Langman's Chapter 7-9 Embryology.pdf

A TUBE ON TOP OF A TUBE_______ During the third and fourth weeks, the top layer (ectoderm) o f the trilaminar embryonic disc forms the neural píate that rolls up into a tube to form the brain and spinal cord by the process called n eu n ü ation (see Chapter 6, p. 71). Paraxial mesoderm Intermedíate m esoderm Almost simultaneously, the ventral layer (endoderm) rolls down to form the gut tube, such that the embryo consists o f a tube on top o f a tube: the neural tube dorsally and the gut tube ventrally (Fig. 7.1). The middle layer (mesoderm) holds the two tubes together and the lateral píate component o f this mesoderm layer also splits Parietal mesoderm layer w a ll of am niotic cavity Dorsal m esentery Visceral m esoderm Parietal m esoderm FIGURE 7.1 Transversa sections through embryos at various stages of closure of the gut tube and ventral body wall. A. At approxim ately 19 days, intercellular clefts are visible In the lateral píate mesoderm. B. At 20 days, the lateral píate is dlvlded Into som atic and visceral mesoderm layers th a t line the phm itive body cavity [Intraembryonic cavity]. C. By 21 days, the prim itive body cavity [intraembryonic cavity] is still in open com munication w ith the extraem bryonic cavity. D. By 24 days, the lateral body wall folds, consisting of the parietal layer of lateral píate mesoderm and overiying ectoderm are approaching each other in the midline. E. A t the end of the fourth week, visceral mesoderm layers are continuous w ith parietal layers as a doublelayered membrane, the dorsal mesentery. Dorsal mesentery extends from the caudal lim it of the foregut to the end of the hindgut. O Part I General Embryology into visceral (splanchnic) and parietal (somatic) layers. The visceral layer rolls ventrally and is intimately connected to the gut tube; the pari etal layer, together with the overlying ectoderm, forms the lateral body wall folds (one on each side o f the embryo), which move ventrally and meet in the midline to cióse the ventral body wall (Fig. 7.1). The space between visceral and parietal layers o f lateral píate mesoderm is the primitive body cavity, which at this early stage is a continuous cavity, because it has not yet been subdivided into the pericardial, pleural, and abdominopelvic regions. FORMATION OF THE BODY CAVITY At the end o f the third week, intraem bryonic m esoderm differentiates into paraxial meso derm, which forms somitomeres and somites that play a m ajor role in forming the skull and vertebrae; interm edíate m esoderm, which con tributes to the urogenital system; and lateral píate m esoderm, which is involved in forming the body cavity (Fig. 7.1). Soon after it forms as a solid mesodermal layer, clefts appear in the lat eral píate mesoderm that coalesces to split the sohd layer into two (Fig. 7.IB ): (1) the parietal (som atic) layer adjacent to the surface ectoderm and continuous with the extraembryonic pari etal mesoderm layer over the amnion. Together, the parietal (somatic) layer o f lateral píate me soderm and overlying ectoderm are called the somatopleure; (2) the visceral (splanchnic) layer adjacent to endoderm forming the gut tube and continuous with the visceral layer o f extraembryonic mesoderm covering the yolk sac (Figs. 7.IB ). Together, the visceral (splanch nic) layer o f lateral píate mesoderm and underlying endoderm are called the splanchnopleure. The space created between the two layers o f lat eral píate mesoderm constitutes the primitive body cavity. During the fourth week, the sides o f the embryo begin to grow ventrally forming two lateral body wall folds (Fig. 7.IB and C). These folds consist o f the parietal layer o f lat eral píate mesoderm, overlying ectoderm, and cells from adjacent somites that migrate into the mesoderm layer across the lateral somitic frontier (see Chapter 11, p. 156). As these folds progress, the endoderm layer also folds ven trally and closes to form the gut tube (Fig. 7. ID and E). By the end o f the fourth week, the lateral body wall folds meet in the midline and fuse to cióse the ventral body wall (Fig. 7.1 C -£ ). This closure is aided by growth o f the head and tail regions (folds) that cause the embryo to curve into the fetal position (Fig. 7.2). Closure o f the ventral body wall is complete except in the re gión o f the connecting stalk (future umbilical cord). Similarly, closure o f the gut tube is com plete except for a connection from the midgut región to the yolk sac called the vitelline (yolk sac) duct (Fig. 7.2D). This duct is incorporated into the umbilical cord, becomes very narrow (Fig. 8.16, p. 118), and degenerates with the yolk sac between the second and third months o f gestation. (Note that throughout the process o f body cavity and gut tube development, the parietal and visceral layers o f lateral píate m e soderm are continuous with each other at the junction o f the gut tube with the posterior body wall [Fig. 7.W ,E ].) SEROUS MEMBRANES____________ Some cells o f the parietal layer o f lateral píate mesoderm lining the body wall o f the primitive embryonic cavity become mesothelial and form the parietal layer of the serous membranes lin ing the outside o f the peritoneal, pleural, and pericardial cavities. In a similar manner, some cells o f the visceral layer o f lateral píate m e soderm form the visceral layer o f the serous membranes covering the abdominal organs, lungs, and heart (Fig. 7.1E). Visceral and pa rietal layers are continuous with each other as the dorsal mesentery (Fig. 7.1E), which suspends the gut tube from the posterior body wall into the peritoneal cavity. Dorsal mesentery extends continuously from the caudal limit o f the foregut to the end o f the hindgut. Ventral m esentery exists only from the caudal foregut to the upper portion o f the duodenum and results from thinning o f mesoderm o f the septum transversum, a block of mesoderm that forms connective tissue in the liver and the central tendon o f the diaphragm (see Figs. 7.2D and 7.5). These mesenteries are double layers o f peritoneum that provide a pathway for blood vessels, nerves, and lymphatics to the organs. Chapter 7 The Gut Tube and the Body Cavities Hindgut A m niotic E ndoderm cavity Cloacal Foregut Ectoderm A ngiogenic cell cluster ~ Midgut FIGURE 7.2 Midsagittal sections of embryos at various stages of developm ent showing cephalocaudal folding and its effects upon position of the heart, septum transversum, yolk sac, and amnion. Note that, as folding progresses, the opening of the gut tube into the yolk sac narrows until it form s a thin