Table 1.1 presents the sequence of the major developmental events during the first 10 weeks of intrauterine life. These events are depicted in Figs. 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 1.10, and 1.11. Each figure is a view of the left side of the embryo. The progression of events can best be appreciated by comparing each figure with the preceding and following figures. Each is labeled with the postconceptual age in days and the greatest length in millimeters, and some have measurement bars which are in millimeters. The postconceptual age and size of embryos are from the revisions by O’Rahilly and Muller in their Tables A-1 and A-2, pp. 490 and 491 (O’Rahilly and Muller 2001). Additional references on human embryology used regarding the figures and their descriptions include Lewis (1912c) and publications by O’Rahilly and Muller (Lewis 1912c; Muller and O’Rahilly 1983, 1985, 1986; O’Rahilly 1970, 1971; O’Rahilly and Muecke 1972; O’Rahilly and Boyden 1973; O’Rahilly and Tucker 1973; O’Rahilly 1978, 1983; O’Rahilly and Muller 1981, 1989).

During the first 2 weeks when the embryo is a bilaminar disc, endodermal development is slow. By the end of the second week, the endoderm forms the secondary yolk sac. The endoderm of the median plane of the roof of the yolk sac will become the gastrointestinal tract (Fig. 1.1a, b). Developmental abnormalities during the first 2 weeks are lethal. During the third and fourth weeks, the structures of the midline developmental field appear. The primitive streak and notochordal apparatus replace the endoderm in the median plane of the roof of the yolk sac, and with the appearance of the mesoderm, the trilaminar disc is formed (Fig. 1.2). During this crucial period, the plan for the future form of the gastrointestinal tract is imprinted on the endoderm by the inductive influences of the notochord, primitive streak, mesoderm, and cardiogenic primordium (see Sect. 1.1.5 below for details). By the end of the fourth week, the lateral folds transform the embryonic disc into a cylinder; the head and tail folds form; the primitive foregut, midgut, and hindgut can be seen; and the respiratory and hepatic primordia appear (Fig. 1.3). Developmental abnormalities that arise during the third and fourth weeks of blastogenesis are often severe, widespread, and sometimes monstrous malformations of the embryo which often involve the gastrointestinal tract (Opitz 1993) (Table 1.3).

Organogenesis begins with the fifth week when suddenly the entire tubular gastrointestinal tract, its major divisions, and its accessory organs of digestion emerge from the imprinted primordium of the primitive endoderm (Figs. 1.4, 1.5, and 1.6). During the sixth week, organogenesis continues, rotation and histogenesis begin, and the digestive tract attains much of its final form (Figs. 1.7, 1.8, and 1.9). During the seventh and eighth weeks, rotation and histogenesis continue, and remodeling of the anal canal and anus is completed (Figs. 1.10 and 1.11). During the ninth and tenth weeks, the intestine returns to the abdomen; rotation and fixation are completed, and sexual differentiation of the perineum takes place. During the remaining 30 weeks of intrauterine life, development consists of continued histogenesis, remodeling, growth, and maturation. Malformations arising during late organogenesis and fetal life are less extensive, more often single, and more likely due to disruptions than those arising during the third and fourth weeks.

This description is compiled from Lewis (1912b), Salenius (1952), Grand et al. (1976), Valdes-Dapena (1979), Semba et al. (1983), O’Rahilly and Muller (1987), and Skandalakis et al. (1994; Skanalakis et al. 1994a, b, c). For uniformity the timing of events is given in gestational ages. When primary sources used greatest lengths, these have been converted to postconceptual ages prior to 20 weeks’ gestation using data from O’Rahilly and Muller (2001) and Kalousek, Fitch, and Paradice (1990) or menstrual ages after 20 weeks using data from Singer, Sung, and Wigglesworth (1991). Mucosal histogenesis begins with a transient phase of epithelial proliferation. The proliferating epithelium completely occludes the lumen of the duodenum, significantly narrows the lumen of the esophagus, and may mildly narrow the lumens of the cardia, pylorus, upper jejunum, and distal ileum. These proliferations may be accompanied by the transient formation of multiple antimesenteric diverticula in the duodenum, upper jejunum, and distal ileum. Some instances of congenital atresia, stenosis, or diverticula may be the result of abnormalities in the formation or resolution of the proliferative phase.

The proliferative phase begins in the 6th and ends in the nineth week. The epithelial membrane becomes stratified. Strands of rapidly proliferating epithelium traverse the lumen without completely occluding it. Ciliated columnar epithelium covers the epithelial surface of the mid-esophagus at 10 weeks and spreads to both ends by the 11th week. Stratified squamous epithelium begins to replace the ciliated columnar epithelium in the mid-esophagus at 16 weeks and spreads proximally and distally to cover the entire esophagus by birth except for the proximal esophagus where islands of ciliated columnar epithelium may persist. These disappear shortly after birth. The superficial cardiac glands of the lamina propria appear in the 13th week. The submucosal mucous glands appear in the 27th week. A recent ultrastructural study suggests slightly different timing and details of esophageal histogenesis (Menard 1995).

