Chapter 17: FETAL GASTROINTESTINAL ANOMALIES

Most parts of the gastrointestinal tract (GIT) may appear as "silent" structures during a routine ultrasonographic examination, which becomes evident when an abnormality is present, such as increased echogenicity or dilation due to obstruction. Nevertheless, careful observation of the fetal gastrointestinal system will reveal its typical appearance on ultrasound and its main differential features compared to other systems: a relevant ultrasonographic variability, not only throughout the pregnancy, but even during the same examination. In fact, swallowing, stomach emptying, and intestinal peristalsis can considerably change the appearance of the GIT during a single examination.

The detection of an intraabdominal abnormality can become particularly challenging due to a variety of systems/ organs that could be involved, including the GIT, genitourinary system, adrenal glands, spleen, liver, pancreas, and lungs. Many of these abnormalities do not give a direct ultrasonographic sign, but may be suspected on the observation of indirect abnormal findings. Topography of the observed abnormality, fetal sex, and gestational age are significantly useful to determine its possible origin.

Another feature of the GIT pathologies rendering their antenatal diagnosis a difficult task is the frequent absence of any ultrasonographic evidence before the third trimester. Furthermore, some abnormalities may not give any ultrasonographic sign during the whole pregnancy, such as an esophageal atresia with tracheal fistula and an almost normally fluid-filled stomach.

The outcome of a gastrointestinal anomaly depends, as for other systems, on the feasibility of the surgical correction, the extension of the damage, and the association with other structural or chromosomal abnormalities.

A discussion of the spleen is included in this chapter. Although the spleen does not make up part of the gastrointestinal system, a specific chapter about spleen and the immune system is unnecessary from an ultrasonographic point of view.

Knowledge of normal embryologic development and normal ultrasonographic appearance of a system are the basis for understanding any congenital abnormality.

The Primitive Gut

During the third week from conception, the embryo appears as a trilaminar flat disc, between the amniotic cavity and the secondary yolk sac. The 3 embryonic layers are represented by ectoderm, facing the amniotic cavity; endoderm, facing the yolk sac; and mesoderm, in between the previous 2 layers (Figure 17-1). Progressive double folding during the fourth fetal week, in both cranial-caudal and lateral-lateral directions, changes the initially flattened embryonic disc into a curved tubular-shaped embryo. During this process, the lateral and ventral walls of the embryo develop by incorporating progressively the dorsal part of the secondary yolk sac. The endodermic layer of the so-formed intraembryonic part of the yolk sac will give rise to the primitive gut tube, while the remaining extraembryonic part will become the definitive yolk sac. The connection between the 2 parts of the yolk sac progressively tightens until it forms a narrow duct called yolk stalk, also referred to as omphalomesenteric or vitelline duct. Near the caudal end of the embryo, the endodermic layer of the yolk sac gives origin to a diverticulum, protruding into the body stalk (or connecting stalk): the allantois (Figure 17-2). At around 7 to 8 menstrual weeks, the yolk stalk undergoes complete obliteration. Yolk stalk and body stalk (including the allantois) fuse and form the umbilical cord.

The primitive gut, formed as previously described, can be distinguished into foregut cranially, midgut in the middle region, and hindgut caudally. From each part of the primitive gut will arise the definitive gastrointestinal and respiratory structures as shown in Table 17-1.

The oropharyngeal membrane represents the cranial extremity of the primitive GIT, whereas the caudal part ends at the cloacal or anal membrane. These membranes are the only 2 points of the embryo where the ectodermic and endodermic layers are in direct contact (without the interposition of mesoderm) (see Figure 17-1). Early rupture of the oropharyngeal membrane forms the cranial opening of the GIT, permitting its filling with amniotic fluid. Caudally, fusion of the final part of the hindgut and the allantois forms the cloacal cavity. The cloacal membrane separates the cloacal cavity from the proctodeum, the ectodermic part of the anus. During the fourth week from conception, the urorectal septum forms by 2 mesodermal folds, one located cranialy and the other developing close to the cloacal membrane. These 2 folds grow slowly in opposite directions until they fuse at a median level. The so-formed urorectal septum divides the cloaca into 2 cavities: the urogenital sinus ventrally and the rectum dorsally. The distal part of the urorectal septum divides the cloacal membrane into 2 portions: the urogenital (anteriorly) and the anal membrane (dorsally). Subsequent rupture of these 2 membranes forms the urogenital and anal orifices, respectively.

Physiologic Herniation of the Midgut and Its Subsequent Reduction

During the sixth to seventh postmenstrual week, a loop of the midgut herniates into the proximal part of the umbilical cord (physiologic exomphalos) due to the relatively reduced intraabdominal space, which is mainly occupied by the fetal liver and kidneys. As development proceeds, the midgut loop extends further into the umbilical coelom and reaches its maximum extension around the eighth to ninth menstrual weeks. After this stage, the herniated midgut returns progressively into the fetal abdomen through a process of physiologic reduction, and at around 11 menstrual weeks the midgut has completely re-entered into the fetal abdomen. Abnormalities of this process can give rise to exomphalos, Meckel diverticulum, umbilico-ileal fistula, or vitelline cyst. During the process of physiologic herniation, progressive rotation of the midgut occurs, which will be completed during its return to and fixation in the fetal abdomen.

The herniated midgut loop is initially positioned in a midsagittal plane; its apex connects to the vitelline duct while the upper and the lower parts correspond, respectively, to the cranial and the caudal limbs of the loop. During its lengthening within the umbilical cord, it undergoes a first rotation of 90 degrees, around its own axis, in a clockwise direction seen from the embryo's side. The axis of rotation is represented by the superior mesenteric artery. The midgut loop is now positioned on a horizontal plane with the cranial limb lying to the right of the superior mesenteric artery and the caudal limb to the left (from the embryo's side). The cranial limb, through further lengthening, forms several loops and will develop into the distal part of the duodenum (postduodenal papilla segment), jejunum, and most of the ileum. The caudal limb elongates more slowly and, contrary to the cranial limb, it does not undergo a looping process; it will give rise to the small remaining part of the ileum and to the cecum/colon. Progressive enlargement of the abdominal cavity permits the physiologic reduction of the herniated midgut loop. During this process, an additional 180-degree clockwise rotation occurs: the proximal part of the cranial limb, which is the first part that enters from the umbilical coelom, moves beneath and then to the left of the superior mesenteric artery, occupying the left part of the fetal abdomen. The rest of the small bowel migrates progressively above the superior mesenteric artery and towards the right part of the abdominal cavity; the cecal diverticulum is the last herniated intestinal part to be reduced, locating initially at the upper right quadrant of the fetal abdomen, just under the liver. The final enteric migration is represented by the descent of the cecum from the initial subhepatic position to its definitive location in the right lower quadrant, forming the ascendant colon and the hepatic flexure.

Through a process of fixation, parts of the GIT become secondary retroperitoneal structures and the mesenteries become firmly attached to the posterior abdominal wall, by fusion of visceral and parietal peritoneal layers. This process stabilizes specific parts of the gut to avoid twisting of the gut during peristalsis (volvulus). The main intestinal structures undergoing fixation by fusion of their peritoneal layers are caudal duodenum, pancreas, transverse mesocolon, small bowel mesentery, and greater omentum.

Abnormalities of the processes of midgut rotation (nonrotation, reversed rotation, uncoordinated rotation, or malrotation) and fixation result in an abnormal position of the entire gut or parts of it. Furthermore, deviations from the normal process of rotation and fixation can lead to abdominal wall defects, diaphragmatic hernia, volvulus, or other kind of intestinal strangulation. Heterotaxia syndromes with either asplenia or polisplenia are strongly associated with intestinal rotation abnormalities.

Liver, Choledocal System, Pancreas, and Spleen

Around the 30th day postconception, an endodermic budding of the ventral side of the duodenum will give rise to three diverticuli: the hepatic diverticulum (distal part), the cystic diverticulum (middle part), and the ventral bud of the pancreas (proximal part) (see Figure 17-2).

The hepatic diverticulum evaginates within the transverse septum (ventral mesentery of the stomach), a mesodermic disc between the pericardium and the yolk stalk. Endodermic hepatoblasts of the hepatic diverticulum, and mesodermal cells and capillary network of the transverse septum contribute to give rise to the complex structure of the liver, while gall bladder and bile ducts develop as cystic structures from the cystic diverticulum.

Contralaterally, at the dorsal side of the duodenum, another endodermic evagination gives rise to the dorsal pancreatic bud. After rotation, the ventral pancreatic bud reaches the dorsal pancreatic bud and they fuse together: the dorsal bud gives rise to the anterior part of the head, the body, and the tail of the pancreas, whereas the ventral bud gives rise to the posterior part of the head and the uncinate process. The outflows of the two buds fuse together giving rise to the major pancreatic duct, which joins the bile duct and discharges into the major duodenal papilla. In some cases there is a persistence of the dorsal bud outflow (minor pancreatic duct), which discharges separately directly in the duodenum via the minor duodenal papilla. A bifid ventral pancreatic bud can give rise to an annular pancreas. This can cause obstruction of the duodenum, but it can also remain asymptomatic.

Although the fetal liver develops in the ventral mesentery, the fetal spleen will develop around the sixth to seventh week of gestation from an aggregation of reticular mesenchymal cells in the dorsal mesentery of the stomach. The spleen contributes to the production of the fetal megakaryocytes and thrombopoiesis, but it is not involved in the production of erythroid precursors.

The fetal lips can be visualized in an oblique coronal view of the fetal face. Due to the usually flexed position of the fetal head, this plane can coincide with the 4-chamber view of the fetal heart or be parallel to it (Figure 17-3A and B). The alveolar ridge of the maxilla is assessed by an axial view of the hard palate. Although two-dimensional (2D) assessment of the fetal lips can offer a 100% detection rate for cleft lip, prenatal diagnosis of cleft palate could significantly improve by three-dimensional (3D) additional techniques in comparison to two-dimenstional.

The tongue can be seen in an axial plane, inferior to the alveolar ridge, especially during fetal swallowing. The pharynx is visualized in the same section posteriorly to the tongue (Figure 17-4).

The esophagus can be assessed in 2D sagittal sections during the second and third trimesters. Usually it is collapsed, and its anterior and posterior walls can appear as 2 or more echogenic parallel lines ("multilayered pattern") (Figure 17-5A and B). The esophagus presents 3 portions: the cervical portion may be difficult to visualize while the thoracic portion, which is the less difficult one to recognize, can be seen behind the trachea, immediately anterior to the descending aorta; whereas the 2 upper portions of the esophagus run in front of the spine, the abdominal portion is deviated to the left.

After fetal swallowing, the esophagus fills with amniotic fluid and it can appear as a thin anechoic structure (Figure 17-6A). In this case, it can easily be confused with a blood vessel, but color Doppler can exclude a vascular origin. In a 4-chamber view especially, the esophagus, when distended by amniotic fluid, may falsely appear as a transverse section of an abnormal venous return, between the left atrium and the descending aorta (Figure 17-6B).

In the midtrimester, complete anatomical ultrasonographic visualization of the esophagus can be achieved in about 85% of fetuses and partial in 95%.¹ An advantageous visualization of the esophagus can be given by a 3D approach, in a coronal volume contrast imaging (VCI-C) view.

The most common pattern of esophageal motility, between 19 and 25 weeks of gestation, is synchronized relaxation of the esophageal upper and lower sphincters, with simultaneous short opening of the whole esophagus or a peristalsis-like motility from the pharynx to the stomach. A reflux-like passage of solid contents, from the stomach to the esophagus, has also been described.¹

In the classic axial section used for the abdominal circumference measurement, it is possible to visualize the stomach, most of the liver, and the intrahepatic tract of the umbilical vein, and examine the correct position and orientation of the viscera. The stomach appears on the left side of the fetal upper abdomen as an anechoic round or oval structure, the so-called gastric bubble (Figure 17-7A). Sometimes it is possible to recognize echogenic debris within its contents, which can be related to swallowed vernix, aggregated cells, or blood after intramniotic bleeding (Figure 17-7B). This particulate content of the stomach appears as a gastric pseudomass, which invariably disappears in a follow-up scan.