connection, the vitelline (yolk sac) duct, between the m idgut and the yolk sac (D). Simultaneously, the amnion is pulled ventrally until the am niotic cavity nearly surrounds the embryo. A. 17 days. B. 22 days. C. 24 days. D. 28 days. Arrows, head and tail folds. Clinical Correlates V e n tral Body W all Defects V entral body w all defects occur in th e th o rax, abdom en, and pelvis and ¡nvolve th e heart (ectopia cordis), abdom inal viscera (gastroschisis], a n d /o r u rogen ital organs (bladder or cloacal exstrophy], depending upon th e locatio n and size o f th e abn orm ality. The m a lfo rm a tio n s are due to a fa ilu re of th e ven tra l body w all to cióse and probab ly involve th e lateral body w all fo ld s to a g re a te r e x te n t th a n th e head and ta il folds. Thus, one or both o f th e lateral body w all fo ld s fail to progress v e n tra lly or th e re are abn orm alities in th e fusión process once th e y m e e t in th e m idline. An om phalocele aiso represents a ve n tra l body w all defect; how ever, its prim a ry cause is n o t due to in h ib itio n o f body w all closure. Instead, th is a b n o rm a lity occurs w hen a p ortion o f th e g u t tu b e fails to re tu rn to th e abdom inal ca v ity fo llo w in g its norm al herniation in to th e um bilical cord (see p. 243]. Ectopia cordis occurs w hen la teral body w a ll fo ld s fa il to cióse th e m idline in th e th o racic región causing th e h e a rt to lie outsid e th e body c a v ity (Fig. 7.3A). S om etim es, th e closure d e fe c t begins a t th e caudal end o f th e s te rn u m and e x te n d s in to th e upp er abdom en re s u ltin g in a s p e c tru m o f a b n o rm a litie s called C antrell pentalogy. This s p e c tru m includes ectopia cordis, d e fe c ts in th e a n te rio r región o f th e diaphragm , absence o f th e pericardium , de fe cts in th e s te rn u m , and a bd om inal w all [c o n tin u e d ] í a _ P art I General Embryology i / ' (with epispadias) Scrotum FIGURE 7.3 Examples of ventral body wall defects due to failure o f the ventral body v/all to cióse. A. Ectopla cordls. The heart lies outslde the thorax, and there Is a cleft In the th o ra d c wall. B. Gastroschisis. Intestlnes have herniated through the abdominal wall to the right of the umbilicus, the m ost common location for this defect. C. Bladder exstrophy. Closure in the pelvic región has failed. In males, the defect usually includes a spiit in the dorsum of the penis, a defect called epispadias. D. Cloacal exstrophy. A larger closure defect in which m ost o f the pelvic región has failed to cióse, leaving the bladder, part of the rectum, and the anal canal exposed. Chapter 7 The Gut Tube and the Body Cavities de fe cts in cluding om phalocele and ga s tro s chisis. (Note: O m phaloceles th a t m ay occur in C antrell p e n ta lo g y are secon dary to th e body w a ll clo sure defect, n o t prim ary. The closure d e fe c t reduces th e size o f th e abd om inal cavity and pre ve n ts th e re tu rn o f th e in te s tin a l loops fro m th e um bilical cord; see p. 243). Gastroschisis occurs w hen body w all c lo sure fails in th e abdom inal región (Fig. 7.3S]. As a result, in testin al loops herniate into th e am niotic ca vity th ro u g h th e defect, w hich usually lies to th e rig h t o f th e um bilicus. The incidence o f gastroschisis is increasing [3.5/10,000], and it is m ost com m on in in fan ts fro m th in w om en y oun ger than 20 years o f age. The defect can be detected by fetal ultrasound and by elevated a -fe to p ro te in [AFP] conce ntrations in m aternal serum and th e a m nio tic fluid. The m alform atio n is no t associated w ith chrom osom e abn orm alities, bu t o th e r defects occur in 15% o f cases. A ffe cted loops o f bow el m ay be dam aged by exposure to a m nio tic fluid, w hich has a corrosive effect, or by tw is tin g around each o ther [volvulus] and com prom ising th e ir blood suppiy. Bladder o r cloacal exstroph y results fro m abn orm al body w a ll clo sure in th e pelvic re gión. B ladder e x s tro p h y represents a less severe closure d e fe c t in th is región and o niy th e bladder is exposed (Fig. 7.3C; in m ales, th e penis m ay be in volved and epispadias [a s p iit in th e dorsum o f th e penis; see C hapter 16, p. 260 ] is com m o n). Cloacal e x s tro p h y results fro m a m ore severe fa ilu re o f body w all c lo sure in th e pelvis such th a t th e bladder and rectu m , w h ich are derived fro m th e cloaca (see C hapter 16, p. 26 0 ], are exposed (Fig. 7.3D). O m phalocele represents a n o th e r ve n tra l b od y w all d e fe c t (Fig. 7.4), b u t it does n o t arise fro m a fa ilu re in body w all closure. Instead, it o rig in a te s w hen p o rtio n s o f th e g u t tu b e (the m idgu t) th a t n o rm a lly h erniate s in to th e u m bilical cord durin g th e 6 th to th e lO th w eeks (physiological um bilical herniation ) fa ils to re tu rn to th e abd om inal c a v ity (see C hapter 15, p. 243]. Subsequently, loops o f bow el, and o th e r viscera, in cluding th e liver, m ay h e rn i ate in to th e defect. Because th e um bilical cord is covered by a re fle c tio n o f th e am nion, th e d e fe c t is covered by th is ep ith e lia l layer. [In co n tra s t, loops o f bow el in g astroschisis are n o t covered by a m nio n because th e y herniate th ro u g h th e a bd om inal w a ll d ire c tly in to th e a m n io tic cavity.] O m phalocele, w h ich occurs in 2.5/1 0 ,0 0 0 births, is associated w ith high m o rta lity rate s and severe m a lfo rm a tio n s , in clu ding cardiac a b n o rm a litie s and neural tu b e defects. Furtherm ore, c h rom osom e a b n o r m a litie s are pre se n t in 15% o f cases. Like gas trosch isis, om phaloceles are associated w ith elevated AFP con ce n tra tio n s. FIGURE 7.4 Examples of omphaloceles, a defect th a t occurs when loops of bowel, which normally herniate into the umbilical cord during the 6th to the lOth weeks of gestation [physiological umbilical herniation], fail to return to the body cavity. A. Drawing showing loops of herniated bowel within the um bilical cord th a t have failed to return to the abdominal cavity. The bowel is covered by amnion because this membrane norm ally reflects onto the umbilical cord. B. Infant w ith an omphalocele. The defect is associated w ith other m ajor malformations and chromosome abnormalities. Part I General Embryology DIAPHRAGMANDTHORACICCAVITY The septum transversum is a thick píate o f mesodermal tissue occupying the space between the thoracic cavity and the stalk o f the yolk sac (Fig. 7. 