The mild proliferative phase is most pronounced in the cardia and pylorus where minor compromise of the lumen is reported by some authors. Gastric mucosa with foveolar epithelium and gastric pits appears at 7–8 weeks. Gastric glands with mucous neck cells, parietal cells, chief cells, and endocrine cells appear at 9–10 weeks. Intestinal villi appear in the cardia and pylorus where they are normally abundant by 30 weeks. They disappear by birth. Intestinal metaplasia of cardiac or pyloric epithelium may be a dedifferentiation to the normal fetal condition. The cardiac mucosa is thought to arise from undifferentiated gastric mucosa and not from esophageal metaplasia (Zhou et al. 2001). The cardia may be extremely short, and parietal cells may be seen within 1 or 2 mm of the esophageal mucosa. The ultrastructure of gastric mucosa in staged human embryos has been described (Otani et al. 1993). See Table 1.4.

In the duodenum exuberant epithelial proliferation begins early in the sixth week and completely occludes the lumen by the end of the sixth week. A recent study suggests that the occlusion is not due to proliferation but to morphogenetic events involved in elongation of the duodenum (Matsumoto et al. 2002). The expanding mass of proliferating epithelium distends the duodenum proximal and distal to the hepatobiliary and pancreatic diverticula imparting an hourglass shape to the duodenum with the narrow waist at the level of the hepatobiliary and pancreatic ducts. Congenital duodenal atresia or stenosis often occurs at the site of this waist and may be associated with hepatobiliary and pancreatic duct abnormalities. Epithelial diverticula form along the antimesenteric border. By the eighth week the proliferation ends, the lumen is reestablished, and the diverticula disappear. Some authors (Matsumoto et al. 2002; Lewis 1912b; Lewis and Thyng 1908) report similar but less exuberant, nonocclusive proliferations accompanied by similar antimesenteric diverticula in the proximal jejunum and distal ileum. These begin in the seventh week and disappear by the 16th week. Villi appear first in the duodenum in the eighth week, and crypts of Lieberkühn appear in the nineth week. Villi are shortest in the proximal duodenum and become progressively longer distally. Brunner’s glands appear in the proximal duodenum by 12–14 weeks and spread caudally to the distal duodenum. They are largest and most numerous in the proximal duodenum and become progressively smaller and less numerous distally. They are sparse distal to the papilla of Vater. Villi and crypts spread from rostral to caudal. They arrive in the mid-small intestine by the nineth week and reach the distal ileum by the 12th week (Siedman and Walker 1987; Dimmick and Hardwick 1992). The stem cells are located in the bases of the crypts. They proliferate and differentiate into enterocytes, goblet cells, and enteroendocrine cells. Enterocytes and goblet cells migrate centripetally up the crypts to the tips of the villi where they may undergo apoptosis and slough into the lumen. Some enteroendocrine cells migrate up to the mid-region of the crypt, while others remain in the depths of the crypts. Paneth cells remain in the depths of the crypts. Cytologic differentiation of the crypts begins with the appearance of goblet cells in the eighth week followed by enterocytes with prominent brush borders, Paneth cells and enteroendocrine cells in the nineth week, and Segi’s cap (Kobayashi et al. 1980) in the 20th week. Paneth cells contain large numbers of coarse, brightly eosinophilic globules in the supranuclear region. Some enteroendocrine cells can be identified in hematoxylin- and eosin-stained sections by the presence of very fine eosinophilic granules in the subnuclear region; however, most enteroendocrine cells can be identified only by immunohistochemical stains which label nonspecific neurosecretory granules or specific neurosecretory products. The time of appearance and electron microscopic features of 13 enteroendocrine cells have been described in human embryos between 9 and 22 weeks’ gestation (Moxey and Trier 1977). The author has identified coarse, brightly eosinophilic, hyaline globules in the cytoplasm of enterocytes of fetuses between 16 and 20 weeks. See Huff in Ernst et al. (2011). They have been described but not illustrated by Semba and Tanaka (1983) and are similar to the thanatosomes described by Dikov et al. (2007). The histologic appearance of the small intestine resembles that of a newborn by 20 weeks (Lebenthal and Lebenthal 1999).

In the colon the proliferative phase is minor. At approximately the tenth week, villi cover the surface of the large intestine and persist until the 28th to 30th week. Intestinal villi are normally seen in the embryo not only in the small intestine but also in the cardia, pylorus, and colon. The stems cells are located in the base of the colonic crypts. By the 14th week, they proliferate and differentiate into colonocytes, goblet cells, Paneth cells, and enteroendocrine cells. The colonocytes and goblet cells migrate centripetally up the sides of the crypts and villi to the tips of the villi. The colonocytes are tall columnar cells with basal nuclei, mucin-filled cytoplasm, and faint brush borders. The enteroendocrine cells migrate up to the mid-region of the crypts. The Paneth cells which are rarely found in the colon and then only in the right colon remain in the depth of the crypts. The intervillous surface epithelium differentiates into a single layer containing goblet cells by the 13th to 16th week. Differentiating between microscopic sections of the colon and small intestine may be very difficult especially prior to 30 weeks’ gestation and in poorly preserved specimens. All of the cells covering the colonic villi are mucus containing, either colonocytes or goblet cells, while the cells covering small intestinal villi are predominately nonmucus-containing enterocytes with a bright brush border interspersed with only a few scattered goblet cells.