Assessment of the fetal stomach starts from the 11⁺⁴- to 13⁺⁶-week scan. The size of the stomach during pregnancy has been described and nomograms of the normal gastric biometry in relation to the gestational age are available. In some cases, nonvisualization of the fetal stomach or detection of a small gastric bubble can be a normal transient finding, due to physiologic emptying of the stomach into the duodenum, and it has to be confirmed by rescanning the patient (Figure 17-8).

Peristaltic movements of the stomach can be observed as early as 14 gestational weeks, while by 23 weeks it is possible to demonstrate gastric motility in all assessed fetuses. Whereas the mean duration of peristalsis progressively increases from 14 to 35 weeks, the period of gastric quiescence is dominant before 24 gestational weeks.² The maximum gastric area increases gradually from 20 weeks to term, with a simultaneous decrease of the minimum gastric area. The change in fetal gastric area, defined as the difference between maximum and minimum gastric area ratios, is significantly increased after 24 weeks.³

The spleen can be seen as a solid, slightly hyperechoic, triangular structure posterior and to the left of the stomach (Figure 17-9A and B). As for the stomach, nomograms regarding splenic size are available.

The fetal liver appears with a typical solid, slightly hyperechogenic and homogeneous pattern, below the diaphragm, to the right side of the fetus (see Figure 17-7A). It can be recognized from the end of the first trimester (Figure 17-10A and B). The examination of the liver size can be better assessed in a right para-sagittal section of the abdomen. During fetal life, the left lobe of the liver is substantially larger. This results in an extension of the fetal liver in the entire upper abdomen.

Going slightly lower from the abdominal circumference section, it is possible to recognize the gall bladder as an anechoic oblong ovoid or rectangular structure, to the right and inferior to the intrahepatic tract of the umbilical vein, extending from the central portion of the abdomen to the anterior abdominal wall, slightly deviated to the right (Figure 17-11). Visualization of the gall bladder has been described from 14 gestational weeks.⁴ Normative data of the fetal gall bladder across gestational age are available as well.

Moving farther caudally, in parallel axial sections, it is possible to recognize the colon with a relatively hypoechoic ultrasonographic appearance; the small bowel, which usually appears more echogenic in comparison to the colon; and the insertion of the umbilical cord into the fetal abdomen.

The small and large bowel can usually be distinguished sonographically after 20 weeks, and it becomes gradually clearer across gestational age. Although the small bowel is located centrally, the colon runs in the periphery of the fetal abdomen (Figure 17-12). The lower echogenicity of the large bowel is due to the meconium, which usually is hypoechoic. However, in some circumstances, an increased or decreased water content of meconium may result in an unusually anechoic or echogenic, respectively, appearance of meconium, with no clinical significance. The rectum can be visualized in a midsagittal section as a hypoechoic pouch behind the bladder, particularly evident in the third trimester, when it is full with meconium (Figure 17-13). There are published nomograms reporting mean bowel diameters related to gestational age, the clinical use of which can be disputable as, especially for the colon, there is a wide variability in size around the mean. The small bowel diameter instead shouldn't exceed 7 mm of transverse diameter.

Occasionally, motility of the fetal anus can be observed, especially at the third trimester, such as contraction and relaxation of the anal sphincter (Figure 17-14A, B, and C).

The insertion of the umbilical cord, as mentioned previously, can be assessed by an axial section (Figure 17-15A and B). However, midsagittal evaluation of the contour of the ventral wall is necessary to assess, in addition to omphalocele and gastroschisis, other midline disruption abnormalities (Figure 17-16A and B).

Emerging Concepts

Three-dimensional and four-dimensional (4D) applications in ultrasound have made impressive strides in the past 2 decades and provided new approaches to fetal evaluation. This resulted in an improvement of the normal and pathologic ultrasonographic assessment of the fetus.^{5, 6, and 7}

With volume sonography, an infinite number of 2D planes of a target anatomic region are acquired. Once a transverse view of the fetal abdomen at the level of the stomach has been obtained, a region of interest (ROI) encompassing the structures of interest (eg, stomach, spine) is selected. The ROI determines the width and height of the volume dataset (x- and y-planes). Although a large ROI may be selected to include all structures of interest, reducing the width of the ROI will maximize the frame rate during acquisition, and this improves the temporal resolution of the volume dataset. The acquisition angle determines acquisition depth (ie, the amount of information that is acquired in the z- or azimuth plane). After acquiring a volume using automated sweeps in the absence of fetal movements, the structures included in the volume can be visualized using the 3 orthogonal planes (multiplanar display) representing the sagittal, transverse, and coronal planes of a reference 2D section within this volume (Figure 17-17). The major advantage of the multiplanar mode is that it enables simultaneous visualization of an anatomic structure in all 3 perpendicular sectional planes. The reference dot guides the operator in navigating within the volume. Sonographic reconstruction of a coronal section of the fetal thorax and abdomen by 3D ultrasound, which is rather difficult to achieve by 2D ultrasound, offers a general view of the fetal body, in which the relations of the thoracic and abdominal structures can be studied.

Tomographic ultrasound imaging (TUI) is a more recent approach for the examination of a volume data set. This multislice analysis mode resembles a magnetic resonance imaging or computer-assisted tomography display. Nine parallel slices are displayed simultaneously from the plane of interest (the "zero" plane), giving sequential views from −4 to +4. The thickness of the slices, ie, the distance between one plane and the next, can be adjusted by the operator. The upper left frame of the display shows the position of each plane within the region of interest, relative to the reference plane. This application has the advantage of displaying sequential parallel planes simultaneously, giving a more complete picture of the fetal abdomen (Figure 17-18).

Volume contrast imaging (VCI) is a new approach that was developed to enhance contrast in B-mode sonography. It is a real-time procedure that involves the display of a rendering volume as a 2D image. Hence, the result of VCI is a surface-rendered image of a solid organ. This may allow better assessment of sizes, margins, and internal aspects of structures and tissues. It can be applied in the C (coronal)-plane. A coronal view of the fetal thorax and abdomen can be more easily obtained applying the VCI-C to an axial scan of the fetal abdomen (Figure 17-19).

Three-dimensional rendering is another analysis capability of an acquired volume. When volume rendering is applied to the data set, a 3D image is displayed in the bottom right panel. Surface rendering mode provides a depth perspective to the structure being examined; it can be used to optimize the contrast and to obtain realistic 4D images of particular structures of interest (Figure 17-20).

The minimum projection mode (MPM) is a rendering algorithm available in some 3D and 4D ultrasonography systems that, in one image, allows the visualization of vessels and cystic anatomic structures located in different scanning planes (Figure 17-21).

The inversion mode is a considerable improvement on a previously described minimum transparency mode for the visualization of "hollow" organs or vessels. The older method displays fluid-filled structures as anechoic structures that are embedded within surrounding fetal soft tissue. The inversion mode inverts the gray scale of the voxels that compose the volume dataset; thus, anechoic structures such as the heart chambers, lumen of the great vessels, stomach, and bladder become echogenic, while the echogenic structures disappear (Figure 17-22). This algorithm provides a new way to examine spatial relationships between fluid-filled structures that can otherwise be difficult to characterize by reviewing only a few image slices, and it can aid the operator in navigating within a complex anomaly scan. In fetal gastrointestinal anomalies, the inversion mode may precisely localize the site of intestinal obstruction.

Furthermore, the inversion mode, using a histogram display and image threshold adjustments, has potential for allowing volume measurements of scattered or irregular fluid-filled spaces. This is possible because each voxel element has known dimensions. However, the accuracy and reproducibility of volume measurements taken in this manner warrant further investigation. Currently, the most frequently used method to obtain volume measurements from 3D volume datasets is VOCAL (Virtual Organ Computer-aided AnaLysis). This tool allows the performance of volume measurements by rotating the organ or structure of interest around a fixed axis, while 2D contours are manually or automatically delineated on each plane.

Finally, the VOCAL software automatically calculates the volume of the organ, which is expressed in cubic centimeters (Figure 17-23).⁷ Volume calculation can be performed by VOCAL and inversion mode; further research to establish its clinical applicability in the fetal gastrointestinal anomalies is needed.

Most of the GIT is located in the abdominal cavity, which contains the other GIT-related structures such as liver, choledochal system, pancreas, and mesentery/omentum, or with non–GIT-related organs, such as kidneys, adrenals, spleen, and ovaries in females. One of the main difficulties in the ultrasonographic examination of the fetal abdomen is to determine the origin of an intraabdominal mass detected during an examination, which could be any of the structures mentioned above or, even more, early embryonic structures not normally developed and embryonic abdominal totipotential cells such as teratomas. For this reason, we start our description of the GIT abnormalities with a general approach to the most frequent intraabdominal cystic masses. Abdominal echogenic masses are less common, although a cystic mass of the abdomen may appear with a variable echogenicity or as a complex structure.

Position, ultrasonographic appearance, associated anomalies, gestational age, and fetal sex provide important information to orientate towards a possible diagnosis. In many cases it will remain difficult to be certain about the origin of the detected mass even until the end of the pregnancy. Topographic assessment of an intraabdominal cystic mass can exclude noncompatible hypothesis about its origin or even lead to a diagnostic clue, as in cases of duodenal, coledochal (Figure 17-24), hepatic (Figure 17-25), splenic (Figure 17-26), or renal cysts (Figure 17-27), or duplex/multicystic kidney, etc. A topographic approach for differential diagnosis between the most frequent intraabdominal fetal masses is proposed in Figure 17-28.

Assessment of the fetal sex is mandatory when an abdominal cyst is detected, as some cystic masses are sex related (ovarian cysts or hydrometrocolpos, exclusively in females; Figures 17-29, and 17-30) or may present a sex predominance (pancreatic or choledocal cysts [see Figure 17-25] are more frequent in female fetuses).

Finally, a cystic mass may be differentiated by assessment of its sonographic appearance (shape, echogenicity, or other specific features) and careful examination for eventual other associated ultrasonographic findings:

• Meconium pseudocyst usually has irregular echogenic borders with calcifications of its walls (Figure 17-31), presenting a gradual reduction in size and a contemporary increasing of the calcifications in the follow-up scans; it is associated with echogenic foci anywhere in the peritoneal cavity and the scrotum, and in 50% of the cases there is ascites.

• Duplication cyst has an ovalar or tubular shape and thick wall, and may show peristalsis. It may be anechoic (Figure 17-32A) or hyperechoic (Figure 17-32B).

• Mesenteric cyst may be septated and abdominal lymphangioma appears as multicystic/multiseptated cystic lesions (Figure 17-33).

The use of color Doppler permits the examination of the vascular supply of a detected intraabdominal mass, its relation with the abdominal blood vessels, and diagnosis of its eventual vascular origin. This is helpful for instance in cases of umbilical vein varix (Figure 17-34) or hepatic arteriovenous (A-V) malformation.

Splenic Cyst

Congenital splenic cysts are very rare and include serous, vascular, and dermoid cysts; hemangioma; and lymphangioma. Approximately 25% of congenital splenic cysts remain of unknown origin.

Etiology

Possible etiologic mechanisms are as follows:

• Inclusion of coelomic mesothelium during organogenesis

• Involution and metaplasia of pluripotent cells or invagination of peritoneal endothelial cells in the splenic parenchyma during development

• Dilatation of normal lymph spaces

Differential Diagnosis

Splenic cysts are observed in the upper left quadrant of the fetal abdomen at up to 17 weeks or later (see Figure 17-26).⁸ The differential diagnosis of fetal splenic cyst can include renal, ovarian, adrenal, duplication, and mesenteric cysts.

