrudes while the chest is still compressed within the birth canal. Delivered by section, some term infants absorb all lung fluid in the absence of oral drainage. Generally, babies delivered by elective cesarean section have a tendency to retain larger volumes of fluid; they do not evacuate it as rapidly as infants delivered vaginally. Transient tachypnea of the newborn (RDS II) is more common after elective sections and is thought to be caused by delayed resorption of pulmonary liquid. Most of the fluid (probably two thirds of it) is evacuated across alveolar membranes into capillaries or into interstitial tissue to lymphatic vessels. The rate of fluid evacuation by each of these routes has not been defined, but data from animals indicate that half of the absorbed lung fluid is evacuated through the lymphatics, and the remainder through blood capillaries.

Several mechanisms seem to be active in promoting fluid removal during early breathing. First, continuous secretion diminishes 48 hours before birth by an unknown mechanism. Second, the pressure relationship between airway (alveoli) and interstitial tissue is altered when descent of the diaphragm generates negative intrapulmonary pressure. Pressure in the interstitial tissue becomes lower than in alveoli, and fluid flows from alveoli to interstitial space along this gradient. Third, expansion of the lungs stretches alveolar walls to enlarge their pores. In the neonate, the pores are 6 to 10 times larger after lung expansion than they were before birth. Increased permeability of alveolar membranes and changes in pressure gradients combine to promote displacement of fluid to the interstitial tissue and to the lymphatics and capillaries. The fourth mechanism in removal of lung fluid entails a decrease in pulmonary vascular pressure and an increase in pulmonary blood flow, both inherent to the circulatory changes that occur during the first breaths (see later). Fluid is displaced from interstitium to blood vessels, along the pressure gradient that is extended to the pulmonary circulation. A fifth mechanism involves the oncotic gradient produced by considerably higher concentration of protein in plasma than in lung liquid. New movement of water from interstitial tissue to blood capillaries is enhanced by osmosis.

Perhaps more important than any of these mechanisms is the active transport of sodium ion across pulmonary epithelium. This moves liquid from potential airway lumen to interstitial tissue and thence to lymphatic and blood vasculature. Sodium ion secretion starts to replace pre-existing chloride ion secretion at about the time of onset of labor, perhaps sooner. The effect is a reversal of fluid flow to the peripheral lung for ultimate evacuation during the immediate postnatal hours.

In essence, the neonate takes the first breaths into a veritable bag of water, which is removed from alveoli into interstitial tissue, and then into the lymphatics and capillaries. In the normal term infant, displacement to interstitial tissue is rapid, often instantaneous. Complete removal into lymphatics and capillaries may take several hours.

ESTABLISHMENT OF FUNCTIONAL RESIDUAL CAPACITY.

Normal respiration requires an alveolar air residuum at end-expiration to maintain a partial lung expansion. The retained air is the functional residual capacity.

At term, in normal human lungs, the first expansion may require an opening pressure of 80 to 100 cm H₂O. Some investigators have demonstrated considerably lower pressures. At end-expiration, intrathoracic and atmospheric pressures are equal. However, to keep airways patent and alveoli distended in relatively stiff lungs during the deflations of early breathing, a positive pressure of 20 to 30 cm H₂O is maintained for short intervals by partial closing of the glottis. The normal infant forces air through a partially closed glottis; this produces the assuring lusty cry. Lung compliance during the first few minutes after birth is only 20% to 30% of its ultimate value several days later. Furthermore, during the earliest moments, airway resistance is two to four times greater than it will be later. Producing a high positive pressure during expiration enhances establishment of FRC. At 10 minutes of age, FRC is approximately 17 mL/kg body weight; at 30 minutes, it has expanded to 25 to 35 mL/kg, and it remains at that volume until about 4 days of age. Recent studies suggest that the neonatal maximum for FRC is attained as early as 3 hours after birth.

If all is well, after the first few breaths the lungs retain about 25% of peak inspiratory volume. From a partially expanded state at the end of the first breath, the second and subsequent breaths require considerably less effort. Small pressure changes produce more extensive lung inflation; high opening pressures required at first are unnecessary later because partial alveolar expansion is maintained at end-expiration and compliance is enhanced. Normal alveolar stability (and thus FRC) is not possible in the absence of adequate surfactant activity.

If the quantity of surfactant is suboptimal, alveolar collapse and failure to retain air are inevitable. Because surfactant activity is deficient, expansion of the immature lung is different from that of the mature one. At end-expiration, alveolar collapse occurs in immature lungs in response to unopposed surface tension forces. When normal FRC is not established, succeeding inflations require high opening pressures. The work of respiration is heavy; continuous alveolar gas exchange is impaired; the infant fatigues rapidly.

CIRCULATORY ADJUSTMENTS: REDISTRIBUTION OF CARDIAC OUTPUT.

Cardiovascular adaptation to extrauterine life proceeds simultaneously with lung expansion. The attributes of the fetal circulation that require alteration fall into two broad categories:

1. Pressure relationships between pulmonary and systemic circuits
   
2. Sites of venous admixture
   

The two factors of pivotal significance in initiating these changes are removal of the placenta and expansion of the lungs.