The histogenesis of the appendiceal mucosa is similar to that of the colon except between 20 and 25 weeks’ gestation when the lengths of the crypts become very irregular resulting in a very uneven undulating muscularis mucosae in contrast to the nearly perfect equality in the lengths of the test tube–like colonic crypts and the straightness of the colonic muscularis mucosae. Some of the appendiceal crypts push into the submucosa somewhat like diverticula, although they are surrounded by muscularis mucosae. Some become microcystically dilated and filled with apoptotic and inflammatory debris particularly intact and degranulated eosinophils. The dilated crypts are surrounded by cuffs of spindle shaped and polygonal mesenchymal cells and inflammatory cells especially eosinophils. At the same time, submucosal aggregated nodules of lymphoid tissue become prominent. No evidence of appendicitis, swallowed infected amniotic material, or other abnormalities accompanies these changes. Evidence of regression of the microcystic cryptitis includes whorled foci of fibrosis surrounding degenerated epithelial cells with or without calcification or multinucleated giant cells. See Huff in Ernst et al. (2011). Similar findings have rarely been reported previously (Lewis 1912a). Because these changes occur at the same time that aggregated lymphoid tissue develops in the mucosa-associated lymphoid tissue, spleen, and other lymphoid tissues, the possibility that they are somehow associated with the normal maturation of the lymphoid system is raised.

The anal canal including the internal sphincter and anal transitional epithelium is well developed by the end of the eighth week. The anal transitional epithelium is composed of irregular stratified cuboidal and columnar epithelium. Peg cells and columnar ciliated cells are sparsely scattered along the surface. A few goblet cells are seen within the epithelium and on the surface reminiscent of conjunctival epithelium. The length of the hypoganglionic segment in fetuses is often 1 cm or less.

As early as the seventh week, scattered lymphoid cells can be found in the lamina propria. By the 11th week, clusters of precursor lymphoid cells can be identified immunohistochemically in sites where lymphoid follicles will develop in the future. Recognizable diffuse and aggregated lymphoid tissue in the lamina propria is very hard to find in routine sections at 14 weeks, only slightly more easily seen at 16 weeks, and occasionally found at 19 weeks. At 20 weeks lymphoid follicles become larger, more well organized, and more frequent and may extend into the submucosa especially in the terminal ileum, appendix, duodenum, and anorectum. By 24 weeks, Peyer’s patches, sheets of aggregated primary follicles in the lamina propria and submucosa, appear especially in the terminal ileum (Spencer et al. 1986). The development of diffuse and aggregated mucosa-associated lymphoid tissue, Peyer’s patches, and primary follicles is independent of stimulation by foreign antigens. Germinal centers and plasma cells develop in response to a foreign antigenic stimulus. The fetal gastrointestinal tract is normally not exposed to such a stimulus and therefore lacks germinal centers and mature plasma cells. The neonate responds to the antigenic stimulus of colonization at birth with the formation of germinal centers and plasma cells 2–4 weeks after birth. The fetal mucosal lymphoid system has the capacity to respond to an abnormal intrauterine antigenic stimulus with the formation of germinal centers and plasma cells prior to 20 weeks possibly as early as 13–14 . The presence of prominent aggregated mucosa-associated lymphoid tissue prior to 20 weeks or the presence of germinal centers or plasma cells at any time during fetal life indicates fetal infection or other abnormal antigenic stimulus. See Table 1.5.

The inner circular muscle appears first followed by the outer longitudinal layer and finally by the muscularis mucosae. The waves of differentiation begin in the esophagus and propagate caudally and then at the anorectal junction and propagate cranially. The two meet at the ileocecal junction. See Table 1.6.

Congenital anomalies of the gastrointestinal tract arise during all developmental periods (Table 1.2). The earlier in embryogenesis a developmental error occurs, the more extensive and severe the resulting anomalies are. Some of the errors of blastogenesis that include anomalies of the gastrointestinal tract are listed in Table 1.3. The causes of anomalies of the gastrointestinal tract include chromosomal abnormalities (numerical and structural), single gene defects, maternal diseases especially diabetes, and maternal exposure to drugs especially hydantoin (pyloric stenosis, duodenal and anal atresia). Causes of disruptions include inherited (Johnson and Meyers 2001) and noninherited maternal and fetal thrombophilic diseases, intrauterine hypoxic/ischemic events, intrauterine infection including varicella (Bruder et al. 2000), iatrogenic vascular disruptions (Stoler et al. 1999), and maternal exposure to vasoactive drugs (Werler et al. 2002). Other diseases of the embryo such as cystic fibrosis and epidermolysis bullosa underlie some gastrointestinal anomalies. Deformations are limited to abnormal shapes of the liver and abnormal rotation and fixation associated with defects of the diaphragm, body wall, and umbilicus. The cause of most anomalies is unknown. Anomalies that arise after completion of organogenesis are often disruptions or deformations; otherwise the causes are not specific to any developmental period.