5 A y B ). The septum is derived from visceral (splanchnic) mesoderm surrounding the heart and assumes its position between the primitive thoracic and abdominal cavities when the cranial end o f the embryo grows and curves ------ Closing cranial neural fold Primitive pericardial cavity Septum transversum Anterior intestinal portal Intraembryonic body cavity Lateral body wall fold Posterior intestinal portal Hindgut Foregut Sinus venosus Septum transversum Lung bud Pleuropericardial fold Common cardinal vein Heart FIGURE 7.5 A. Drawlng shov^ing the ventral view of an embryo a t 24 days of gestation. The gut tube is closing, the anterior and posterior intestinal portáis are visible, and the heart lies in the prim itiva pleuroperi cardial cavity, v^hich is partially separated from the abdominal cavity by the septum transversum. B. Portion of an embryo at approxim ately 5 weeks v/ith parts o f the body v/all and septum transversum removed to show the pericardioperitoneal canals. Note the slze and thickness of the septum transversum and llver cords penetratlng the septum. C. Growth of the lung buds Into the pericardioperitoneal canals. Note the pleuro pericardial folds. Chapter 7 The Gut Tube and the Body Cavities [ il Pleural cavity Phrenic nerve FIGURE 7.6 A. Transformation of the pericardioperitoneal canals into the pleural cavities and form ation of the pleuropericardial membranes. Note the pleuropericardial folds containing the common cardinal vein and phrenic nerve. Mesenchyme of the body wall form s the pleuropericardial membranes and definitive body wall. B. The thorax after fusión of the pleuropericardial folds w ith each other and with the root of the lungs. Note the position of the phrenic nerve, now in the fibrous pericardium. The right common cardinal vein has developed into the superior vena cava. into the fetal position (Fig. 7.2B -D ). This sep tum dees not separate the thoracic and abdomi nal cavities completely but leaves large openings, the pericardioperitoneal canals, on each side o f the foregut (Fig. 7.5B). W hen lung buds begin to grow, they expand caudolaterally within the pericardioperito neal canals (Fig. 7.5C). As a result o f the rapid growth o f the lungs, the pericardioperitoneal canals becom e too small, and the lungs begin to expand into the mesenchyme o f the body wall dorsally, laterally, and ventrally (Fig. 7.5C). Ventral and lateral expansión is posterior to the pleuropericardial folds. At first, these folds appear as small ridges projecting into the primitive undivided thoracic cavity (Fig. 7.5C). W ith expansión o f the lungs, mesoderm o f the body wall forms two components (Fig. 7.6): (1) the definitive wall o f the thorax and (2) the pleuropericardial m embranes, which are extensions o f the pleuropericardial folds that contain the com m on cardinal veins and phrenic nerves. Subsequently, descent o f the heart and positional changes o f the sinus ve nosas shift the com m on cardinal veins toward the m idline, and the pleuropericardial m em branes are drawn out in m esentery-like fashion (Fig. 7.6A). Finally, they fuse with each other and with the root o f the lungs, and the thoracic cavity is divided into the definitive pericardial cavity and two pleural cavities (Fig. 7.6 5 ). In the adult, the pleuropericardial membranes form the fibrous pericardium. FORMATION OF THE DIAPHRAGM Although the pleural cavities are separate from the pericardial cavity, they remain in open com m unication with the abdom inal (peritoneal) cavity by way o f the pericardioperitoneal canals (Fig. 7.5B). During further development, the opening between the prospective pleural and peritoneal cavities is closed by crescentshaped folds, the pleuroperitoneal folds, which project into the caudal end o f the peri cardioperitoneal canals (Fig. 7.7A). Gradually, the folds extend medially and ventrally, so that by the seventh week, they fuse with the mesentery o f the esophagus and with the septum transversum (Fig. 7.7 5 ). Henee, the connection between the pleural and peritoneal portions o f the body cavity is closed by the pleuroperi toneal membranes. Further expansión o f the pleural cavities relative to mesenchyme o f the body wall adds a peripheral rim to the pleuro peritoneal mem branes (Fig. 7.7C). Once this rim is established, myoblasts originating from somites at cervical segments three to five (C 3 -5 ) penetrate the m em branes to form the muscular part o f the diaphragm. mwM Part I General Embryology Esophagus mesentery Pericardioperitoneal Pleuroperitoneal / canal \ fold. Aorta / Pleuroperitoneal membrane. Esophagus ^ Septum transversum FIGURE 7.7 Development o f the diaphragm. A. Pleuroperitoneal folds appear at the beginnlng of the flfth week. B. Pleuroperitoneal folds fuse w lth the septum transversum and mesentery of the esophagus in the seventh week, separatlng the thoraclc cavlty from the abdominal cavity. C. Transverse section at the fourth month of development. An additional rim derived from the body wall form s the m ost peripheral part of the diaphragm. Clinical Correlates B- D iaph ragm atic Hernias A congenital diaphragm atic hernia, one o f th e m ore com m o n m a lfo rm a tio n s in th e new born [1/2,000 ], ¡s m o st fre q u e n tly caused by fa ilu re o f one or b oth o f th e p le uroperitoneal m em b ran es to cióse th e p e rica rdioperitone al canals (Fig. 7.8). In th a t case, th e peritone al and pleural ca vitie s are c o n tin u o u s w ith one a n o th e r along th e p o s te rio r body w a ll. This hernia allo w s a bd om inal viscera to e n te r th e pleural cavity. In 8 5 % to 9 0 % o f cases, th e hernia is on th e le ft side, and in te s tin a l loops, stom a ch, spieen, and p a rt o f th e liver m ay e n te r th e th o ra c lc c a v ity [Fig. 7.8). The O p e n in g b e tw ee n s te rn a l Inferior a nd c o sta l h e a d s ve n a cava C en tra l te n d ó n ' O p e n in g fo r esophagus D ia ph ragm ple u ro p e rito n e a l m em b ra n e FIGURE 7.8 Congenital diaphragm atic hernia. A. Abdominal surface of the diaphragm shov/ing a large defect of the pleuroperitoneal membrane. B. Hernia of the intestinal loops and part of the stomach into the le ft pleural cavity. The heart and mediastinum are frequently pushed to the right, and the le ft lung is compressed. C. Radiograph o f a nev/born v^ith a large defect in the le ft side of the diaphragm. Abdominal viscera have entered the thorax through the defect. Chapter 7 The Gut Tube and the Body Cavities abd om inal viscera in th e chest push th e hea rt a n te rio rly and com press th e lungs, w h ich are co m m o n ly