PULMONARY-SYSTEMIC PRESSURE RELATIONSHIPS.

The placenta receives 40% to 50% of the fetal cardiac output. Fetal placental vessels offer little resistance to blood flow. Blood enters the placenta from the aorta, and it returns to the inferior vena cava, thus making the placenta a prominent low-resistance component of systemic circulation. Clamping the cord eliminates the low-resistance placental vascular bed. As a consequence, the aortic blood pressure rises. Simultaneously, return flow to the inferior vena cava is reduced, and a small drop in pressure occurs on the venous side of the circulation. Pulmonary artery pressure is higher than aortic pressure in the fetus because pulmonary vascular resistance is high. Resistance to blood flow through the fetal lungs permits only 5% to 7% of cardiac output to perfuse them. This is in sharp contrast to low resistance in the placental circuit, which steadily accommodates 40% to 50% of cardiac output. If the lungs expand sufficiently, vasodilation causes a precipitous fall in pulmonary vascular resistance within minutes. Resistance has been calculated to fall by 80% from fetal levels. A more gradual reduction in resistance is seen over the next 6 to 8 weeks. With abrupt diminution of resistance, pulmonary blood flow perfusion increases sharply. Relaxation of the pulmonary arterioles occurs principally in the precapillary segments.

With the first breath, pulmonary vascular resistance drops instantly, and blood flow increases approximately 10-fold. The abrupt decrease of pulmonary vascular resistance is largely attributable to increased oxygen tension and to expansion of the lungs with a gas. Either of these factors alone has been shown to diminish pulmonary vascular resistance and thus enhance blood flow. Simultaneous occurrence of both factors produces the most enhancement of pulmonary perfusion.

The precise mechanism is unknown, but oxygen is apparently a strong stimulus for the release of nitric oxide from endothelial cells. Nitric oxide is an inorganic gas, a free radical that was formerly known as endothelium-derived relaxing factor. By increasing concentrations of cyclic guanylic acid (cGMP) and activating protein kinase G; smooth muscle relaxes to reduce vascular resistance and increase pulmonary perfusion during the first breaths.

High fetal pulmonary arteriolar resistance is not solely a function of constriction. The relative thickness of the muscle layer is considerably greater than later in postnatal life. The gradual diminution of vascular resistance that occurs over the first 6 to 8 weeks is related to thinning of the muscle layer rather than to ongoing relaxation of existing muscle. In summary, initial lung expansion and adequate oxygenation diminish pressure in the pulmonary circuit by relaxation of arterioles. At the same time, systemic blood pressure increases because of increased resistance to flow that is brought about by removal of the placenta. With reversal of pressure relationships in the pulmonary and systemic circuits, the stage is set for elimination of the fetal sites of venous admixture.

FETAL SITES OF VENOUS ADMIXTURE

Closure of the Foramen Ovale.

The foramen ovale is covered by a thin flap of tissue that opens like a door in only one direction—into the left atrium. Because in the fetus, pressure in the right atrium is higher than in the left (because pulmonary circuit pressure is high), the flap is held open to permit most of the well-oxygenated blood from the inferior vena cava to flow from the right atrium to the left. The position of the flap depends on the pressure relationship between the atria. If pressure in the right atrium is higher than in the left, the flap opens and blood flows from right to left. This is normal for the fetus. When pressure in the right atrium is lower than in the left, the flap closes. This is normal for the neonate. Lung expansion during the first breaths causes an abrupt decline in pulmonary vascular resistance and a marked increase in pulmonary blood flow, thus increasing the volume of blood that flows in to the left atrium (pulmonary venous return). As a consequence, left atrial pressure rises while right atrial pressure falls because of diminished pulmonary vascular resistance. The pressure relationship between the atria is now reversed. When the left atrial pressure increases over that of the right, the open flap closes against the margins of the foramen ovale, which is now functionally closed. The tissue flap does not adhere to the atrial septum for several months, sometimes for years. It is held in the closed position by the higher left atrial pressure. If right atrial pressure becomes higher than the left, the foramen reopens.

Closure of the Ductus Arteriosus.

The fetal ductus arteriosus is a large vessel, almost equal in diameter to the pulmonary artery. A substantial muscle layer has the capacity to obliterate its lumen by constriction. Constriction occurs in response to increased arterial PO₂. Ductal vasoconstriction to oxygen contrasts with the vasodilation of pulmonary arterioles. If the lungs do not expand normally, failure of PO₂ to rise causes sustained ductus patency and pulmonary arteriolar constriction. Normally, functional closure of the ductus is completed every 24 to 96 hours after a term birth. Anatomic closure usually is complete by 3 weeks of age. In premature infants, the ductus remains patent for much longer periods of time because the capacity to constrict in response to elevated oxygen tension is not developed. In the presence of prostaglandins, heightened oxygen tension fails to constrict the ductus. The effectiveness of prostaglandins in precluding the effect of oxygen on ductal constriction is a function of gestational age. As gestational age progresses, the influence of prostaglandins diminishes. At or near term, the ductus is sensitive to the constricting influence of rising PaO₂ during early breathing.