Prognosis and Management

Prenatally diagnosed splenic cysts usually tend to disappear later in pregnancy or after birth.^9,10 On the contrary, if a splenic cyst increases in size, rupture of the cyst, internal hemorrhage, or compression of adjacent structures are eventual complications that may occur. Both prenatal and postnatal care requires expectant management and surveillance. Postnatal surgical treatment will be needed only if the splenic cyst becomes symptomatic due to its volume. In these cases a conservative approach, such as partial splenectomy or laparoscopic aspiration, is more often indicated compared to the classic total splenectomy.

Choledochal Cyst

Choledochal cysts are very rare and their incidence in Western countries is around 1in 100,000 with a 3 to 4:1 ratio between females and males, while a much higher incidence has been observed in Japan with an equal ratio between sexes.

Three distinct types of choledochal cysts have initially been classified by Alonso-Lej et al, enlarged into 5 by the classification of Todani et al, and subsequently subdivided into further subtypes.^11,12 A new classification has been proposed by Visser et al in an attempt to simplify the numbering system by introducing a nomenclature that follows a pathogenetic approach which distinguishes 4 entities: choledochal cyst, choledochocele, choledochal diverticulum, and Caroli disease. A comparison of the 3 classifications is reported in Table 17-2.¹³ Type I is the most frequent antenatally diagnosed type.¹⁴

Etiology

Three possible mechanisms regarding the pathogenesis of choledochal cysts are proposed:

• Pancreaticobiliary malunion (type Ic of the Todani classification) with an anomalously long common duct, causing reflux of the pancreatic secretions into the biliary duct system (this kind of pathogenesis is prevalent in Japanese patients)

• Primary ductal stricture around the hepatic hilum with intrahepatic dilatation (type IVa of the Todani classification)

• Atresia, stenosis, or dysfunction of the sphincter of Oddi (type III of the Todani classification)

The presence of familial cases suggest a possible inherited component.

Ancillary Ultrasound Signs

A choledocal cyst is detected as a simple cystic mass in the upper or right upper quadrant of the abdomen near the gall bladder. The identification of the biliary ducts leading to the cystic mass could allow a definitive diagnosis of a choledochal cyst (see Figure 17-24). Antenatal detection has been reported from 20 weeks of gestation.

Differential Diagnosis

Differential diagnosis includes cystic biliary atresia, hepatic cyst, gall bladder duplication, ovarian cyst, and enteric duplication cyst. In a series of 13 cases of biliary abnormalities, the correct diagnosis was made in only 15%, whereas other types of cystic mass were erroneously defined in the remaining cases.¹⁵ An antenatal differential diagnosis between cystic biliary atresia and choledocal cyst is not feasible, and it remains difficult to distinguish the 2 conditions even after birth.

Caroli Disease

Caroli disease is a rare autosomal recessive inherited condition (type V of Todani's classification). According to its pathologic mechanism, it is also known as ductal plate malformation due to a developmental aberration that consists of a complete or partial arrest of ductal plate remodelling. It is characterized by cystic congenital dilation of the segmental intrahepatic bile ducts. The hepatic involvement can be isolated or associated with renal abnormalities, in most cases autosomal recessive polycystic kidney disease (ARPKD), and/or with congenital hepatic fibrosis. Only 4 cases of antenatal diagnosis of Caroli disease have been reported so far.

Prognosis and Management

Postnatal complications include acute or recurrent cholangitis, intrahepatic calculi, cholestasis, cirrhosis, and liver failure. Furthermore, there is an increased risk for malignant degeneration of the choledochal system. The diagnosis of the disease is usually symptomatic, and it can be achieved even around the second or third decade of life, with a worse outcome at that stage. Therefore, the prenatal detection of a choledochal cyst permits an earlier assessment with improved outcome. Choledochal cysts associated with biliar atresia have a worse prognosis compared to isolated cysts.

Pancreatic Cyst

True congenital pancreatic cysts are very rare. They arise from an aberration of the embryologic development of the pancreatic ductal system. There is a female predominance.

Sonographic Appearance

Congenital pancreatic cysts can be solitary or multiple (Figure 17-35A and B). They usually are unilocular, nonenzymatic fluid-filled cysts located generally at the pancreatic tail or body, surrounded by normal pancreatic parenchyma. In some cases they can be so numerous that the whole pancreas may appear as a cystic mass.

Associated Anomalies

In many cases of a pancreatic cyst detected by ultrasound, associated anomalies can be observed. The most frequent associations with pancreatic cysts are as follows:

• Beckwith-Wiedemann syndrome

• Polycystic disease of the pancreas and kidneys

• von Hippel-Lindau disease

• Asphyxiating thoracic dysplasia, short limb dwarfism (Jeune syndrome)

• Hemihypertrophy

Prognosis and Management

Complications are very rare in isolated pancreatic cysts detected antenatally. They may become symptomatic postnatally due to an increase in size. In this case they might require surgical excision or internal drainage by cystoenterostomy.

Other abnormalities with cystic appearance are described later in this chapter.

Esophageal Atresia

Definition and Incidence

Esophageal atresia (EA) encompasses a group of congenital anomalies comprising an interruption of the continuity of the esophagus with or without a persistent communication with the trachea. In most cases there is a tracheoesophageal fistula (TEF); in 7% there is no fistulous connection, while in 4% there is a TEF without atresia. EA with or without TEF accounts is seen in about 1:3000 to 1:4000 live births. It is 2 to 3 times more frequent among twins, and males are affected slightly more than females.

Esophageal atresia is classified into 5 types on the basis of the anatomy and site of the TEF (Gross classification) (Figure 17-37).¹⁶

• Type A. This represents the isolated form of esophageal atresia without TEF and accounts for 7% to 8% of cases. The esophagus is divided in a proximal segment, which is dilated, thick walled, and reaches the posterior mediastinum at the second thoracic vertebra, and a distal segment, which is short and ends above the diaphragm.

• Type B. This variant is described as the combination of esophageal atresia with proximal TEF and occurs in 2% of cases. The fistula is located on the anterior wall of the esophagus and 1 to 2 cm above the end.

• Type C. This is the most common variant (86%) and consists of a dilated esophagus with a thickened muscular wall, which ends blindly in the superior mediastinum at the level of the third and fourth thoracic vertebra. The distal esophagus is thinner and narrower and enters the posterior wall of the trachea at the carina or more proximally. The distance between the proximal portion of the esophagus and the distal fistula varies from overlapping segments to a wide gap.

• Type D. This is defined as esophageal atresia with proximal and distal TEF. It is the less frequent form, occurring in less than 1% of cases.

• Type E. This is the TEF without esophageal atresia and represents 4% of cases. This form is characterized by an anatomically normal esophagus, which is connected with the trachea through a fistula commonly located in the lower cervical region. The fistula may be very narrow or 3 to 5 mm in diameter, and is usually single, although multiple fistulas have been occasionally reported.

Etiology

The mechanism that leads to esophageal atresia/TEF is still unknown, although animal studies have allowed detailed analysis of failed organogenesis underlying the condition. The most accredited theory postulates that the primary defect consists of the incomplete separation of the foregut into the ventral respiratory portion and the distal digestive portion at 8 weeks' gestation, because of either failure of tracheal growth or failure of the normally developed trachea to separate from the esophagus.¹⁷ Alternatively, it has been proposed that the primary insult is the atresia of the proximal esophagus followed by the establishment of a connection between the trachea and esophagus (TEF).¹⁸

Ancillary Ultrasound Signs

The anatomical visualization of the esophagus by echogenic lines, which represents the apposition of the collapsed anterior and posterior esophageal walls (see Figure 17-5A and B), might in and of itself not be sufficient to aid in the diagnosis of esophageal anomalies.

The sonographic diagnosis of esophageal atresia/TEF is based on the detection of both polyhydramnios and a small or absent fetal stomach bubble (Figure 17-38). Absent or a subjectively small stomach bubble must be followed up, because of its association with esophageal atresia. Other sonographic signs are polyhydramnios combined with fetal growth restriction, a C loop indicating the association with duodenal atresia or stenosis, and the detection of a proximal esophageal pouch.

Because esophageal atresia/TEF is commonly associated with an upper pouch, the presence of polyhydramnios and absent fetal stomach should prompt the evaluation of the upper esophageal segment in order to identify the "pouch sign" in the neck or mediastinum. This sonographic marker appears as an anechoic mass (Figure 17-39) and can be observed in the early third trimester, although its detection as early as 23 weeks' gestation has been reported.¹⁹ Because of paucity of reports described in the literature, the sensitivity and accuracy of the pouch sign in identifying fetuses with esophageal atresia/TEF is still undetected. The differential diagnosis of the pouch sign includes lymphovascular malformations and cervical cyst teratoma.

Another additional and inconstant sign is fetal growth restriction. Because polyhydramnios is usually associated with fetal macrosomia, the presence of increased amniotic fluid and restricted growth should raise the suspicion of esophageal atresia/TEF. Fetal growth restriction affects 40% of fetuses with esophageal atresia/TEF, probably as a result of reduced intestinal absorption mainly in late gestation.

The combination of duodenal and esophageal atresia is characterized by a C-shaped fluid collection in the fetal abdomen (Figure 17-40), which results from a closed-loop bowel obstruction involving the distal esophagus, stomach, and duodenum.

The prenatal diagnosis of esophageal atresia/TEF is limited by several factors. Although the presence of polyhydramnios, small or absent stomach, and pouch sign is highly suggestive for esophageal atresia/TEF, a wide range of pathologic conditions is associated with increased amniotic fluid and nonvisualization of the gastric bubble. Furthermore, the definition of a "small" gastric bubble is subjective and fairly reproducible.¹⁹ In addition, the presence of an upper pouch and distal fistula allows the amniotic fluid to flow and fill the stomach. The amount of fluid able to cross the fistula channel is not enough to prevent the onset of polyhydramnios, but is responsible for the detection of a constantly small gastric bubble, which makes the ultrasonographic diagnosis of esophageal atresia/TEF virtually impossible. Finally, the pouch sign is a transient finding that can be detected only when the fetus swallows.

The differential diagnosis includes a number of conditions associated with polyhydramnios and reduced size of the fetal stomach. Obstruction of the fetal GIT proximal to the ileum, facial cleft, and central nervous system disorders leading to depression of swallowing are common causes of polyhydramnios. A nonvisible stomach is present in up to 1% of normal fetuses on initial scans, for which strict follow-up is mandatory. The C-loop sign should be differentiated from other intraabdominal cysts.

Associated Anomalies

Associated anomalies can be found in 50% to 70% of infants with esophageal atresia/TEF.²⁰ Esophageal atresia/ TEF is part of a phenotype of associations and syndromes, such as VACTERL (vertebral, anorectal, tracheoesophageal, renal, and limb anomalies), CHARGE (coloboma, heart defects, atresia choanal, retarde growth, genital hypoplasia, and ear deformities), Potter syndrome (renal agenesia, pulmonary hypoplasia, typical dysmorfic facies), and Schiss association (omphalocele, cleft lip/palate, genital hypoplasia). Trisomy 21 and 18, and 13q deletion may also present esophageal atresia/TEF in their spectrum of features. Fetuses with Down syndrome are more likely to present isolated esophageal atresia in as many as 50% of cases. The most frequent cardiac anomalies are ventricular septal defects and tetralogy of Fallot. The vertebral anomalies regard mainly the thoracic region and lead to scoliosis in later stages. Other structural defects associated with esophageal atresia/TEF include duodenal atresia, malrotation, pyloric stenosis, cleft lip/palate, omphalocele, Meckel diverticulum, annular pancreas, lung abnormalities, choanal atresia, and hypospadia. However, 78% of these anomalies may be undetected prenatally.²⁰

Recurrent Risk

The majority of cases of esophageal atresia are sporadic and nonsyndromic, and familial cases account for less than 1%. There is no known pattern of inheritance and the recurrent risk in a sibling of an affected child is approximately 1%.