h ypo plastic. A large d e fe c t is ass ociate d w ith a high ra te o f m o rta lity [75%] fro m p u lm o n a ry hypo plasia and dys fu n c tio n. O ccasionally, a sm all p a rt o f th e m us c u la r fibers o f th e diaphragm fa ils to develop, and a hernia m ay rem ain undiscovered u n til th e child is several years oíd. Such a defect, fre q u e n tly seen in th e a n te rio r p o rtio n o f th e diaphragm , Thus, the diaphragm is derived from the following structures: The septum transversum, which forms the central tendón o f the diaphragm The two pleuroperitoneal membranes Muscular components from somites at cervi cal segments three to five The mesentery o f the esophagus, in which the crura o f the diaphragm develop (Fig. 7.7C) During the fourth week, the septum transver sum lies opposite cervical somites, and nerve components o f the third, fourth, and fifth cervical segments o f the spinal cord grow into the septum. At first, the nerves, known as phrenic nerves, pass into the septum through the pleuropericardial folds (Fig. 7.5B). This explains why further expansión o f the lungs and descent o f the septum shift the phrenic nerves that innervate the diaphragm into the fibrous pericardium (Fig. 7.6). Although the septum transversum lies op posite cervical segments during the fourth week, by the sixth week, the developing diaphragm is at the level o f thoracic somites. The repositioning o f the diaphragm is caused by rapid growth of the dorsal part o f the embryo (vertebral column), compared with that o f the ventral part. By the beginning o f the third m onth, some o f the dorsal bands of the diaphragm origínate at the level o f the first lumbar vertebra. The phrenic nerves supply the diaphragm with its m oto r and sensory innervation. Because the m ost peripheral part o f the diaphragm is derived from mesenchyme o f the thoracic wall, it is generally accepted that some o f the lower intercostal (thoracic) nerves contribute sensory fibers to the peripheral part o f the diaphragm. is a parasternal hernia. A sm all peritone al sac c o n ta in in g in te s tin a l loops m ay e n te r th e c hest betw e en th e stern al and costal p o rtio n s o f th e diaphragm (Fig. 7.84). A n o th e r ty p e o f d ia p h ra g m a tic hernia, esophageal hernia, is th o u g h t to be due to c ong enital s h o rtn e s s o f th e esophagus. Upper p o rtio n s o f th e sto m a ch are reta ined in th e th o ra x , and th e stom a ch Is c o n s tric te d a t th e level o f th e diaphragm. SUMMARY At the end o f the third week, the neural tube is elevating and closing dorsally while the gut tube is roUing and closing ventraUy to create a “tube on top o f a tube.” Mesoderm holds the tubes together and the lateral píate mesoderm splits to form a visceral (splanchnic) layer associated with the gut and a parietal (somatic) layer that, together with overlylng ectoderm, forms the lat eral body wall folds. The space between the vis ceral and parietal layers o f lateral píate mesoderm is the primitive body cavity (Fig. 7.1). W hen the lateral body wall folds move ventrally and fuse in the midline, the body cavity is closed, except in the región o f the connecting stalk (Figs. 7.1 and 7.2). Here the gut tube maintains an attachment to the yolk sac as the yolk sac (vitelline) duct. The lateral body wall folds also pulí the amnion with them so that the amnion surrounds the embryo and extends over the connecting stalk, which becomes the umbilical cord (Fig. 7. ID and 7.2D). Failure o f the ventral body wall to cióse results in ventral body wall defects, such as ectopia cordis, gastroschisis, and exstrophy of the bladder and cloaca (Fig. 7.3). Parietal mesoderm will form the parietal layer o f serous membranes lining the outside (walls) o f the peritoneal, pleural, and pericardial cavities. The visceral layer will form the visceral layer o f the serous membranes covering the lungs, heart, and abdominal organs. These layers are continuous at the root o f each organ as the organs lie in their respec tive cavities. (This relationship is similar to the picture created when you stick a finger [organ] into the side o f a balloon: The layer o f the balloon surrounding the finger [organ] being the visceral layer, and the rest o f the balloon being i r n Part I General Embryology the somatic or parietal layer. The space between is the “primitive body cavity.” The two layers o f the balloon are continuous at the base [root] o f the finger.) In the gut, the layers form the peritoneum and in places suspend the gut from the body wall as double layers o f peritoneum called mesenteries (Fig. 7.1E). Mesenteries provide a pathway for vessels, nerves, and lymphatics to the organs. Initially, the gut tube from the cau dal end o f the foregut to the end o f the hindgut is suspended from the dorsal body wall by dorsal m esentery (Fig. 7.1E). Ventral mesentery, derived from the septum transversum, exists only in the región o f the terminal part o f the esophagus, the stomach, and the upper portion o f the duodenum (see Chapter 15). The diaphragm divides the body cavity into the thoracic and peritoneal cavlties. It develops from four components: (1) septum trans versum (central tendón), (2) pleuroperitoneal membranas, (3) dorsal mesentery o f the esophagus, and (4) m uscular com ponents from somítes a t cervical levels three to five (C 3-5) o f the body wall (Fig. 7.7). Because the septum transversum is located initially opposite cervi cal segments three to five and because muscle cells for the diaphragm origínate from somites at these segments, the phrenic nerve also arises from these segments o f the spinal cord (C3, C4, and C5 keep the diaphragm alive!). Congenital diaphragmatic hernias involving a defect o f the pleuroperitoneal membrane on the left side occur frequently. The thoracic cavity is divided into the pericardial cavity and two pleural cavities for the lungs by the pleuropericardial membranas (Fig. 7.6). Problems to Solve 1. A newborn infant cannot breathe and soon dies. An autopsy reveáis a large dia phragmatic defect on the left side, with the stomach and the intestines occupying the left side of the thorax. Both lungs are severely hypoplastic. W hat is the embryological basis for this defect? 2. A child is born with a large defect lateral to the umbilicus. M ost of the large and the small bowel protrude through the defect and are not covered by amnion. W hat is the embryo logical basis for this abnormality, and should you be concerned that other malformations may be present? 