Closure of the Ductus Venosus.

In the fetus, the ductus venosus provides a direct connection between the portal venous circulation and the inferior vena cava. Blood in the umbilical vein passes through the liver into the ductus venosus, and thence to the inferior vena cava. The mechanism of closure of the ductus venosus is not known. After birth, little blood flows through it; anatomic closure is completed in approximately 7 to 10 days.

The Gastrointestinal Tract, Liver, and Pancreas

As a result of folding in the cephalocaudal and lateral dimensions, the dorsal part of the extraembryonic yolk sac is incorporated into the embryo at about 4 weeks to give rise to the primitive gut.^1,2,18,19,20 The primitive gut is an elongated tube that extends the entire length of the embryo. At this stage, the primitive gut is composed of the foregut and hindgut, each ending blindly, and the midgut, which is connected to the yolk sac by the yolk stalk.

The foregut begins just caudal to the lung bud and extends to the liver outgrowth. The latter makes its appearance at about 4 weeks. The midgut begins just past the liver outgrowth and extends to the junction between the proximal two thirds and distal one third of the mature transverse colon. The hindgut extends from this point to the cloacal membrane.

The foregut gives rise to the pharynx and lower respiratory tract, the esophagus and stomach, the duodenum proximal to the bile duct opening, the liver and biliary apparatus, and the pancreas. At maturity, all of these derivatives, except the pharynx, respiratory tract, and most of the esophagus, receive their blood supply from the celiac axis. The circulatory supply of most of the gut is from blood vessels that originally were situated in the yolk sac.

The midgut develops into the small intestine (including the distal duodenum), the cecum and appendix, the ascending colon, and the proximal two thirds of the transverse colon. At maturity, these structures are supplied by the superior mesenteric artery.

Derivatives of the hindgut include the distal one third of the transverse colon, the descending colon, the sigmoid, rectum, and the superior segment of the anus. The blood supply of these mature derivatives is provided by the interior mesenteric artery. The cloaca is the terminal portion of the hindgut. It is an endodermal cavity that contacts the ectodermal surface distally. The cloaca gives rise to the proximal two thirds of the anal canal and the ectodermal proctodeum develops into the distal one third. The cloaca is divided into an anterior portion (urogenital sinus) and a posterior portion (anorectal canal) by the urorectal septum, which slowly grows caudally.

DEVELOPMENT OF FOREGUT DERIVATIVES.

The trachea and esophagus are partitioned at the time of lung bud outgrowth by the tracheoesophageal septum. The esophagus elongates largely as a function of the cranial displacement of the primitive pharynx. The esophageal epithelium obliterates the lumen by proliferation; recanalization occurs by the end of the eighth week. The esophagus is composed of striated muscle at its upper reaches and smooth muscle at the lower. The striated muscle is derived from mesenchyme in the lower branchial arches, whereas the smooth muscle of the lower esophagus is from splanchnic mesenchyme. Esophageal atresia and tracheoesophageal fistulas are thought to result from defects in growth of the tracheoesophageal septum. Esophageal atresia also may be the result of defective recanalization. The well-known association of polyhydramnios and esophageal atresia is the result of obstructed swallowing of amniotic fluid. Esophageal stenosis generally occurs at the lower portions of the esophagus, probably as a result of disrupted recanalization.

The stomach is distinctly recognizable during the fourth week. It appears as a dilation of the caudal end of the foregut. During its enlargement, the stomach rotates 90 degrees in a clockwise direction on its longitudinal axis. The primitive left side becomes the mature anterior surface of the stomach, and the right side becomes the posterior surface.

The duodenum develops during the fourth week from the caudal part of the foregut and the cranial portion of the midgut. As a result of its dual derivation, the duodenum receives blood from both the celiac and superior mesenteric arteries. Between the fifth and sixth weeks, its lumen is transiently occluded by epithelial cells, but it recanalizes 1 or 2 weeks later. Duodenal stenosis is the result of incomplete canalization. Stenosis may occur in any portion of the duodenum, but it is most frequent in the third (horizontal) or fourth (ascending) portions. These sites are distal to the entry of bile into the proximal duodenum. Retention of bile-stained gastric content is a common sign in affected neonates. Duodenal atresia is the result of the total failure of recanalization. Short segments of the duodenum are completely obstructed. In most instances, the second (descending) and third (horizontal) portions of the duodenum are involved. In affected neonates, dramatic distention of the first part of the duodenum and the stomach produce the widely recognized “double bubble” sign of obstruction on x-ray studies. Accumulated gastric fluid is characteristically bile stained.