Management

Because 20% to 44% of fetuses with esophageal atresia/TEF present chromosomal anomalies, mainly trisomy 21 and 18, fetal karyotype is recommended. The risk of carrying trisomy 21 is particularly enhanced if esophageal atresia is associated with duodenal atresia.

The peristalsis of the esophagus is always compromised in infants affected with esophageal atresia/TEF due to abnormal neuropeptide distribution or vagal nerve damage occurring during surgical repair. The trachea is also anomalous because of an absolute deficiency of the tracheal cartilage and an increased length of the transverse muscle in the posterior wall. In the severe forms, tracheomalacia with tracheal collapse may develop in proximity of the fistula. Therefore, delivery should take place in a tertiary referral center, which can provide neonatal intensive care and pediatric surgery.

When lethal congenital anomalies are not present, the survival rate is more than 95%. At birth, a suction catheter, located in the upper esophageal pouch, is necessary to remove secretions and prevent aspiration. Furthermore, the increased pulmonary resistance induces respiratory gases moving down through the distal fistula into the stomach, leading to distension and rupture of the stomach. Particular attention is warranted in preterm infants, who are likely to need endotracheal intubation and mechanical ventilation.

Postnatal surgery consists of dividing the fistula distal to its entry in the trachea and closing the defect with interrupted sutures. Successively, the proximal blind end of the esophagus is linked to the lower esophageal segment. On the second or third day after surgery, feeding via the transanastomotic tube may be allowed, and oral feeding is gradually introduced. Stenosis at the site of anastomosis can be observed in one-third of the infants, and in most cases it resolves after dilatation.¹⁶ In later infancy, substitution of the esophagus with stomach or bowel can be attempted. Long-term complications include food bolus obstruction (16%), tracheomalacia (10%), and gastroesophageal reflux with recurrent respiratory infections, and vomiting and poor growth (40%).¹⁶ The quality of life for adults after at least 20 years from surgical repair of esophageal atresia/TEF is comparable to the normal population.²¹

Emerging Concepts and Future Directions

Direct visualization of the fetal esophagus is feasible with very high frequency transducers in approximately 87% of midtrimester fetuses, and esophageal motility can be followed from pharynx to stomach in 30% of cases.²¹ However, the efficacy of the anatomical assessment of the esophagus in identifying fetuses with esophageal atresia/TEF is still undetected, and further investigations are required before incorporating this examination in sonographic surveys of fetal anatomy.

Magnetic resonance (MR) has revealed a useful tool to assess fetal thoracic lesions. The sensitivity of MR in diagnosing esophageal atresia/TEF is not well established because of different criteria in selecting fetuses, which may benefit of further studies. Langer et al reported a 100% sensitivity of MR for the identification of 5 fetuses with esophageal atresia/TEF,²² whereas in the series presented by Levine et al, nonvisualization of the esophagus in MR scans occurred in 64% of examinations.²³ Such a discrepancy may be explained by the different indications for performing MR, being ultrasound findings of polyhydramnios and absent stomach bubble in the series by Langer et al, and suspicion of chest lesions in the series by Levine et al. Further studies are needed to investigate the efficacy of MR as a complement to the sonographic evaluation.

Duodenal Atresia

Definition and Incidence

Duodenal atresia is the absence or abnormal narrowing of the segment between the proximal and distal portions of the duodenum. It occurs in 1:5000 pregnancies and 0.6:10,000 live births.²⁴ In 80% of cases, the obstruction of the lumen is located caudally to the Vater ampulla and is complete, whereas in the remaining 20% of cases a membrane or diaphragm within the duodenal lumen is responsible for partial (stenosis) or complete occlusion.

Etiology

During the fifth week of embryonic life, the epithelium of the primitive duodenum proliferates and obliterates the lumen, up to 11 weeks' gestation when vascularization restores the luminal patency. Duodenal atresia is caused by failed recanalization of the duodenum during organogenesis. Another theory suggests an interruption of blood supply during embryogenensis as the main mechanism underlying the condition, although according to some authors a vascular insult leads to atresia of the jejunal and ileum rather than a maldevelopment of duodenum.²⁵

Ancillary Ultrasound Signs

At 18 to 21 weeks' gestation, the only sonographic marker consistent with an abnormal development of duodenum is a dilated stomach with a mild dilatation of the duodenum. During follow-up scans the typical "double bubble" (Figure 17-41A and B) sign becomes more evident, and in the late second to early third trimester polyhydramnios develops. The recognition of polyhydramnios and double bubble sign allows definitive diagnosis of duodenal atresia. When the double bubble is absent but with evidence of a dilated stomach (Figure 17-42), a duodenal stenosis should be suspected.

The differential diagnosis is posed with enteric duplication cyst, choledochal cyst, and hepatic cyst, which are characterized by noncommunicating anechoic cysts. Therefore, when 2 abdominal anechoic cysts are detected during ultrasound examination, the presence of an inter-cysts communication should be demonstrated in order to distinguish a duodenal atresia from other cystic structures in the middle or right upper abdomen. In addition, 3D imaging may be helpful in differentiating the gastric from the duodenal cavities, and identifying the communication between the pylorus and duodenum. Extrinsic obstruction, duodenal diverticula, and duplication should also be differentiated from a duodenal atresia.

Associated Anomalies

Major structural anomalies associated with duodenal atresia can be found in 40% to 50% of affected fetuses and include gastrointestinal (malrotation, biliary tract disorders, annular pancreas), vertebral (33%), and cardiac defects (30%). A massive overdistension of the stomach and proximal duodenum, and a C-loop sign are indicative of an associated esophageal atresia. Other structural associated anomalies include anorectal malformation and renal anomalies.

The risk of abnormal karyotype, mainly trisomy 21, is very high, since 40% (range 20% to 50%) of fetuses with duodenal atresia are affected with trisomy 21, and 5% to 15% of neonates with Down syndrome have duodenal atresia. In a review of 275 cases of duodenal atresia, Down syndrome was present in 30%, Down syndrome and cardiac malformation in 14%, cardiac anomaly without trisomy 21 in 23%, and other gastrointestinal defects in 42%.²⁶

Management

Fetal karyotype analysis is mandatory. Infants with duodenal atresia and Down syndrome should undergo rectal biopsy to exclude Hirschsprung disease. A detailed survey of fetal anatomy, including echocardiography, should be performed to rule out associated structural anomalies. Postnatal surgery can be performed just after birth and consists of bypass procedures with duodenoduodenostomy or duodenojejunostomy. In the presence of associated intestinal, pancreatic, and biliary anomalies, additional surgical procedures are needed.

In the isolated forms of duodenal atresia, the prognosis is good with an early postoperative mortality rate of 3% to 5% and a late mortality incidence of less than 6%.²⁷ Of the approximately 90% of surviving infants, 25% will undergo an additional surgical procedure at 6 years to resolve a recurrent stenosis or postoperative complications, such as a gastroesophageal reflux. In contrast, the presence of severe biliary tract defects is responsible for 20% to 40% of neonatal mortality.

Long-term sequelae encompass megaduodenum, duodenogastroesophageal reflux, peptic ulcers, and biliary-pancreatic disorders.

Jejunoileal Stenosis and Atresia

Definition and Incidence

Jejunoileal atresia is slightly more common than duodenal atresia, occurring in 1 in 3000 to 4000 births. Variation in prevalence between regions has been observed.²⁵

Considered as a whole, the jejunum is slightly more frequently affected (50%) than the ileum (43%) and both of the 2 intestinal tracts are involved in the remaining 7%. Multiple pregnancies and male fetuses are more likely to be affected by the disease than singleton or female fetuses.

Jejunoileal atresia is classified as follows (Figure 17-43):

• Type I. Accounts for 20% of cases and is secondary to an intraluminal diaphragm or membrane.

• Type II. A fibrous ring connects 2 blind-ending stumps of intestine. This form represents 32% of cases.

• Type III. This form consists of 2 portions of intestine, which are completely separated by a mesenteric gap. It occurs in 48% of cases. Type III exists in 2 variants, which carry the worst prognosis because of reduced intestinal surface: type IIIB (11%), which is characterized by the so-called apple-peel aspect of the bowel and involvement of the entire jejunum, proximal ileum, and distal duodenum; and type IV (17%), in which the atresia involves multiple sites.

Etiology

Etiological factors are unknown, although animal models have shown that bowel atresia may be due to atresia or torsion of the feeding artery during the rotation of the midgut. The vascular occlusion of a superior mesenteric artery branch may be the underlying mechanism of the apple-peel variant.

Ancillary Ultrasound Signs

The ultrasound diagnosis is based on the visualization of a severe dilatation of the intestinal loops, proximal tothe obstruction (Figure 17-44A and B). In most cases, this sign appears after 25 weeks' gestation. Polyhydramnios is also a late sign and is more likely associated with a proximal lesion. According to nomograms, an ileal loop with transverse diameter greater than 7 mm is suspicious for atresia or stenosis of the small intestine. Additional markers, which could be helpful for diagnosis, are the location of the obstructed loop in the middle of the abdomen, hyperechoic walls (Figure 17-45A), increased peristalsis, and the detection of intraluminal calcifications suggestive of a meconium ileus (Figure 17-45B). The precise site of obstruction (jejunum or ileus) cannot be directly identified by ultrasound, but indirect signs can be demonstrated. In particular, the detection of ascites and/or abdominal calcifications is indicative of intestinal perforation, which is commonly associated with ileal atresia and complicates 6% of cases, whereas the extreme bowel dilatation without signs of perforation is typical of the jejunum atresia.

The differential diagnosis with Hirschsprung disease, meconium ileus, and volvulus is virtually impossible with prenatal assessment, although the loop dilatation is gradual for intestinal atresia and within 3 to 4 days for volvulus. Hydroureter can also mimic a small intestine atresia, and oligohydramnios and/or hydronephrosis are important clues for differential diagnosis. A small bowel atresia has been occasionally described as a cyst-like mass, which needs to be distinguished from ovarian cysts, enteric duplication cyst, and mesenteric cyst.

Associated Anomalies

Jejunoileal atresia/stenosis is usually isolated. In the few cases with multiple malformations, the associated anomalies are represented by the probable cause of atresia (malrotation, volvulus, intestinal duplications, meconium ileus, gastroschisis) in 27%, complications of atresia (intestinal perforation with meconium peritonitis) in 6%, and concurrent bowel defects (colon atresia, esophageal atresia, enteric duplications) in 5%. Cystic fibrosis should also be considered in a fetus with small bowel atresia. The risk of chromosomal defects is not increased in this case; therefore, fetal karyotype analysis is not recommended on the basis of jejunoileal atresia or stenosis.

Management

The progression of jejunoileal atresia is strictly related to the anatomic site of the lesion. Ileal atresia is usually isolated, tends to perforate in utero, and is less frequently associated to preterm delivery compared to jejunal atresia. The detection of abdominal calcifications represents a poor prognostic factor, because it is highly indicative of bowel perforation secondary to ischemia and infarction, which represents the primary complication of small bowel atresia and occurs in 6% of cases. Conversely, jejuneal atresia is usually multiple, tends to dilatation rather than perforation, and is associated with earlier gestational age at delivery and lower birth weight compared with ileal atresia.