3. Explain why the phrenic nerve, which supplies m otor and sensory fibers to the dia phragm, originates from cervical segments when most o f the diaphragm is in the thorax. From which cervical segments does the nerve origínate? DEVELOPMENTOFTHEFETUS The period from the beginning o f the ninth week to birth is known as the fetal period. It is characterized by m aturation o f tissues and organs and rapid growth o f the body. The length o f the fetus is usually indicated as the crownrum p length (CRL) (sitting height) or as the crow n-heel length (C H L), the measurement from the vertex o f the skull to the heel (standing height). These m easurements, expressed in centim eters, are correlated with the age o f the fetus in weeks or m onths (Table 8.1). Growth in length is particularly striking during the third, fourth, and fifth m onths, whereas an increase in weight is m ost striking during the last 2 m onths o f gestation. In general, the length o f pregnancy is considered to be 2 8 0 days, o r 4 0 weeks after the onset o f the last n o rm al m enstrual period (LNM P) or, m ore accurately, 2 6 6 days o r 38 weeks after fertilization. For the purposes o f the following discussion, age is calculated from the time o f fertilization and is expressed in weeks or calendar m onths. Growth in Length and W eight during the Fetal Period Age (wk) CRL (cm] 9-12 5 -8 W eight [g) 10-45 13-16 9-14 6 0 -2 0 0 17-20 15-19 2 5 0 -4 5 0 21-24 2 0 -2 3 5 0 0 -8 2 0 2 5 -2 8 2 4 -2 7 9 0 0 -1 ,3 0 0 2 9 -3 2 2 8 -3 0 1,400-2,100 3 3 -3 6 31-34 2 ,2 0 0 -2 ,9 0 0 37 -3 8 3 5 -3 6 3 ,0 0 0 -3 ,4 0 0 CRL, c ro w n -ru m p le ng th. M o n th ly C h a n g e s One o f the most striking changes taking place during fetal life is the relative slowdown in growth o f the head compared with the rest o f the body. At the beginning o f the third month, the head constitutes approximately half of the CRL (Figs. 8.1 and 8.2). By the beginning o f the fifth month, the size o f the head is about one third o f the CHL, and at birth, it is approximately one quarter of the CHL (Fig. 8.2). Henee, over time, growth o f the body accelerates but that o f the head slows down. During the third m onth, the face becomes more human looking (Figs. 8.3 and 8.4). The eyes, initially directed laterally, move to the ven tral aspect o f the face, and the ears come to lie cióse to their definitive position at the side o f the head (Fig. 8.3). The limbs reach their relative length in comparison with the rest o f the body, although the lower limbs are still a little shorter and less well developed than the upper extremities. Prim ary ossifícation centers are present in the long bones and skull by the 12th week. Also by the 12th week, external genitalia develop to such a degree that the sex o f the fetus can be determined by external examination (ultrasound). During the sixth week, intestinal loops cause a large swelling (herniation) in the umbilical cord, but by the 12th week, the loops have withdrawn into the abdominal cavity. At the end o f the third month, reflex activity can be evoked in aborted fetuses, indicating muscular activity. During the fourth and fifth months, the fetus lengthens rapidly (Fig. 8.5 and Table 8.1), and at the end of the first half o f intrauterine life, its CRL is approximately 15 cm, about half the total length o f the newborn. The weight o f the fetus increases litüe during this period and by the end o f the fifth month is still < 500 g. The fetus is covered with fine hair, called lanugo hair; eyebrows and head hair are also visible. During the fifth m onth, movements of the fetus can be felt by the mother. Part I General Embryology FIGURE 8.1 A 9-week fetus. Note the large head size compared w ith that o f the rest of the body. The yolk sac and long vitelline duct are visible in the chorionic cavity. Note the umbilical cord and herniation of intestinal loops. One side of the chorion has many villi (chorion frondosum ], whereas the other side is almost smooth [chorion laeve]. During the second h a lf o f intrau terine life, weight increases considerably, particularly dur ing the last 2.5 months, when 50% o f the fullterm weight (approximately 3,200 g) is added. During the sixth m onth, the skin o f the fetus is reddish and has a wrinkled appearance because o f the lack o f underlying connective tissue. 3rd month A fetus born early in the sixth m onth has great difficuhy surviving. Although several organ systems are able to function, the respiratory system and the central nervous system have not differentiated sufíiciently, and coordination between the two systems is not yet well estabhshed. By 6.5 to 7 months, the fetus has a CRL o f about 25 cm 5th month At birth FIGURE 8.2 Size o f the head in relation to the rest of the body at various stages of development. Chapter 8 Third Month to Birth: The Fetus and Placenta FIGURE 8.4 A 12-week fetus in útero. Note the extrem ely thin skin and underiying blood vessels. The face has all of the human characteristics, but the ears are still prim itive. Movements begin a t this tim e but are usually not fe it by the mother. FIGURE 8.3 An 11-week fetus. The umbilical cord stil! shows a sweiling at its base, caused by herniated intestinal loops. The skuli of this fetus lacks the normal smooth contours. Fingers and toes are well developed. FIGURE 8.5 An 18-week fetus connected to the placenta by its umbilical cord. The skin of the fetus is thin because of lack of subcutaneous fat. Note the placenta w ith its cotyiedons and the amnion. [ K l Part I General Embryology Developm ental Horizons During Fetal Life Event ________________________________ Age [wk] Taste buds appear S w ailow ing R espiratory m ovem ents Sucking m ovem ents Some sounds can be heard Eyes sensitive to lig h t° 7 10 14-16 24 2 4 -2 6 28 “ R e cog nitio n o f fo rm and c o lo r o ccurs postn a ta lly. and weighs approximately 1,100 g. If born at this time, the infant has a 90% chance o f surviving. Some developmental events occurring during the first 7 months are indicated in Table 8.2. During the last 2 months, the fetus obtains well-rounded contours as the result o f deposition o f subcutaneous fat (Fig. 8.6). By the end o f intrauterine Ufe, the skin is covered by a whitish, fatty substance (vernix caseosa) composed o f secretory products from sebaceous glands. At the end o f the ninth m onth, the skull has the largest circumference o f all parts o f the body, an important fact with regard to its passage through the birth canal. At the time o f birth, the FIGURE 8.6 A 7-m onth fetus. This fetus would be able to survive. It has well-rounded contours as a result of depositlon of subcutaneous