The primordium of the liver (hepatic diverticulum, liver bud) arises from endoderm at the distal end of the foregut in the middle of the third week. Subsequently, growth is characterized by proliferation of cell strands that penetrate the septum transversum, which is a platelike mesodermal structure that incompletely separates the thoracic from the abdominal cavities. The septum transversum also gives rise to a major portion of the diaphragm. The growing cell strands evolve into hepatic cords that anastomose and surround endothelium-lined spaces that develop into hepatic sinusoids. Proliferating cell strands from the liver bud also give rise to the intrahepatic bile ducts. The extrahepatic bile ducts are formed by narrowing of the proximal portion of the growing liver bud. A small outpouching in this area produces the gallbladder and the cystic duct. Hemopoietic cells, Kupffer cells, and connective tissue are derived from the mesenchyme of the septum transversum. With growth, the liver enlarges disproportionately to surrounding organs; by the end of the second month, it constitutes 10% of total embryonic weight. The large size of the liver is attributable to hemopoietic activity, which continues until late in fetal development, when the bone marrow replaces the liver as a major site of hemopoiesis. At term, the liver is but 5% of the total body weight.

The anlage of the pancreas appears at about the fifth week. The pancreas develops from two diverticula that arise from the caudal end of the foregut while it is developing into the proximal part of the duodenum. These are dorsal and ventral pancreatic buds; they arise from endoderm. The dorsal bud is larger, and it gives rise to most of the pancreas. The pancreatic buds fuse and the ducts that develop from each of them also fuse. The pancreatic acini develop around the primitive ducts. The islets of Langerhans develop from ductal cells that separate from their tubular origin. Insulin is secreted at about 20 weeks.

DEVELOPMENT OF MIDGUT DERIVATIVES.

The midgut lengthens rapidly, soon outgrowing available space in the abdominal cavity. At the beginning of the sixth week the midgut migrates into the umbilical cord, carrying with it the superior mesenteric artery. Continued growth during the period of herniation into the umbilical cord forms loops of jejunum and ileum. The loop rotates counterclockwise around the superior mesenteric artery. At approximately 10 weeks, the herniated intestines return to the abdominal space. During the process of regression into the abdomen, the intestines continue their counterclockwise rotation. As a result, the proximal jejunum re-enters the abdominal cavity first, and it occupies the left side. The loops that follow gradually come to rest to the right. The last segment of gut to re-enter the abdomen is the cecal swelling, which appears at the caudal end of the returning primitive loop. At first, it occupies the right upper quadrant directly beneath the liver. It subsequently migrates inferiorly into the right iliac fossa while the ascending colon and hepatic flexure develop.

Congenital malformations of the midgut are caused by the following: faulty rotation and fixation of intestinal loops during the process of reentry into the abdominal cavity, incomplete return of intestinal loops from the umbilical cord, intrauterine vascular accidents that preclude normal blood supply to segments of the intestine, and persistence of embryonic ductal structures that connect the primitive gut to other cavities.

Malrotations and faulty fixations present themselves clinically as various forms of intestinal obstruction such as the type caused by peritoneal bands. Vascular occlusion may follow volvulus, which is itself caused by faulty fixation. Omphalocele is the result of incomplete return of the midgut loop from its temporary position in the umbilical cord. The omphalocele may contain a small segment of intestine, or it may contain the entire midgut loop. The omphalocele is a persistent hernial sac that is covered by peritoneum and by amniotic membrane of the umbilical cord. An umbilical hernia also is a protruding mass, but it is covered by subcutaneous tissue and skin. The hernia generally contains omentum and sometimes a loop of bowel as well. Meckel's diverticulum is a remnant of the proximal yolk stalk, which in the embryo, was a connection between the midgut and the yolk sac. It arises from the antimesenteric surface of the ileum. Occasionally, the diverticula contain normal gastric and pancreatic tissue. Ulceration and bleeding occur if gastric mucosa secretes sufficient acid. Meckel's diverticulum is not symptomatic in the neonatal period. Duplications probably are caused by faulty recanalization, resulting in the formation of two lumens in a given segment of gut. They are either cystic or tubular. The cystic duplications regularly occupy the mesenteric surface of the intestine and they do not communicate with the normal lumen. Tubular duplications are fused for varying lengths to normal gut, often sharing a common wall. They are more likely to communicate at one end with the normal lumen.

MALFORMATIONS OF HINDGUT DERIVATIVES.

The most common malformations in the hindgut are anorectal. In most instances, they result from abnormal development of the urorectal septum, which separates the cloaca into urogenital and anorectal channels. Anorectal agenesis is characterized by a rectum that ends blindly just proximal to the anal canal. This is the most common of anorectal malformations, and it usually is associated with a fistula that connects the rectum to the male urethra or to the vagina. It develops from an incomplete separation of the cloaca when faulty growth of the urorectal septum occurs. Agenesis of the anal canal is a blind-ending anal canal that may be associated with an ectopic opening or a fistula. The fistula generally opens onto the perineum. Less frequently, it opens into the vulva or the male urethra.

DEVELOPMENT OF MUSCLE FUNCTION: SUCK, SWALLOW, AND INTESTINAL MOTILITY.