Fetal growth restriction can develop, mainly in association with jejunum atresia, secondary to the consequent protein malabsorption. Because of severe polyhydramnios, amniodrainage may be necessary to reduce the risk of preterm delivery. Intestinal atresia is not considered an indication for cesarean delivery, although severe polyhydramnios can lead to malpresentation during labor. The delivery should be performed in a tertiary referral center, because postnatal surgery is to be performed soon after birth. This consists of the removal of the atretic segments and application of end-to-end bowel anastomosis. The prognosis is usually good, except for types IIIB and IV, in which postnatal repair requires a significant reduction of the small intestine length, which consequently leads to malabsorption (short bowel syndrome). Less than 10% of infants are complicated with volvulus, perforation, and meconium peritonitis, which is associated with up to a 10% postoperative mortality rate.

Emerging Concepts

MR images can be useful in identifying the site of intestinal obstruction. Furthermore, when the lesion obliterates multiple sites of small bowel, characteristic signals have been described.²⁸

Anal Atresia and Other Anorectal Abnormalities

Definition and Incidence

Anorectal malformations (ARMs) represent a spectrum of abnormalities ranging from mild anal anomalies to complex cloacal malformations and account for approximately 1 in 5000 live births. ARMs may be subdivided into high, low, and intermediate types according to their relationship with the levator ani muscle.

Etiology

The abnormal partitioning of the cloaca by the urorectal septum is the underlying mechanism responsible for ARMs.

During the fourth week of human embryonic development, the urogenital system and gastrointestinal system empty into a common draining structure—the cloaca—consisting of the yolk sac derived, distal hindgut, and the allantois.

The caudal end of the cloaca is fused with the intact cloacal membrane, and therefore has no caudal openings. Subsequently, the cloaca is divided into an anterior (urogenital sinus) and a posterior (rectum and the proximal part of the anal canal) part by the developing urorectal septum. The urorectal septum fuses with the cloacal membrane by the seventh week of development dividing it into the ventral urogenital membrane and the dorsal anal membrane. Both urogenital and anal membranes normally rupture around the eighth week of development, creating communications between the anal/urogenital tract and the amniotic cavity.

Failure of perforation of the anal membrane leads to imperforate anus. If the rectum, vagina, and urinary system open to the perineum through a single orifice, a persistent cloaca will develop.

Ancillary Ultrasound Signs

Prenatal diagnosis of ARMs can be suspected when a dilated rectosigmoid intestinal tract is detected, usually from 22 gestational weeks (Figure 17-46), although case reports of imperforate anus as early as 12 gestational weeks have been described.²⁹ However, the majority of ARMs are missed prenatally.³⁰

Occasionally, the meconium in the dilated rectal pouch becomes hyperechoic either proximally or distally to the site of obstruction. Intraluminal calcifications (Figure 17-47) can result from prolonged stasis of the meconium and/or indicate the presence of alkaline urine derived from a colovesical fistula. It is probable that a change of pH causes precipitation of the calcium salt. Enterolithiasis represents a warning sign for large bowel obstruction with or without urorectal fistula.³⁰ Therefore, adequate gastrointestinal and urologic studies must be undertaken after birth for the final diagnosis.

Differential diagnosis is made with the higher bowel obstructions. If the rectal pouch is larger than the filled bladder and appears bilobed, anorectal obstruction is likely. It is noteworthy that, because bowel dilatation may be a transient finding, serial ultrasound examinations are recommended whenever an enlarged bowel is detected.

Persistent cloaca is more commonly seen in the female fetus and is characterized by a single perineal/anal opening that serves as a common outlet for urine and feces to the outside.

Prenatal ultrasound findings may vary considerably and encompass transient fetal ascites, a multiloculated cystic structure arising from the fetal pelvis that may contain debris, bilateral hydronephrosis, dysplastic kidneys, intraluminal colonic calcifications, reduction in amniotic fluid volume, growth retardation, vertebral anomalies, and ambiguous genitalia (Figure 17-48).

Associated Anomalies

Genitourinary defects occur in approximately 50% of patients with ARMs. Other frequent associated malformations are vertebral anomalies. The sacral segment is the most frequently involved tract including sacral deficiency and hemisacrum. Associated hemivertebrae can involve the thoracic and lumbar tracts, leading to scoliosis. Spinal defects may include a tethered spinal cord, which is the intravertebral fixation of the phylum terminale. This anomaly, which is highly associated with hypodeveloped sacrum and urologic abnormalities, results in motor and sensory disorders. Syringomyelia and myelomeningocele are rarely described in association with anorectal malformations.

The risk of chromosomal anomalies is high, mainly for trisomies 18 and 21. Although the etiology of ARMs is unknown, the mutation of a variety of different genes can manifest with anal defects. Furthermore, anorectal defects are phenotypic of a large spectrum of nonchromosomal syndromes, including VACTERL, MURCS (müllerian duct aplasia, renal aplasia, cervicothoracic somite dysplasia), and OEIS (omphalocele, extrophy, imperforate anus, spinal defect).

Management

All patients with prenatal detection of dilated bowel must be evaluated at birth to rule out associated anomalies. The presence of an abdominal mass is suggestive for a distended vagina (hydrocolpos), which affects 50% of patients with persistent cloaca. Abdominal ultrasound and radiographs of the spine are mandatory in newborns with imperforate anus. At 3 months of age, MR imaging is useful to detect tethered spinal cord and other spinal anomalies.

Prognosis varies widely from minor and easily treated defects to complex and difficult to manage anomalies, which are often associated with other structural malformations and poor functional prognosis. After surgery with sagittal anorectoplasty, neonates are classified into 3 groups on the basis of postoperative complications:

• Group I: Poor anatomy, flat bottom, poor quality of muscle, sacral defects, and urinary incontinence. These defects are managed with muscle transfer and/or colostomy.

• Group II: Good quality of muscle and normal sacrum, but displaced bowel. The treatment consists in repositioning of the bowel.

• Group III: Constipation. Enemas, suppositories, or anterior resection are necessary.

When ARMs are associated with sirenomelia or caudal regression syndrome, the prognosis is very poor due to the associated bilateral renal agenesia.

Definition and Incidence

Hyperechogenic bowel is not a truly pathological event but a nonspecific ultrasound sign. It is not a pathological entity, but its detection is important to prenatal diagnosis. The incidence of hyperechogenic bowel is 0.5% of second trimester pregnancies.

Etiology

Hyperechogenic bowel may result from alteration in meconium with increased protein content and/or decreased water content, swallowed blood following intraamniotic hemorrhage, intestinal wall edema, and ischemia. Decreased water content is the most frequent alteration observed in fetuses with hyperechogenic bowel and may derive from hypoperistalsis secondary to decreased bowel function or vascular injury. In fetuses with trisomy syndromes and cystic fibrosis, the reduction of microvillar enzymes leads to constipation and thickened calcified meconium. In a minority of growth restricted fetuses, hyperechogenic bowel may occur as a result of impaired bowel function secondary to hemodynamic redistribution and consequent mesenteric ischemia.

Ancillary Ultrasound Signs

Hyperechogenic bowel is mainly detected in the first and early second trimesters, because the fetus swallows less fluid at this time, whereas in advanced gestational age the swallowed fluid allows passage of intestinal content. Because the definition and interpretation of hyperechogenic bowel are subjective, various grading systems have been proposed in order to minimize subjectivity; one of the most used is based on comparison of the intestinal and iliac bone echogenicity.³¹

• Grade 1: Less echogenic than fetal iliac bone

• Grade 2: As echogenic as fetal iliac bone

• Grade 3: More echogenic than fetal iliac bone

The normal echogenicity of the bowel changes along pregnancy: a mild hypercogenity is normally seen in the first trimester, in early midtrimester, and in the third trimester. Figure 17-49 illustrates a normal echogenicity of the bowel at 21 weeks and diffused hyperechogenic bowel at the same gestational age.

Differential diagnosis of hyperechogenic bowel includes echogenic intraabdominal masses such as dysplastic kidneys, intraabdominal extrathoracic pulmonary sequestration (Figure 17-50), duplication cyst, and meconium peritonitis, which will be discussed later in this chapter. In the third trimester, the location of hyperechogenic bowel can be helpful to assess prognosis: if confined to the colon, hyperechogenic bowel may be transient, whereas in the small bowel it is associated with adverse outcome.

Associated Anomalies

Hyperechogenic bowel is found in association with fetal aneuploidy, bowel obstruction or atresia, congenital infection, intrauterine growth restriction (IUGR), fetal demise, and cystic fibrosis. The likelihood of association between hyperechogenic bowel and cystic fibrosis increases with the degree of the intestinal echogenicity.

Management

Karyotype, screening for viral infection, and screening for cystic fibrosis should be performed in the presence of hyperechogenic bowel. In a large series of approximately 680 fetuses with hyperechogenic bowel in the second or third trimester, 65% had normal outcomes, 7% had multiple malformations, 3% had chromosomal anomalies, 3% had cystic fibrosis, and less than 3% had viral infections.³² Hyperechogenic bowel is associatd with trisomy 21,³³ thus increased intestinal echogenicity is actually considered a soft marker for fetal aneuploidy.

Emerging Concepts

Biochemical studies of meconium and histological examination of the small bowel after termination of pregnancy could provide important information on the natural history of hyperechogenic bowel.

Definition and Incidence

Meconium ileus is a mechanical obstruction of the ileum that is caused by thickened meconium due to high protein content, which in turn is mainly caused by cystic fibrosis. The intestinal occlusion may lead to ileal perforation and meconium peritonitis, and when it occurs distally in the colon, a mucus plug, which obliterates the rectum, may develop.

Etiology

Cystic fibrosis represents the most frequent cause of meconium ileus, accounting for more than 90% of cases. In the remaining 10% of cases, the etiology is unknown. In fetuses affected with cystic fibrosis, meconium consists of very high protein content and less fluids because of impaired intraluminal secretion. Consequently, the meconium thickens and blocks the intestinal transit, and the loops proximal to the obstruction dilate and often perforate because of the weak elasticity of the ileal walls. When the obstruction involves the colon, the likelihood of associated cystic fibrosis is 25%.

Ancillary Ultrasound Signs

The ultrasound diagnosis is characterized by the detection of multiple dilated loops with hyperechoic content and walls (Figure 17-51A). The visualization of diffuse intraabdominal calcifications indicates the occurrence of meconium peritonitis (Figure 17-51B). The most frequent locations of the focus are left upper abdominal quadrant near the stomach (Figure 17-51C) and hepatic capsula. The obstruction is usually visualized in the late second trimester.

The differential diagnosis includes ileal ischemia and small bowel atresia. The presence of intraluminal and/or intraabdominal calcifications should point towards meconium ileus.

Associated Anomalies

Approximately 90% of fetuses with meconium ileus are affected with cystic fibrosis. Up to 25% of fetuses with mucosal plug in the colon are also affected with cystic fibrosis. Cases of meconium ileus not associated with cystic fibrosis are found in extreme prematurity with intestinal dysmotility, swallowed blood because of intraamniotic bleeding, infection, and multiple anomaly syndromes.

Management

Meconium ileus is considered as a soft marker of Down syndrome and carries a risk of trisomy 21 of approximately 3%. Therefore, testing fetal karyotype is justified. Fetal DNA examination with amniocentesis is helpful to identify fetuses affected with cystic fibrosis. The gene disorder of cystic fibrosis has been detected on chromosome 7 and more than 900 gene mutations have been identified.

Postnatal management requires a computed tomography scan in order to highlight intestinal perforation missed prenatally. Up to 50% of fetuses with meconium ileus present additional gastrointestinal complications, such as volvulus, atresia, bowel perforation, and meconium peritonitis. If bowel atresia is associated, surgery consists of bowel resection with end-to-end anastomosis and should be performed soon after birth. If meconium ileus is isolated, simple saline, water-soluble contrast enema or N-acetylcysteine therapy may allow meconium passage. Prognosis, survival, and quality of life depend on the severity of cystic fibrosis.