fat. Note the tw istlng of the umbilical cord. weight o f a normal fetus is 3,000 to 3,400 g, its CRL is about 36 cm, and its CHL is about 50 cm. Sexual characteristics are pronounced, and the testes should be in the scrotum. Time of Birth The date o f birth is most accurately indicated as 266 days, or 38 weeks, after fertilization. The oocyte is usually fertilized within 12 hours o f ovulation; however, sperm deposited in the reproductive tract up to 6 days prior to ovulation can survive to fertilize oocytes. Thus, most pregnancies occur when sexual intercourse occurs within a 6-day period that ends on the day o f ovulation. A pregnant woman usually will see her obstetrician when she has missed two successive menstrual bleeds. By that time, her recollection about coitus is usually vague, and it is readily understandable that the day o f fertiliza tion is difficult to determine. The obstetrician calculates the date o f birth as 280 days or 40 weeks from the first day o f the LNMP. In women with regular 28-day m en strual periods, the method is fairly accurate, but when cycles are irregular, substantial miscalculations may be made. An additional complication occurs when the woman has some bleeding about 14 days after fertilization as a result o f erosive activity by the implanting blastocyst (see Chapter 4, “Day 13,” p. 52). Henee, the day o f delivery is not always easy to determine. Most fetuses are born within 10 to 14 days o f the calculated delivery date. If they are born much earlier, they are categorized as prem atura; if born later, they are considered postm ature. Occasionally, the age o f an embryo or small fetus must be determined. By combining data on the onset o f the last menstrual period with fetal length, weight, and other morphological characteristics typical for a given m onth o f development, a reasonable estimate o f the age o f the fetus can be formulated. A valuable tool for assisting in this determination is ultrasound, which can provide an accurate (1 to 2 days) measurement of CRL during the 7th to 14th weeks. Measurements commonly used in the 16th to 30th weeks are biparietal diameter (BPD), head and abdominal circumference, and fémur length. An accurate determination o f fetal size and age is important for managing pregnancy, especially if the m other has a small pelvis or if the baby has a birth defect. Chapter 8 Third Month to Birth: The Fetus and Placenta Clinical Correlates Low Birth W eight There is considerable va ria tio n in fe ta l le ngth and w e ig h t, and so m e tim e s these valúes do n o t corre spond w ith th e c alculated age o f th e fe tu s in m o n th s or w eeks. M ost fa c to rs in flu e n d n g le ngth and w e ig h t are g e n e tic a lly determ ined, b u t e n viro n m e n ta l fa c to rs aiso play an im p o rta n t role. The average size o f a new born is 2,5 0 0 to 4 ,0 0 0 g (6 to 9 Ib] w ith a le ngth o f 51 cm [20 in], The te rm low birth w eig h t (LBW) refe rs to a w e ig h t < 2 ,5 0 0 g, regardiess o f gesta tio n a l age. M any in fa n ts w e igh < 2 ,5 0 0 g because th e y are p reterm (born before 37 w eeks o f gesta tio n ]. In c o n tra st, th e te rm s in trauterin e g ro w th restriction (lUGR) and sm all fo r gestational age (SGA) ta k e in to accou nt g e sta tio n a l age. lUGR is a te rm applied to in fa n ts w h o do n o t a tta in th e ir o p tim a l in tra u te rin e g ro w th. These in fa n ts are p a th o lo g ic a lly s m all and a t risk fo r poo r outcom es. Infa n ts w h o are SGA have a b irth w e ig h t th a t is b elow th e lO th percen tile fo r th e ir g e sta tio n a l age. These babies m ay be p a th o lo g ica lly sm all (th e y m ay have lUGR) o r th e y m ay be c o n s titu tio n a lly sm all (healthy b u t sm a lle r in sizej. The challenge is to d iffe re n tia te th e tw o c o n d itio n s so th a t h e a lth y b u t sm all babies are n o t subjected to h ig h -ris k pro to co ls used fo r babies w ith lUGR. A p p ro x im a te ly 1 in 10 babies have lUGR and th e re fo re have an increased risk o f neuro log ical problem s, cong enital m a lfo rm a tio n s , m econium aspira tion, hypo glycem ia , hypo calcem ia, and re s p ira to ry d istre ss syndrom e [RDS). There are aiso lo n g -te rm e ffe c ts on these in fa n ts: In o th e r w o rds, w h a t happens in th e w o m b does n o t s ta y in th e w o m b and a d verse fe ta l expo sure s m ay predispose in d iv id uáis to h ea lth problem s as th e y g e t oider. For exam ple, babies w ith lUGR have been show n to have a g re a te r chance as ad u lts to develop a m eta b o lic dis o rd e r la ter in life, such as obes ity , h ype rtension, h ype rcho lestero lem ia , c a rdio vascula r disease, and ty p e 2 diabetes (called th e Barker hypothesis]. The incidence o f lUGR is hig h e r in blacks th a n in w h ites. C ausative fa c to rs include chrom osom al a b n o rm a litie s ; te ra to g e n s ; co n g e n ital in fe c tio n s (rubella, cytom e g a lo v iru s , toxo p la s m o s is , and syphilis); poo r m aternal h ea lth (hyperte nsion and renal and cardiac disease): th e m o th e r’s n u tritio n a l s ta tu s and s ocioeconom ic level; her use o f cig are ttes, alcohol, and o th e r drugs; placental in s u fficiency: and m ú ltip le b irth s (e.g., tw in s , trip le ts ). The m a jo r g ro w th -p ro m o tin g fa c to r d u ring d e v e lo p m e n t before and a fte r b irth is insulin-like g ro w th fa c to r-l (IGF-I), w h ich has m itogenic and anabolic effects. Fetal tissues express IGF-I, and serum leveis are corre lated w ith fe ta l g ro w th. M u ta tio n s in th e IGF-I gene re s u lt in lUGR, and th is g ro w th re ta rd a tio n Is c o ntin ued a fte r b irth. In c o n tra s t to th e p re nata l period, p o s tn a ta l g ro w th depends on gro w th horm one (GHj. This horm one binds to its re c e p to r [GHR], a c tiv a tin g a sig nal tra n s ductio n p a th w a y and re s u ltin g in synthesis and s ecretion o f IGF-I. M u ta tio n s in th e GHR re s u lt in Laron dw arfism , w h ic h is c h a ra c te rized by m arked s h o rt s ta tu re , and so m e tim e s blue sciera. These in d iv id u á is s h o w littie or no lUGR because IGF-I pro d u c tio n does no t depend on GH durin g fe ta l deve lopm ent. FETAL MEMBRANES AND PLACENTA Changes in the Trophoblast The placenta is the organ that facihtates nutrient and gas exchange between the maternal and fetal compartments. As the fetus begins the ninth week o f development, its demands for nutri tional and other factors increase, causing major changes in the placenta. Foremost among these is an