The suck and swallow functions have been observed at 16 to 18 weeks, but the coordination of these functions with respiration does not occur until approximately 34 gestational weeks. The suck of the term newborn occurs in bursts of three to four motions per minute during the first day, increasing to a rate of 10 to 30 per minute over the ensuing few days. Fetal swallowing has been amply documented in several studies. During the second trimester, amniotic fluid is swallowed at a rate of 2 to 7 mL daily; at 21 to 23 weeks, rates vary between 13 mL daily and 5 mL/kg per hour. At term, the fetus swallows 500 mL of amniotic fluid per 24 hours. Meconium is present at 16 weeks. It is composed of epithelium desquamated from the intestine and skin. It also contains bile, pancreatic and intestinal secretions, lanugo, and swallowed amniotic fluid. It contains little fat and virtually no protein. Water accounts for approximately 75% of meconium by weight.

Some enzymes in the gut wall appear during the first trimester, but in most instances, activity is not demonstrable until the second trimester. Thus, alkaline phosphatase, aminopeptidase, and the disaccharidases are identifiable during the first trimester, but significant activity does not develop until the 23rd or 24th weeks. Activity of lactase lags beyond the other disaccharidases. It becomes active in the early part of the last trimester.

Gastrointestinal motility increases with fetal maturity. Peristalsis appears at 13 to 14 weeks. In the preterm infant, at 32 weeks, contrast material passes to the cecum 9 hours after administration. At this gestational age, muscle layers of the gastrointestinal tract are immature; peristaltic waves are not coordinated. At term, the transit time is 4 to 7 hours.

The gastrointestinal tract is not well adapted to extrauterine life until the 36th week. Enteral feedings are difficult in premature infants, and often they must be postponed. Several characteristics of the premature infant impair adaptation and thus interfere with enteral feeding:

1. Suck and swallow are not coordinated.
   
2. The gastroesophageal sphincter is incompetent.
   
3. Gastric emptying time is delayed.
   
4. The capacity to absorb fat is significantly diminished.
   
5. Protein digestion is not complete.
   
6. Lactase activity is decreased.
   
7. Intestinal motility is poorly coordinated.
   

These problems are of greater clinical significance than in the past because the increased effectiveness of cardiorespiratory support has resulted in the survival of more small, premature infants. For these premature infants, the essence of intact survival is our capacity to provide adequate nutrition over protracted periods of time. Although parenteral nutrition is a partial solution, it would be more desirable to develop methods to accelerate gut maturity, similar to the pharmacologic approach to accelerating maturity of the lung.

The Urinary System

KIDNEYS AND URETERS.

Development of the kidneys aptly illustrates the relationship between phylogeny and ontogeny.^1,2,21 Three generations of kidneys evolve; the third gives rise to the mature organ. The first generation is the pronephros. It forms in the embryonic cervical region, is rudimentary, and is similar in structure to the kidneys of several species of primitive fishes. The pronephros disappears by the end of the fourth week. Most of the pronephric ducts are incorporated into the next renal generation, the mesonephros. These kidneys are similar to those of fishes and amphibians. There is no evidence that they are functional in the human, although function has been demonstrated in rabbit, cat, and pig embryos. Mesonephric tubules, at their medial ends, develop a glomerular capsule consisting of a cluster of capillaries that indents the end of the tubule until surrounded by it. In the aggregate, the tubules constitute oval kidneys, one situated on each side of the abdominal cavity. The tubules of each kidney empty into a collecting duct known as the mesonephric (wolffian) duct. The tubules and glomeruli of the mesonephros have largely disappeared by the end of the second month. The mesonephric ducts persist in the male to function as genital ducts; in the female, they degenerate and are identifiable only as vestiges.

The metanephros, the permanent kidney, appears in the fifth week. It begins to function in the 11th or 12th weeks, and the fetus excretes urine into the amniotic fluid. Because the placenta eliminates metabolic end products from the fetus, true renal excretory function does not begin until after birth. The mature kidney arises from two primordial structures: the ureteric bud (metanephric diverticulum) and the metanephric mesoderm. Both of these structures originate from the embryonic mesoderm. The ureteric bud is an outgrowth of the mesonephric duct. Continued growth and division result in the ultimate formation of the ureter, renal pelvis, major and minor calices, and more than 1 million collecting tubules. The excretory system of each kidney derives from the metanephric mesoderm. Collecting tubules grow into this mesodermal tissue mass, which itself forms small tubules that differentiate into nephrons. Glomeruli and Bowman's capsules are elaborated at the proximal end of each nephron, while at the distal end, the tubule of the nephron unit becomes continuous with a collecting tubule. At maturity, a uriniferous tubule is formed. It consists of the nephron (derived from metanephric mesoderm) and a collecting tubule (which arises from the ureteric bud). The nephron increases considerably in length, and as a result, convolutions develop. The proximal convoluted tubule, the loop of Henle, and the distal convoluted tubule are thus formed. Throughout their development, the kidneys progressively assume a more superior position, migrating from their point of origin in the pelvis to a more cephalic position in the abdomen. The blood supply changes as migration of the kidneys proceeds. Branches from the aorta supply the kidneys transiently. The aortic branches degenerate as the kidney migrates to a more cephalic location. The ultimate renal arteries make their appearance in the ninth week.