Definition and Incidence

Enteric duplication cysts are rarely detected prenatally, although they are commonly diagnosed at birth with a higher prevalence in males rather than females. The incidence is approximately 1 per 10,000 live births.³⁴

Etiology

Failed recanalization of the intestinal lumen and missed separation of the nothocord from the endoderm are the 2 most accepted mechanisms underlying the condition. The latter theory involves the transient attachment of the endodermal roof with the nothocord during the fifth week of gestation. This hypothesis would explain the association of enteric duplication cysts with vertebral anomalies. Enteric duplication cysts may occur anywhere along the gastrointestinal tract, the stomach being the least frequent site of the lesion. The cysts are placed on the mesenteric side of the digestive system and do not communicate with the normal bowel, except for the tubular variant.

Ancillary Ultrasound Signs

Enteric duplication cysts are most common in the abdomen, although case reports have described the cysts in the mouth and thorax. The mass may appear hyperechoic (see Figure 17-32A) or even cystic (see Figure 17-32B). About one-half of cases are in the midgut, one-third in the foregut (esophagus, stomach, and proximal duodenum), and the remaining cases are in the colon.

Differential Diagnosis

The differential diagnosis includes other intraabdominal cysts, such as ovarian, mesenteric, choledochal, renal, and urachal cysts. The location is useful to identify the origin of the cysts. The double bubble sign of the duodenal atresia should also be excluded. Demonstration of peristalsis within the cyst has been reported and may be helpful for correct diagnosis. A Meckel diverticulum also presents peristalsis, but, as opposed to a bowel duplication, it is not located on the mesenteric side.

Associated Anomalies

In a discrete number of cases, anomalies such as gastrointestinal, genitourinary, and split notochord syndrome are associated.

Management

Intussusception, pain, progressive dilatation, perforation, and bleeding are symptoms that manifest in 85% of infants affected with enteric duplication cysts, for which surgical resection is curative.

Hepatic Echogenicities

Definition and Incidence

Punctuate echogenic foci within the liver are intrahepatic calcifications that occur in 1 to 1750 fetuses at 15 to 26 weeks' gestation.³⁵

Etiology

A vascular injury, leading to liver infarction or ischemia, has been supposed as an etiological factor of intrahepatic calcifications.

Ancillary Ultrasound Signs

Intrahepatic calcifications are generally identified as 1 or 2 echogenic foci within the liver parenchyma. Multiple calcifications are more likely to be associated with fetal infections (Figure 17-52) or aneuploidy.

The most important differential diagnosis is meconium peritonitis. In fact, bowel perforation with meconium peritonitis is the most common cause of hepatic capsular calcification (Figure 17-53) as opposed to intrahepatic calcifications. Small hemangiomas may also present hepatic hyperechogenicity.

Associated Anomalies

Intrahepatic calcifications may be isolated or associated with abnormal karyotype (trisomy 18 and trisomy 13), dwarfism, and hydronephrosis. Widespread liver calcifications are symptoms of varicella, cytomegalovirus (CMV), and toxoplasmosis.

Management

Fetal karyotype is recommended when additional anomalies are detected. When isolated, intrahepatic calcifications have a good prognosis.

Hepatomegaly and Splenomegaly

Definition and Incidence

Hepatomegaly and splenomegaly are defined as an increased volume of fetal liver and spleen, respectively. They may be associated or develop independently.

Etiology

The most frequent cause of hepatomegaly is intrauterine infection. The myeloproliferative disorder associated with Down syndrome and benign or malignant hepatic tumors, such as hemangioma or hepatoblastoma, may also induce moderate or severe hepatomegaly. It is noteworthy that hepatomegaly could result from cardiac failure because of an increased central venous pressure, which is in turn responsible for venous congestion in the liver. Finally, hepatomegaly is part of the phenotype of Beckwith-Wiedemann and Zellweger syndromes.

Splenomegaly is often a sign of fetal infection, mainly CMV infection, and is associated with hepatomegaly and ascites in the severe cases. Storage disorders, such as Gaucher, Wolman, and Niemann-Pick syndromes, manifest splenomegaly in the late third trimester.

Ancillary Ultrasound Signs

Because of their increased volume, the liver and/or spleen occupy most of the abdomen (Figure 17-54). When ascites is present, the detection of the enlarged liver and/or spleen is easier because ascites acts as an intraabdominal contrast medium. Nomograms of the maximum diameter of liver and spleen are useful to assess the growth of the 2 organs.

Management

Despite that only a minority of Down fetuses present hepatosplenomegaly, testing karyotype should be recommended in the case that all the other causes are excluded. In fact, when hepatomegaly and splenomegaly are detected, the first issue to consider is an intrauterine infection (see Figure 17-52). Maternal serologic markers of CMV and toxoplasmosis infection should be investigated. A detailed survey of fetal anatomy should be performed to rule out further signs of fetal infections, such as cerebral calcification, hydrocephalus, ascites, and cardiomegaly. In CMV infection, splenomegaly is more marked than hepatomegaly.

The prognosis is obviously related to the underlying condition. Storage diseases are usually lethal in the first months or years after birth.

Comment

An increased risk for leukemia is a well-recognized feature in children and infants with trisomy 21. In addition, neonates with trisomy 21 may present with a distinct transient form of hematologic abnormalities that is often indistinguishable from acute leukemia. In most of these cases there is spontaneous regression, and therefore this disorder is called transient myeloproliferative disorder (TMD). Its clinical manifestations are hepatosplenomegaly and abnormal peripheral blood test findings. In the rare prenatal reports of TMD associated with trisomy 21, the predominant ultrasound and/or clinical features of reported cases were hydrops and hepatosplenomegaly.

Final Consideration

Fetal hepatosplenomegaly is a specific finding in cases of severe isoimmunization disorder, in utero infection, fetal congestive heart failure, and metabolic disorder. Our case suggests that hepatosplenomegaly with or without hydrops can be also a marker for trisomy 21.

If the aforementioned conditions are excluded, then fetal hepatosplenomegaly is thought to be associated with trisomy 21 and fetal amniocentesis should be performed.

Definition and Incidence

Gall bladder agenesis is a relatively rare finding, which accounts for less than 1 in 6000 live births.

Ancillary Ultrasound Signs

When the gall bladder is not visualized on the early scan, it may be detected later in pregnancy and even after delivery. However, nonvisualization of the gall bladder can be associated with aberrant location and abnormal karyotype.

Associated Anomalies

The congenital absence of the gall bladder can be found in association with cardiovascular (58.3%), gastrointestinal/ genitourinary (25%), anterior abdominal wall (10.4%), and central nervous system disorders (6.3%).³⁶ Various syndromes, such as Steinfeld syndrome, Alagille syndrome, or craniomicromelic syndrome are associated with gall bladder agenesis. In a recent case report, gall bladder agenesis associated with absence of thyroid was described.³⁷ Intestinal obstruction and cystic fibrosis should be suspected when the gall bladder is not visualized.

Management

The isolated forms of gall bladder agenesis have a favorable prognosis, whereas the association with additional malformations may be associated with poor outcomes.

The venous perfusion of the liver in utero differs substantially from that after delivery. While postnatally all the venous blood is supplied by the portal vein, during prenatal life the liver receives venous blood from both the portal and the umbilical veins.

The umbilical vein enters the fetal abdomen within the falciform ligament, ascending steeply towards the liver. It enters the liver anteriorly and runs along its inferior surface in a cephalad direction. It then joins a confluence of vessels termed the portal sinus. The portal sinus is a wide L-shaped vessel at the terminal end of the umbilical vein, connecting 2 main vessels termed the right and left intrahepatic portal veins perfusing the right and left hepatic lobes.³⁸

While 20% to 30% of the umbilical venous blood leaves the intraabdominal umbilical vein and enters the portal sinus to reach the ductus venosus, the fetal liver receives the remaining 70% to 80% of the venous return from the placenta.

There are a number of vessels arising from the left and right hepatic lobes converging into the 3 main (right, middle, and left) hepatic veins. The right, middle, and left hepatic veins appear to have the same caliber. They join the inferior vena cava (IVC) (Figure 17-55A) and the ductus venosus in the subdiaphragmatic vestibulum, an inverted, funnel-shaped vascular space just below the diaphragm. The vestibulum continues through the diaphragm and joins the right atrium.

The fetal ductus venosus is a slender trumpet-like shunt, connecting the intraabdominal umbilical vein to the IVC (Figures 17-55B, and 17-56A) at its inlet to the heart. Because the well-oxygenated blood from the ductus venosus is loaded with the highest kinetic energy in the IVC, it will predominantly be this blood that presses open the foramen ovale valve to enter the left atrium, thus forming the "preferential streaming" of the via sinistra.³⁹

Umbilical and Portal Venous Systems Malformations

Definition and Anatomy

In recent years improvements of color Doppler technology and increasing interest in the fetal venous systems have enabled extensive investigation of fetal venous anomalies,^{40, 41, 42, 43, and 44} leading to greater insight into prenatal diagnosis of the different types of umbilical and portal venous systems and malformations, and a better understanding of their pathophysiology and clinical implications.

They often affect the hemodynamics of fetal circulation and, in particular, the ductus venosus that shunts well-oxygenated blood through the foramen ovale towards the left atrium and left ventricle, and to the fetal cerebral and coronary circulation.^{39, 40, 41, 42, and 43}

Absence of ductus venosus (ADV) in the fetus has been reported using ultrasound in the last decade. Two different routes for umbilical venous return have been described in fetuses with ADV:

• Extrahepatic umbilical venous drainage^{39, 40, 41, 42, and 43} bypassing the liver (the umbilical vein directly connects to the iliac vein, the inferior vena cava, the renal vein, the right atrium, or the left atrium or the coronary sinus)

• Intrahepatic umbilical venous drainage^39,42 without liver bypass (the umbilical vein connects to the portal sinus in its usual way without giving rise to the DV)

Etiology

During the fifth week of gestation in normal embryonic development, the embryonic venous system has 3 pairs of veins running into the cardiac sinus: the cardinal veins, the umbilical veins (bringing the blood from the trophoblast), and the vitelline or omphalomesenteric veins taking the blood from the yolk sac to the fetal heart. Development of the liver plays a role in modifying the primitive vitelline and umbilical systems to their final form. In fact, the vitelline veins (VV) and umbilical veins (UV) connect to the liver before entering the sinus venosus. During their course through the liver, they are interrupted by the hepatic sinusoids and linked to them. The right UV and the part of the left UV between the liver and the sinus venosus disappear and the remaining part of the left UV carries all the blood from the placenta to the fetus. The portal vein develops from three main anastomoses between the VV at the caudal end of the liver; gradually these anastomoses form the portal vein (the cranial-most part of the right vitelline), which passes dorsal to the duodenum and branches to form the splenic vein and mesenteric vein, which run ventral to the duodenum. Thus the VV anastomoses around the gut are established and the portal vein anlage is present at the 35-day stage, connected to the superior mesenteric vein and emptying into the left UV in the liver. The left proximal and right distal VV disappear. A direct communication between the left UV, the IVC, and the DV, bypassing the liver sinusoids, is later established. The DV links the portal and umbilical venous circulation with the IVC.

Failure of this obliteration of primitive veins or nondevelopment of new vessels and anastomoses can produce abnormalities of umbilical-portal circulation (ie, portal agenesis), often associated with ductal agenesis.^{39, 40, 41, 42, and 43}

Ancillary Ultrasound Signs

The diagnosis of ADV is established by color Doppler demonstration of absence of DV in optimal scanning planes for the visualization of ductal blood flow.