increase in surface area between maternal and fetal components to facilítate exchange. The disposition o f fetal membranes is also altered as production o f amniotic fluid increases. The fetal component o f the placenta is derived from the trophoblast and extraembryonic mesoderm (the chorionic píate); the maternal compo nent is derived from the uterine endometrium. By the beginning o f the second month, the tro phoblast is characterized by a great number o f secondary and tertiary villi, which give it a radial appearance (Fig. 8.7). Stem (anchoring) villi extend from the mesoderm o f the chorionic píate to the cytotrophoblast shell. The surface o f the villi P art I General Embryology Spiral artery Venous return Secondary and tertiary villi Outer cytotrophoblast Shell Chorionic píate (extraembtyonic mesoderm) Chorionic cavity (extraembtyonic cavity) Decidua capsularis FIGURE 8.7 Human em bryo a t the beginning of the second m onth o f developm ent. At the em bryonic poie, villi are num erous and well form ed; at the abem bryonlc pole, they are fev/ In num ber and poorly developed. is formed by the syncytium, resting on a layer of cytotrophoblastic cells that in turn cover a core ofvascular mesoderm (Fig. 8.8A,C). The capillary system developing in the core of the villous stems soon comes in contact with capillaries o f the cho rionic píate and connecting stalk, thus giving rise to the extraembryonic vascular system. Maternal blood is delivered to the placenta by spiral arteries in the uterus. Erosion o f these ma ternal vessels to release blood into intervillous spaces (Figs. 8.7 and 8.8) is accomplished by endovascular invasión by cytotrophoblast cells. These cells, released from the ends o f anchoring villi (Figs. 8.7 and 8.8), invade the terminal ends o f spiral arteries, where they replace maternal endothelial cells in the vessels’ walls, creating hybrid vessels containing both fetal and maternal cells. To accomplish this process, cytotropho blast ceUs undergo an epithelial-to-endothelial transition. Invasión o f the spiral arteries by cytotrophoblast cells transforms these vessels from small-diameter, high-resistance vessels to larger diameter, low-resistance vessels that can provide increased quantities o f maternal blood to intervillous spaces (Figs. 8.7 and 8.8). During the following months, numerous small extensions grow out from existing stem villi and extend as free villi into the surrounding lacunar or intervillous spaces. Initially, these newly formed free villi are primitive (Fig. 8.8C), but by the beginning o f the fourth month, cytotrophoblastic cells and some connective tissue cells disappear. The syncytium and endothe lial wall o f the blood vessels are then the only layers that separate the maternal and fetal circulations (Fig. 8.85,D ). Frequently, the syncytium becomes very thin, and large pieces containing several nuclei may break o íf and drop into the intervillous blood lakes. These pieces, known as syncytial knots, enter the maternal circulation and usually degenerate without causing any symptoms. Disappearance o f cytotrophoblastic cells progresses from the smaller to larger villi, and although some always persist in large villi, they do not particípate in the exchange between the two circulations. Chapter 8 Third Month to Birth: The Fetus and Placenta _ i n r Clinical Correlates Preeclampsia is a c o n d itio n c h a ra c te riz e d by m a te rn a l h y p e rte n s io n and p ro te in u ria due to reduced o rg a n p e rfu s ió n and o c c u rs in a p p ro x im a te ly 5% o f p re gna ncies. The c o n d itio n m ay p ro g re ss to e clam p sia, w h ic h is c h a ra c te riz e d by seizure s. P reeclam psia beg ins su d d e n ly a n y tim e fro m a p p ro x im a te ly 20 w e e ks’ g e s ta tio n to te rm and m ay re s u lt in fe ta l g ro w th re ta rd a tio n , fe ta l de a th , or d e a th o f th e m o th e r. In fa c t, p re e c la m p s ia is a le ad in g cause o f m a te rn a l m o rta lity in th e U n ited S ta te s and is c o m p le te ly re v e rs ib le by d e liv e ry o f th e baby. H o w ever, d e liv e ry to o e a rly p u ts th e in fa n t a t ris k fo r c o m p lic a tio n s re la te d to p re te rm b irth. D e spite m any y e a rs o f research, th e cause o f p re e c la m p sia is u n kn o w n. The c o n d itio n a p p e a rs to be a tro p h o b la s tic d is o rd e r re la te d to fa ile d or in c o m p le te d iffe re n tia tio n o f c y to tro p h o b la s t cells, m a n y o f w h ic h do n o t u n d e rg o th e ir n o r m al e p ith e lia l-to -e n d o th e lia l tra n s fo rm a tio n. As a re s u lt, in va s ió n o f m a te rn a l blood v e s seis b y th e s e c e lls is ru d im e n ta ry. How th e s e c e llu la r a b n o rm a litie s lead to h y p e rte n s io n and o th e r p ro b le m s is n o t clear. Risk fa c to rs fo r pre e c la m p s ia in c lu d e pre e c la m p s ia in a p re v io u s pre g n a n cy, n u llip a rity ( firs t p re g na n cy], o b e s ity , fa m ily h is to ry o f p re e c la m p sia, m ú ltip le g e s ta tio n (tw in s o r m ore ], and m e d ica l c o n d itio n s , such as h y p e rte n s io n and dia b e te s. P reeclam psia aiso c o m m o n ly o ccurs in w o m e n w ith h y d a tid ifo rm m oles (see C h apter 4, p. 56) in w h ic h case it o ccurs e a rly in pregna ncy. Cytotrophoblast Shell Spiral artery Intervillous space Blood vessel Cytotrophoblast^ Barrierformed by 1. Syncytium 2. Cytotrophoblast 3. Connective tissue 4. Endothelium Barrierformed by 1. Syncytium 2. Endothelium FIGURE 8.8 Structure of villi at various stages of development. A. During the fourth week. The extraembryonic mesoderm penetrales the stem villi in the direction of the decidual píate. B. During the fourth month. In many small villi, the wall of the capillaries Is in direct contact with the syncytium. C,D. Enlargement of the villus as shown in Figures 8.8/4,6. E a _ Part I General Embryology CHORION FRONDOSUM AND DECIDUA BASALIS In the early weeks o f development, villi cover the entire surface o f the chorion (Fig. 8.7). As pregnancy advances, villi on the embryonic pole continué to grow and expand, giving rise to the chorion írondosum (bushy chorion). Villi on the abembryonic pole degenerate, and by the third month, this side of the chorion, now known as the chorion laeve, is smooth (Figs. 8.9 and 8.10A). The difFerence between the embryonic and abembryonic poles o f the chorion is also reflected in the structure o f the decidua, the ftinctional layer o f the endometrium, which is shed during parturition. The decidua over the cho rion frondosum, the