The urinary bladder is derived from the uppermost, largest part of the urogenital sinus, which was formed when the primitive urorectal septum divided the cloaca into a posterior anorectal canal and an anterior urogenital sinus. The female urethra in its entirety and nearly all of the male urethra also are developed from the urogenital sinus.

At birth, the kidneys of premature and term infants are relatively inactive. Compared with that of the adult, glomerular filtration rate is low. At 34 weeks (conceptual age), an abrupt increment in glomerular filtration rate occurs, whether in utero or after birth. The neonate's capacity to excrete excess water and solute is significantly limited. The capacity to concentrate urine does not exceed 700 mOsm/L. Later in childhood, the concentrating capacity is 1300 mOsm/L. Function of nephrons varies considerably in the neonate, and this seems to be related to marked differences in tubular length. The difference in tubular length in any one kidney is as great as 11-fold. Because glomeruli are more homogeneous in structure, there seems to be an imbalance between the ability of glomeruli to filter and a lesser capacity of tubules to secrete and reabsorb. There may thus be urinary loss of substances such as amino acids and bicarbonate, which, once filtrated through the glomerulus, are lost because of the limited tubular capacity to reabsorb them.

Blood (Hemopoiesis)

All hemopoietic cells originate in mesenchyme, making their first appearance as primordial cells (hemangioblasts) in the extraembryonic mesoderm of the yolk sac.²² Hemangioblasts populate blood islands that first appear in the yolk sac. The hemangioblasts are directed along two different lines of differentiation: vascular endothelium and pluripotent hemopoietic stem cells called hemocytoblasts. The latter have a capacity to self-replicate as well as to differentiate into all of the diverse blood cell lines.

Hemangioblasts at the periphery of blood islands become flattened endothelial cells typical of the type that line blood vessels. Hemangioblasts in the center of a blood island develop into hemocytoblasts. Blood islands similar to those in the yolk sac also arise in the chorion and within the embryo. The blood vessels that evolve at these sites eventually connect with those from blood islands in the yolk sac and elsewhere, and by this process, an embryonic circulation is established at 3 weeks of gestation.

Hemopoiesis progresses through three overlapping stages of maturation: a mesoblastic period, a hepatic period, and a myeloid period. During the mesoblastic period, cells in blood islands are first released into the bloodstream at 16 to 19 days, at which time unidirectional movement of blood becomes possible because contractions of the heart have become activated. The mesoblastic period ends at approximately 12 weeks. The second phase of hemopoiesis, the hepatic period, begins at approximately 5 weeks and ends in the sixth month. During this stage of blood cell development, hemopoiesis occurs primarily in the liver. The spleen contributes to some extent during the third and fourth months. Hepatic hemopoiesis is mostly an erythropoietic endeavor that transpires outside of blood vessels. Megakaryocytes that produce platelets also are identifiable in the liver. Granulocytic activity is completely absent.

The myeloid period begins between the fourth and fifth months and continues throughout life. Hemopoiesis moves to bone marrow. During the early phase, bone marrow is engaged in granulocytic production while the liver is preoccupied with erythropoiesis. Megakaryocytic activity is ongoing at both sites. During the last trimester, hepatic erythropoiesis diminishes substantially, and the bone marrow becomes the principal hemopoietic organ. Some hepatic erythropoiesis continues for about 1 week postnatally.

Erythropoiesis begins when the hemocytoblasts are committed to an erythrocytic line of maturation, as indicated by the appearance of hemoglobin in the cytoplasm. Red cell precursors are the erythroblasts that are produced from hemocytoblasts. Primitive erythroblasts are the first generation. They appear in blood islands of the yolk sac, retain their nuclei, and do not develop into mature erythrocytes. These are the cells to first enter the embryonic circulation at 16 to 19 days. They cease to exist at approximately 10 weeks. Definitive erythroblasts are a second generation of red cell precursors that appear in the liver, spleen, and bone marrow. They gradually replace their predecessors and ultimately become mature erythrocytes. At 8 weeks, these erythroblasts are approximately 30% of circulating blood cells; at 10 weeks, they constitute 80% of them.

Erythropoiesis probably is controlled by erythropoietin beginning with the third trimester. Hypoxia in utero and after birth stimulates enhanced erythropoietin production, which is the principal mediator of the erythropoietic response to hypoxia. Apparently, it circulates in an inactive form that is converted to an active one by erythrogenin, which is produced in the kidney. In the fetus, erythropoietin probably is produced in the liver. It is detectable in plasma at birth; elevated levels are identified in circumstances that demand increased erythropoietic activity, such as hemolytic anemia or hypoxia.

The development of hemoglobin begins with the appearance of two embryonic types, Gowers I and Gowers II. These early embryonic hemoglobins are replaced by hemoglobin F at 6 to 8 weeks. Until 36 weeks, hemoglobin F comprises 90% to 95% of hemoglobin in the fetus. After 36 weeks, hemoglobin A (adult hemoglobin) is produced; the elaboration of hemoglobin F begins to decline. At term, hemoglobin F constitutes 75% to 90% of the hemoglobin in cord blood. The remainder is hemoglobin A.