• In cases of extrahepatic umbilical venous drainage bypassing the liver, the umbilical vein directly connects to the iliac vein, the inferior vena cava, the renal vein, or the right atrium (Figure 17-56B) or left atrium or the coronary sinus.

• In cases of intrahepatic umbilical venous drainage without liver bypass, the umbilical vein connects to the portal sinus without giving rise to the DV (Figure 17-56C).

While ADV with extrahepatic umbilical venous drainage can be detected by the aberrant course of the intraabdominal umbilical vein on gray-scale sonography, ADV without liver bypass is only reliably diagnosed by meticulous color flow mapping of the portal circulation in various planes.

Associated Anomalies

ADV is significantly associated with fetal hydrops and structural and/or chromosomal abnormalities independently of the type of umbilical venous drainage. An association with Noonan syndrome has also been described³⁹ and mutations of the PTPN11 gene can be detected in a substantial proportion of affected individuals.

Fetuses with liver bypass have an additional risk of developing congestive heart failure that significantly affects the outcome, even in those with otherwise normal fetal anatomy. In addition, the association with agenesis of the portal venous system is present in a discrete number of cases.

ADV without liver bypass seems to have a more favorable prognosis if it is not associated with other malformations.^39,42

Management

Although knowledge of the mechanisms involved in the genesis of these anomalies is limited, in case of prenatal diagnosis of DV agenesis, fetal karyotyping is recomended due to the important association with aneuploidies, especially when other anomalies are present. Careful serial ultrasound examinations should be recommended and, in the presence of severe heart failure, delivery could be anticipated.

Emerging Concepts and Future Directions

The diagnosis of umbilical and portal venous systems associated with ADV can be detailed with the help of 4D ultrasound. In fact 4D ultrasound with B-flow imaging and spatiotemporal image correlation (STIC) is able to thoroughly assess the anatomy of the fetal venous system,⁴⁴ supplying valuable information that cannot be obtained reliably by 2D fetal sonography.

Umbilical Vein Varix

Definition and Incidence

Fetal umbilical vein (FUV) varix is a focal dilatation, nearly always, of the intraabdominal part of it and represents a rare prenatal sonographic finding of uncertain clinical significance.⁴⁵

Etiology

An umbilical vein varix is a developmental rather an embryologic anomaly. The extrahepatic, intraabdominal portion of the umbilical vein has the weakest supporting structure of any part of the umbilical circulation. Therefore, any condition that increases venous pressure could potentially dilate this portion of the umbilical vein, resulting in an umbilical vein varix.⁴⁵

Ancillary Ultrasound Signs

The umbilical vein is considered dilated when the measurement is above 2 standard deviations of the mean for gestational age (Figure 17-57A, B, and C). Color and pulsed Doppler examination indicate umbilical venous flow within the cystic intraabdominal mass (see Figure 17-57B). Several differential diagnoses can be considered when ultrasound examination reveals an intraabdominal cystic mass. If flow is noted on Doppler ultrasound examination, certain nonvascular structures can be eliminated as the cause. These include choledochal cyst, hepatic cyst, mesenteric cyst, or enteric cyst duplication.

Associated Anomalies

Associated abnormalities are reported in a discrete number of cases, most commonly anomalies of the cardiovascular system and chromosomal abnormalities. When the diagnosis of FUV varix is made before 26 weeks, an increased incidence of fetal death and obstetrical complication has been reported.⁴⁵

Management

In the presence of FUV varix, fetal echocardiography and detailed ultrasound study of fetal anatomy is needed to exclude associated anomalies. Serial ultrasound scans should be performed to assess fetal cardiac function, using color Doppler to exclude thrombosis of the umbilical vein. However, if no associated anomalies are present, the prognosis is generally good.

Persistent Right Umbilical Vein

Definition and Incidence

Persistent right umbilical vein (PRUV) is a relatively common variation in which the left umbilical vein becomes occluded and the right vein persists in remaining open.⁴⁶

Etiology

The right umbilical vein starts obliterating around the fourth week of pregnancy, and disappears by the seventh week of gestation. Its persistence does not alter blood flow distribution to the fetus.

Ancillary Ultrasound Signs

The ultrasound appearance is characteristic, with the umbilical vein curving to the left, toward the stomach, instead of its usual course. The gall bladder will be on the left of the umbilical vein (Figure 17-58).

Associated Anomalies

PRUV is associated with other anomalies in a discrete number of cases. Among the different anomalies reported in association with PRUV are gastrointestinal malformations, heart anomalies, urinary tract malformations, and single umbilical artery.

Management

Ultrasound finding of PRUV is an indication for conducting targeted fetal sonography. When isolated, the prognosis for PRUV is favorable.⁴⁶

Exomphalos (omphalocele) and gastroschisis are the most frequent abdominal wall defects with an incidence of around 1 in 4000 each. They are distinguished by important differences in embryologic pathogenesis, ultrasonographic features, association with other anomalies, and outcome of the pregnancy. Thus, a different approach is required in each case, and a correct ultrasonographic diagnosis is extremely important. Table 17-3 illustrates the major key points for a differential diagnosis between the two entities.

Gastroschisis

Definitions

Gastroschisis is a paraumbilical defect of the abdominal wall (usually right sided) through which parts of the bowel eviscerate directly in the amniotic cavity while the abdominal insertion of the umbilical cord appears intact.

The location of the wall defect is almost always to the right of the umbilical cord. In a minority of cases the gastroschisis can be left sided. Left-sided gastroschisis is more frequent in females, and a higher association with extraintestinal anomalies compared with right-sided lesions is reported.⁴⁷ A case of gastroschisis-like defect located in the left hypochondrium has also been reported.⁴⁸

Incidence

Gastroschisis is a rare condition. Although there is a big variation in incidence depending on the geographic area, a common worldwide evidence of a 3- to 10-fold increasing prevalence is reported in the last three decades. The higher rate reported is in the United Kingdom (4.4 per 10,000 births) and the lower in Singapore (0.46 per 10,000 births). The increased incidence of gastroschisis does not appear to be due to an increase in teenage pregnancies, proportion of primigravida, tobacco or illicit drug use, or conception while on contraceptive pill, which are causative factors of gastroschisis. The reason for this increasing trend needs to be further elucidated. Reports from China and Italy show, conversely, a stable incidence through the years in these countries.^{49, 50, 51, and 52}

Embryogenetic Mechanism

Gastroschisis appears to be the result of a vascular abnormality encompassing possible intrauterine interruption of the omphalomesenteric artery or abnormal involution of the right umbilical vein.^53,54 Other proposed hypotheses include rupture of the amnion around the umbilical ring, and failure of one or more folds responsible for the closure of the abdominal wall in an early embryologic stage.

Risk of Recurrence

Gastroschisis does not appear to have a genetic cause as it occurs sporadically and has a relatively low recurrence rate.

Causative Factors

Gastroschisis is consistently associated with young maternal age. Maternal exposure to vasoactive substances, including medications (salicylates, pseudoephedrine, ibuprofen, phenylpropanolamine), recreational drugs (cocaine, amphetamines, ecstasy), smoking (tobacco, marijuana), and chemicals (solvents, colorants) demonstrates an increased incidence of gastroschisis and an association with a greater severity of gastroschisis in terms of both the degree of intestinal injury and functional outcomes. The vasoactive nature of these causative agents supports the model of vascular pathogenesis of gastroschisis.^{55, 56, 57, and 58}

Ancillary Ultrasound Signs

The defect is para-sagittal, usually to the right of the abdominal insertion of the umbilical cord (Figure 17-59). The characteristic ultrasonographic feature is that of a cauliflower-like appearance of the freely floating bowel in the amniotic fluid (Figure 17-60). Accordingly, there is no membranous sac covering the eviscerated structures and the umbilical cord insertion is seen intact, most of the times to the left of the herniated gut. The abdominal defect is usually less than 2 cm, and the herniated structures can be small bowel (always), accompanied by large bowel (frequently), and the stomach or parts of the genitourinary system (rarely). The presence of liver or part of it, outside the abdominal wall defect, is never observed in true gastroschisis and should suggest a different diagnosis.

The abdominal circumference may be reduced proportionally to the amount of eviscerated bowel. Consequently, the ultrasonographic estimation of the fetal weight is difficult and underestimated fetal size can lead to a false IUGR diagnosis. Nevertheless, real IUGR, not rarely, can complicate gastroschisis due to fetal distress.

A mild dilation of the bowel should be considered normal in gastroschisis. On the contrary, marked progressive dilation with reduced or absent peristalsis are bad prognostic factors associated with worse postnatal outcome and postoperative complications. Dilated and thickened bowel can be a marker of associated necrosis or obstruction/atresia. It appears that only intra-abdominal dilation of the bowel on prenatal ultrasound may predict obstruction requiring surgery while extra-abdominal dilation is frequent and not predictive.⁵⁹ It is important to distinguish small bowel from colon in cases of detected intestinal dilation, as colon can be significantly dilated with no adverse outcome.

The amniotic fluid in gastroschisis is usually normal. Nevertheless, both reduced or increased amount of amniotic fluid can be found due to fetal distress/IUGR or bowel obstruction, respectively.

Complications

Peritonitis and intestinal damage may develop due to exposure of the bowel to fetal urine and meconium. If peritonitis is severe, perforation may additionally occur.

Another not rare complication of gastroschisis is torsion around the mesenteric axis or obstruction of the blood vessels at the level of the rim of the abdominal defect, which can lead to bowel infarction and necrosis. Bowel necrosis can result in entirely reabsorbed bowel segments ("vanishing bowel").⁶⁰

Associated Anomalies

Associated extra-GIT malformations are rare in true gastroschisis. An association has been noted between gastroschisis and arthrogryposis congenita of the amyoplasia type, which would underline a vascular compromise for both entities.⁶¹ In a recent report, a possible association between gastroschisis and neonatal hemochromatosis has been suggested.⁶²

There is no evidence of association between gastroschisis and chromosomal abnormalities, thus the presence of gastroschisis does not increase the background risk for aneuploidies.⁶³ Diagnosis of gastroschisis can be achieved from the first trimester, during the screening scan for chromosomal abnormalities. The calculation of the risk, in this case, does not differ when gastroschisis is present.

Management

Fetal karyotyping is not necessary. The overall prognosis depends on the condition of the eviscerated bowel at birth. Amnio-infusion/amniotic fluid exchange are suggested in clinical and experimental animal models to reduce intestinal damage, especially in cases of associated oligohydramnios, although its effectiveness in humans still needs to be proved.

The timing and mode of delivery remains controversial. Planned preterm delivery at around 36 weeks has been suggested to reduce the time of exposure of the bowel to the amniotic fluid. However, there is no proven significant difference in neonatal outcome. Conversely, at-term delivery could be a benefit for the fetal outcome. Fetal well-being should thus be the primary determinant of the timing of delivery for gastroschisis.^{64, 65, and 66}

Regarding the mode of delivery, the initial evidence of the benefit obtained with cesarean section in reducing the presumed damage of the herniated loops during vaginal delivery, as referred in earlier papers, was not confirmed in later studies. However, cesarean section for gastroschisis seems to be the current trend.

Postnatal repair and closure of gastroschisis can be achieved by primary operative closure (POC) when the amount of eviscerated bowel permits its replacement in the fetal abdomen without dangerously increasing the intraabdominal pressure, which would cause renal damage and respiratory compromise. When primary closure is not possible, silo placement is required to reduce infectious complications, with a 2-step procedure, until the growth of the abdominal cavity would permit the definitive closure.