Early granulocyte forms, produced by leukopoiesis, first appear in the embryonic circulation at 10 gestational weeks. After the 20th week, most of the circulating granulocytes are mature. More of them appear in the circulation as bone marrow takes over hemopoiesis. Eosinophils appear soon after the 12th week, and monocytes, during the 8th week. Lymphopoiesis is initiated in lymph nodes and thymus during the third month. At about this time, mature lymphocytes are first identified in the circulation.

Central Nervous System

The central nervous system is derived from ectoderm.^1,2,23,24 It first appears at about 22 days as the neural plate. The neural tube is formed when folds of the neural plate fuse at the midline. The process of fusion is initiated in the cervical area, and from this point, it continues simultaneously in both a cephalic and a caudal direction. At the cranial and caudal ends of the tube, neuropores remain temporarily as openings that connect the neural tube lumen with the amniotic cavity. The cranial neuropore closes on the 25th day; the caudal neuropore closes 2 days later. The primitive central nervous system now is a tubular structure that will mature as brain at the broadened cephalic end and as spinal cord from the elongated caudal portion.

Three primary brain vesicles are formed at the expanded cephalic end of the neural tube. These are the forebrain, the midbrain, and the hindbrain. The anterior part of the forebrain (telencephalon) contains the primordia of the cerebral hemispheres. The posterior portion of the forebrain gives rise to the diencephalon. The cavities within these structures become the third ventricle. The cavity in the midbrain forms the cerebral aqueduct. Migration of neuroblasts ultimately forms the four colliculi, one pair superior and another pair inferior. Ongoing differentiation in the midbrain culminates in the tegmentum in which are situated the red nuclei, nuclei of the third and fourth cranial nerves, and the substantia nigra.

The hindbrain differentiates into caudal and rostral structures. The caudal Myelencephalon will become the medulla, and the rostral metencephalon will give rise to both the pons and cerebellum. The cavity within the hindbrain becomes the fourth ventricle.

The spinal cord develops from the caudal portion of the neural tube. It is primarily composed of a basal plate, which contains motor neurons, and an alar plate, which contains sensory neurons.

The arterial supply of the brain arises in its entirety from the internal carotid artery. Early in the embryonic period, the internal carotid artery divides into cranial and caudal branches. A plexus forms over the forebrain from the cranial portion, and over the midbrain from the caudal portion. The anterior and middle cerebral arteries develop from the cranial division. The posterior cerebral artery and the posterior communicating artery develop from the caudal portion. The primitive arterial system is organized into definitive major branches early in development. The early establishment of this pattern does not change; subsequent expansion of the arterial system is characterized by elaboration of peripheral branches that correspond to areas of the brain growth, particularly the hemispheres. The peripheral changes primarily involve the smaller arterial branches, arterioles, and capillary bed. The basic arterial stem that was formed at the earliest stage of development remains unchanged.

Ultimate development of the veins occurs late compared with that of the arteries. Development of the venous system is complex. The draining veins develop from several plexuses, which become distorted as the hemispheres expand. The hemispheric expansion rearranges plexus channels by stretching some and attenuating others. In maturity, the end-development of venous plexuses is subject to considerable variation.

After the embryonic period, development of the fetal brain is characterized by tremendous growth of cerebral hemispheres. The vascular pattern grows concordantly; the internal carotid artery gives off branches from the anterior, middle, and posterior cerebral arteries. The basic pattern is in place at 7 weeks; it remains unchanged throughout life thereafter. Development of basal ganglia is well advanced over that of the cortex and cerebral white matter. Thus, arteries that supply basal ganglia are correspondingly mature at an earlier stage of development. Basal arteries are large compared with other vessels in the hemisphere. The most significant architectural aspect of basal ganglia, specific to premature infants, is the germinal matrix tissue that is primarily located over the head and body of the caudate nucleus. Heubner's artery is a principal supplier of blood to germinal matrix. The vascular bed of the germinal matrix is the most critically important locus of fetal central nervous system blood supply. More than 80% of the intraventricular hemorrhages in newborn premature infants are demonstrable in this area. After 24 weeks, large vessels that resemble capillaries but are not definitively identified are prominent in the germinal matrix. Delicate capillaries intermingle with large vessels that cannot be identified as arterioles, venules, or capillaries by the light microscope.

After 32 gestational weeks, the germinal matrix disappears and the capillary bed is blended with other vessels. The previously prominent Heubner's artery is smaller and no longer is the major source of blood for the germinal matrix. Rather, it is relegated to supply a small area in the head of the caudate nucleus. Changes in the vascular supply of the basal ganglia are related to advancing gestational age, and they represent maturational evolution from a circulation primarily oriented to the brain stem and basal ganglia, to one that is more committed to the cortex. These vascular changes correlate to the shifting predominance of growth from the germinal matrix from 24 to 28 weeks, to the cortex and white matter by 32 to 34 weeks. The changing vascular pattern is significant in relation to the incidence of intraventricular hemorrhage in premature infants.

Hemorrhage into the germinal layer can occur at the lateral aspect of the lateral ventricle, the lateral aspect of the occipital horns, or the roof of the fourth ventricle. Hemorrhage is most common over the head of the caudate nucleus. The site of germinal layer hemorrhage varies with gestational age, suggesting that maturity of the capillary bed may be a significant determinant.

1. Carlson BM: Human Embryology and Developmental Biology. 2nd ed. St Louis, Mosby, 1999

2. Moore KL, Persaud TVN: The Developing Human: Clinically Oriented Embryology. 6th ed. Philadelphia, WB Saunders, 1998

3. Kliegman RM: Intrauterine growth retardation. In Fanaroff AA, Martin RJ (eds): Neonatal-Perinatal Medicine: Diseases of the Fetus and Infant, pp 203–240. 6th ed. St Louis, Mosby, 1997

4. Sparks JW, Ross JC, Cetin I: Intrauterine growth and nutrition. In Polin RA, Fox WW (eds): Fetal and Neonatal Physiology, pp 267–289. 2nd ed. Philadelphia, WB Saunders, 1998

5. Jobe AH: The respiratory system. In Fanaroff AA, Martin RJ (eds): Neonatal-Perinatal Medicine: Diseases of the Fetus and Infant, pp 991–1009. 6th ed. Philadelphia, WB Saunders, 1998

6. O'Rahilly R, Muller F: The respiratory system. In O'Rahilly R, Muller F (eds): Human Embryology and Teratology, pp 259–271. 2nd ed. New York, Wiley-Liss, 1996

7. Kirby ML: Development of the fetal heart. In Polin RA, Fox WW (eds): Fetal and Neonatal Physiology, pp 793–801. 2nd ed. Philadelphia, WB Saunders, 1998

8. Teitel DF: Physiologic development of the cardiovascular system in the fetus. In Polin RA, Fox WW (eds): Fetal and Neonatal Physiology, pp 827–836. 2nd ed. Philadelphia, WB Saunders, 1998

9. Long WA: Fetal and Neonatal Cardiology. Philadelphia, WB Saunders, 1990

10. Burnard ED: Cardiorespiratory events at birth. In Davis JA, Dobbing J (eds): Scientific Foundations of Paediatrics, pp 75–87. 2nd ed. Baltimore, University Park Press, 1982

11. Strang LB: Neonatal Respiration: Physiological and Clinical Studies. Oxford, Blackwell Scientific Publications, 1977

12. Harned HS Jr, Ferreiro J: Initiation of breathing by cold stimulation: Effects of change in ambient temperature on respiratory activity of the full-term fetal lamb. J Pediatr 83: 663, 1973

13. Jain L: Alveolar fluid clearance in developing lungs and its role in neonatal transition. Clin Perinatol 26: 585– 599, 1999

14. Lakshminrusimha S, Steinhorn RH: Pulmonary vascular biology during neonatal transition. Clin Perinatol 26: 601– 619, 1999

15. Milner AD: Adaptation at birth. In Greenough A, Milner AD, Roberton NRC (eds): Neonatal Respiratory Disorders, pp 48–56. New York, Oxford University Press, 1996

16. Rudolph AM: Congenital Diseases of the Heart: Clinical-Physiologic Considerations in Diagnosis and Management. Chicago, Year Book Medical Publishers, 1974

17. Bland RD: Formation of fetal lung liquid and its removal near birth. In Polin RA, Fox WW (eds): Fetal and Neonatal Physiology, pp 1047–1054. 2nd ed. Philadelphia, WB Saunders, 1998

18. Bucuvalas JC, Balistreri WF: The Neonatal Gastrointestinal Tract: Part I. Development. In Fanaroff AA, Martin RJ (eds): Neonatal-Perinatal Medicine: Diseases of the Fetus and Infant, pp 1288–1294. 6th ed. St Louis, Mosby, 1997

19. Ross AJ: Organogenesis, innervation, and histologic development of the gastrointestinal tract. In Polin RA, Fox WW (eds): Fetal and Neonatal Physiology, pp 1342–1353. 2nd ed. Philadelphia, WB Saunders, 1998

20. Lebenthal E (ed): Human Gastrointestinal Development. New York, Raven Press, 1989

21. Brion LC, Bernstein J, Spitzer A: Kidney and urinary tract. In Fanaroff AA, Martin RJ (eds): Neonatal-Perinatal Medicine: Diseases of the Fetus and Infant, pp 1564–1567. 6th ed. St Louis, Mosby, 1997

22. Sieff CA, Nathan DG, Clark SC: The anatomy and physiology of hematopoiesis. In Nathan DG, Orkin SH (eds): Nathan and Oski's Hematology of Infancy and Childhood, pp 161–236. 5th ed. Philadelphia, WB Saunders, 1998

23. Volpe JJ: Neural tube formation and prosencephalic development. In: Neurology of the Newborn, pp 3–42. 3rd ed. Philadelphia, WB Saunders, 1995

24. Volpe JJ: Neuronal proliferation, migration, organization, and myelination. In: Neurology of the Newborn, pp 43–92. 3rd ed. Philadelphia, WB Saunders, 1995