A suggested alternative to primary operative closure is the "plastic closure" technique, a nonoperative treatment of gastroschisis that appears to minimize intraabdominal pressure after bowel reduction. However, this technique has a higher risk of secondary umbilical hernia.^67,68

If intrauterine infarction or ischemia occurs, bowel resection is needed. With major damage and consequent removal of a large portion of the gut, there is a high risk for progression to short bowel syndrome (SBS), which would require intestinal transplantation. The use of trophic factors for enhancing mucosal hyperplasia has not been encouraging. However, aggressive medical and nutritional intervention programs are still being studied in order to reduce the need for transplantation.^69,70 Recently, a novel technique of rectal feeding was referred to stimulate bowel growth and adaptation in neonatal SBS.⁷¹ A multidisciplinary approach with high expertise in pediatric gastroenterology, pediatric surgery, and parenteral nutrition is mandatory in these cases.

Exomphalos (Omphalocele)

Definition and Incidence

Exomphalos is a midline abdominal wall defect, with herniation of abdominal content into the base of the umbilical cord. The herniated structures are covered by a double layer of membranes represented by the fetal peritoneum (inner layer) and the umbilical cord's amnion (outer layer). Thus, contrary to gastroschisis, there is no direct contact between herniated structures and the amniotic fluid unless a rupture of the 2-layered hernial sac occurs.

There is a high variability in the literature regarding the incidence of exomphalos, with reported rates from 0.3 to 3.9 in 10,000 births.^{72, 73, and 74} The reported incidence in antenatally diagnosed exomphalos is higher compared to the postnatally diagnosed cases, and it is reduced with advancing of gestational age. Spontaneously resolved exomphalos when the hernial sac is small and it contains only some loops of bowel has been reported.⁷⁵

Embryogenetic Mechanism

A different embryogenetic mechanism is suggested depending on the presence or absence of the liver in the hernial sac. In cases of exomphalos with intracorporeal liver, the abdominal wall defect could be considered as a failure of spontaneous reduction of the midgut into the fetal abdomen. In the extracorporeal liver type, the defect could be due to the failure of closure of the body wall.

Risk of Recurrence

The general risk of recurrence of exomphalos is less than 1 in 100. When the abdominal wall defect makes part of a chromosomal abnormality (mainly trisomy 18 and 13) or a genetic syndrome the risk of recurrence is the one of the major disease.

Causative Factors

Contrary to gastroschisis, the prevalence of exomphalos increases with maternal age. Probably this could be due to the increasing prevalence of aneuploidies with advancing of the maternal age, and the association between exomphalos and some chromosomal abnormalities.

Exomphalos can also be part of nonchromosomal syndromes (Beckwith-Wiedemann syndrome, Meckel-Gruber syndrome, Goltz syndrome, CHARGE syndrome, Marshall-Smith syndrome) or complex malformation sequences (pentalogy of Cantrell, ectopia cordis, body stalk anomaly, exstrophy of bladder, exstrophy of cloaca, OEIS).

Ancillary Ultrasound Signs

The abdominal defect is midsagittal, at the base of the abdominal insertion of the umbilical cord. The most common herniated structure is the small bowel. Less frequently, the liver, large bowel, stomach, and spleen have been observed herniating through the abdominal wall defect.

The herniated organs are covered by the double-layered membrane (peritoneum/amnion). On ultrasound, it is often difficult to visualize the membrane itself. However, the absence of the typical cauliflower-like appearance of gastroschisis due to the freely floating bowel in the amniotic fluid is an indirect sign that the herniated structures are contained within a membranous sac (Figure 17-61A). The presence of a limiting membrane protects the bowel from exposure to amniotic fluid. The insertion of the umbilical cord is seen at the apex of the sac (central exomphalos) (Figure 17-61B). Epigastric omphalocele has also been reported with a lower association with abnormal karyotype compared to the usual central variant. This would suggest that central and epigastric omphaloceles may be different entities. Nevertheless, no difference in the outcome of fetuses with omphalocele has been shown, irrespective of the type of omphalocele.⁷⁶

The size of the abdominal defect is usually bigger compared to gastroschisis. Therefore, the bowel complications frequently observed with gastroschisis, such as bowel thickening and bowel dilation, are rare in exomphalos. However, midgut strangulation with subsequent duodenal atresia has been reported.

According to the presence or absence of the liver in the hernial sac, we can distinguish an exomphalos with extracorporeal liver (Figure 17-61) and an exomphalos with intracorporeal liver, respectively. During the ultrasound examination of the contents of exomphalos, the bowel appears more echogenic compared to the liver, which has a homogeneous appearance, and in addition, intrahepatic vessels can be demonstrated in its contents by color Doppler. However, when only a small part of the liver herniates through the abdominal wall defect, it might be very difficult to distinguish by ultrasound its presence in the hernial sac. There is a big difference in the reported incidence of the two types of exomphalos, depending on the timing of diagnosis: in the studies where the defect has been diagnosed prenatally, the extracorporeal liver type appears to be the most frequent one; the studies based on the postnatal diagnosis of exomphalos report, in contrast, a higher incidence of the intracorporeal liver type. This difference could be due an often-misdiagnosed small exomphalos by ultrasound.

The spontaneous reduction of the normally herniated midgut in early pregnancy is usually completed by 11 weeks. The integrity of the abdominal wall should always be demonstrated at the 11- to 14-week scan. Detection of exomphalos at that stage would increase the risk for aneuploidies but a 1-week second scan would be recommended. If the liver is present in the hernial sac the diagnosis of exomphalos is certain even at this early stage of pregnancy (Figure 17-63).

Exomphalos should be distinguished from umbilical hernia in which the hernial sac is covered by skin. Umbilical cord cyst or urachal cyst can erroneously be interpreted as exomphalos.

Complications

The presence of ascites is quite common in exomphalos (see Figure 17-62). When moderate, it makes the ultrasonographic demonstration of the membranes containing the herniated organs easier. When the ascites is severe, however, it may lead to an erroneous impression of a floating bowel in the amniotic fluid and a false diagnosis of gastroschisis.

Polyhydramios can be observed in one-third of cases, due to high intestinal obstruction or a major chromosomal abnormality. The presence of polyhydramnios is associated with a worse fetal outcome.

An in utero rupture of the hernial sac membranes can occur in about 10% of cases. In this circumstance, the differential diagnosis with gastroschisis becomes difficult.

Associated Anomalies

Unlike gastroschisis, exomphalos has a high association with chromosomal abnormalities. The reported frequency of aneuploidies in cases of exomphalos diagnosed prenatally, after birth, or both, is shown in Tables 17-4, 17-5, and 17-6, respectively. A considerably higher association with chromosomal abnormalities can be observed in the series based on antenatally diagnosed exomphalos (with a mean rate up to 45%) compared to the postnatal series (10%). This difference is possibly due to a less accurate estimation of associated aneuploidies on postnatal data, which may not include spontaneous abortion/intrauterine death, or termination due to positive karyotyping. As expected, an intermediate mean rate can be seen in the series including mixed data.

Furthermore, the gestational age at time of diagnosis presents different rates of associated chromosomal defects in association with exomphalos, being higher in earlier stages. Snijders et al calculated the estimated risk for aneuploidies associated with exomphalos by gestational age as follows: 39.5% at 12 weeks of gestation, 27.0% at midtrimester, and 14.4% in live births.⁷² Moreover, the authors compared the observed and the expected frequencies of chromosomal abnormalities in prenatally and postnatally detected exomphalos: the frequencies between observed and expected were similar at 16 to 26 gestational weeks, whereas a statistically significant difference was observed in postnatally diagnosed exomphalos, with a lower observed rate than expected rate. This difference converges to the hypothesis of an increased prenatal diagnosis of exomphalos and aneuploidy, which would lead parents opting for termination. Regarding the content of the sac, the authors report a 46% chance of an underlying chromosomal abnormality at 20 weeks of gestation, when the sac contains only bowel. The risk of associated aneuploidies is much lower when additional organs are contained in the hernial sac (19%).

The frequency of exomphalos in fetuses with trisomy 18 or 13 was 340 times higher compared to those with no evidence of these trisomies (17% and 0.05%, respectively).⁹⁴

The most frequently detected chromosomal abnormality in exomphalos is trisomy 18. Trisomy 13 and triploidy are other aneuploidies frequently associated with exomphalos. Other, less frequent associated chromosomal abnormalities are 47,XXY and 47,XXX, and familial unbalanced translocations.

While almost half of the prenatally diagnosed exomphalos is associated with aneuploidies, approximately another half of the remaining euploid fetuses will present other associated abnormalities.⁹⁸

Cardiac defects have been reported with an overall frequency of up to 50% of fetuses with detected exomphalos. When exomphalos is associated with a chromosomal abnormality, the frequency of congenital heart defects (CHD) is even more increased. In fetuses with ascertained normal karyotype there is a 40% reported possibility of an associated cardiac defect. Significantly lower frequency has been reported when exomphalos has been diagnosed at birth (20%). The most frequent cardiac defects associated with exomphalos are septal defects, either ventricular or atrial. Other congenital heart diseases detected pre- or postnatally in exomphalos are tetralogy of Fallot, ectopia cordis, aortic coarctation, septum defects, double outlet right ventricle, bicuspid aortic valve, persistent pulmonary hypertension (PPHN) of the newborn, and persistent ductus arteriosus.^{82,114, 115, and 116}

In view of the very high association of aneuploidies and congenital heart defects, when exomphalos is diagnosed prenatally, fetal karyotyping and echocardiography should be offered.

Other structural abnormalities that can coexist with exomphalos involve mostly the genitourinary and central nervous system (neural tube included), musculoskeletal defects (including skeletal dysplasias), and other gastrointestinal malformations (renal dysplasia, renal agenesis, ventriculomegaly, encephalocele, esophageal atresia, anal atresia, ileal atresia, Meckel diverticulum, gall bladder agenesis, diaphragmatic hernia, etc).

Exomphalos is associated with more than 50 genetic syndromes and several malformation sequences. It can be part of a failure of the closure of the cranial or the caudal fold: pentalogy of Cantrell (Figure 17-64) (omphalocele, anterior diaphragmatic hernia, sternal cleft, ectopia cordis, and intracardiac defects), associated bladder or cloacal extrophy, or OEIS complex.

Ten percent of exomphalos in postnatal and up to 20% in prenatal series is associated with Beckwith-Wiedemann syndrome (BWS), while exomphalos is present in 80% of Beckwith-Wiedemann syndrome cases. Usually, the exomphalos is the intracorporeal liver type. It is a sporadic (occasionally familiar with autosomal dominant, recessive, X-linked, and polygenic patterns of inheritance) syndrome, with a birth prevalence of about 1 in 14,000. Other frequent features are macroglossia (97%), abdominal wall defect (80%), birth weight or postnatal growth greater than the 90th centile (88%), and nephromegaly (59%). Visceromegaly, accelerated growth, polyhydramnios, macroglossia, and exomphalos during ultrasound examination should suggest the presence of BWS. In all cases of exomphalos with intracorporeal liver and normal karyotype, BWS should be suspected. Affected neonates present severe hypoglycemia at birth, which, if not correctly treated, could lead to mental handicap. About 5% of affected individuals develop nephroblastoma and hepatoblastoma during childhood and mental handicap.^{117, 118, and 119}

Management

When exomphalos is diagnosed, meticulous examination of all fetal structures, in particular the heart, should be performed to detect eventual associated abnormalities. Even if exomphalos appears to be an isolated ultrasonographic finding, the option of fetal karyotyping is mandatory. Isolated exomphalos with normal karyotype has a very good prognosis. On the contrary, when the scan reveals a nonisolated exomphalos, the prognosis becomes poor. Cesarean section is recommended in cases of large herniation.

Postnatal surgery includes 1-stage primary closure and delayed surgical closure via silo. One-stage primary closure should be applied for exomphalos minor and some selected cases of exomphalos major, while in other cases exomphalos major requires staged closure involving a silo.