decidua basalis, consists o f a compact layer o f large cells, decidual cells, with abundant amounts o f lipids and glycogen. This layer, the decidual píate, is tightly connected to the chorion. The decidual layer over the abembryonic pole is the decidua capsularis (Fig. 8.10A). W ith growth o f the chorionic vesicle, this layer becomes stretched and degenerates. FIGURE 8.9 A 6-week embryo. The am niotic sao and chorionic cavity have been opened to expose the embryo, showing the bushy appearance of the trophoblast at the em bryonic pole in contrast to small villi a t the abembryonic pole. Note the connecting stalk and yolk sac w ith its extrem ely long vitelline duct. Subsequently, the chorion laeve comes into con ta d with the uterine wall (decidua parietalis) on the opposite side o f the uterus, and the two fuse (Figs. 8.10 to 8.12), obliterating the uterine lumen. Henee, the only portion o f the chorion participating in the exchange process is the cho rion frondosum, which, together with the de cidua basalis, makes up the placenta. Similarly, fusión o f the amnion and chorion to form the am niochorionic membrane obliterates the chorionic cavity (Fig. 8.10A,B). It is this m em brane that ruptures during labor (breaking o f the water). STRUCTURE OF THE PLACENTA By the beginning o f the fourth m onth, the pla centa has two components: (1) a fetal portion, formed by the chorion frondosum, and (2) a m aternal portion, formed by the decidua basalis (Fig. 8.10B). On the fetal side, the placenta is bordered by the chorionic píate (Fig. 8.13); on its maternal side, it is bordered by the decidua basalis, o f which the decidual píate is most intimately incorporated into the placenta. In the junctional zone, trophoblast and decidual cells intermingle. This zone, characterized by de cidual and syncytial giant cells, is rich in amorphous extracellular material. By this time, most cytotrophoblast cells have degenerated. Between the chorionic and decidual plates are the intervillous spaces, which are filled with maternal blood. They are derived from lacunae in the syncytiotrophoblast and are lined with syncytium o f fetal origin. The villous trees grow into the intervillous blood lakes (Figs. 8.8 and 8.13). During the fourth and fifth months, the de cidua forms a number o f decidual septa, which project into intervillous spaces but do not reach the chorionic píate (Fig. 8.13). These septa have a core o f maternal tissue, but their surface is covered by a layer o f syncytial cells, so that at all times, a syncytial layer separates maternal blood in intervillous lakes from fetal tissue o f the villi. As a result ofthis septum formation, the placenta is divided into a number of compartments, or cotyledons (Fig. 8.14). Because the decidual septa do not reach the chorionic píate, contact between intervillous spaces in the various cotyledons is maintained. As a result o f the continuous growth o f the fetus and expansión o f the uterus, the placenta Chapter 8 Third Month to Birth: The Fetus and Placenta _ i E r Fused decidua parietalis, chorion laeve and amnion Decidua basaiis DeciduarVs^: capsuiaris ^ Chorion laeve A FIGURE 8.10 Relation of fetal membranes to wall of the uterus. A. End of the second month. Note the yolk sac in the chohonic cavity between the amnion and chorion. At the abembryonic pole, villi have disappeared (chorion laeve]. B. End of the third month. The amnion and chorion have fused, and the uterine cavity is obliterated by fusión o f the chorion laeve and the decidua parietalis. also enlarges. Its increase in surface area roughly parallels that o f the expanding uterus, and throughout pregnancy, it covers approximately 15% to 30% o f the internal surface o f the uterus. The increase in thickness o f the placenta results from arborization o f existing villi and is not caused by further penetration into maternal tissues. Full-Term Placenta At fuU term, the placenta is discoid with a diameter of 15 to 25 cm, is approximately 3 cm thick, and weighs about 500 to 600 g. At birth, it is torn from the uterine wall and, approximately 30 minutes after birth o f the child, is expelled from the uterine cavity as the afterbirth. W hen the placenta is viewed from the maternal side, 15 to 20 slightly bulging areas, the cotyledons, covered by a thin layer o f decidua basaiis, are clearly recognizable (Fig. 8.145). Grooves between the cotyledons are formed by decidual septa. The fetal surface o f the placenta is covered entirely by the chorionic píate. A number o f large arteries and veins, the chorionic vessels, converge toward the umbilical cord (Fig. 8.14A). The chorion, in turn, is covered by the amnion. Attachm ent o f the umbilical cord is usually eccentric and occasionally even marginal. Rarely, however, does it insert into the chorionic membranes outside the placenta (velamentous insertion). Circulatíon of the Placenta FIGURE 8.11 A 19-week fetus in its natural position in the uterus, showing the umbilical cord and pla centa. The lumen of the uterus is obliterated. In the wall of the uterus is a large growth, a myofibroma. Cotyledons receive their blood through 80 to 100 spiral arteries that pierce the decidual píate and enter the intervillous spaces at more or less regular intervals (Fig. 8.13). Pressure in these arteries forces the blood deep into the intervil lous spaces and bathes the numerous small villi o f the villous tree in oxygenated blood. As the Part I General Embryology FIGURE 8.12 A 23-week fetus in the uterus. Portions of the wall of the uterus and the amnion have been removed to show the fetus. In the background are placental vesseis converging toward the umbilical cord. The umbilical cord is tightly wound around the abdomen, possibly causing abnormal fetal position in the uterus (breech position). Decidual píate Endometrial veins Spiral artery Decidual septum FIGURE 8.13 The placenta in the second half o f pregnancy. The cotyiedons are partially separated by the decidual (maternal) septa. Most of the Intervillous blood returns to the maternal circulation by way of the endometrial veins. A small portion enters neighboring cotyiedons. The intervillous spaces are lined by syncytium. Chapter 8 Third Month to Birth: The Fetus and Placenta umbilical cord Cotyiedon Decidua basalis removed FIGURE 8.14 A full-term placenta. A. Fetal side. The chorionic píate and umbilical cord are covered by amnion. B. Maternal side showing the cotyiedons. In one area, the decidua has been removed. The m ater nal side of the placenta is always carefully inspected at birth, and frequently one or more cotyiedons with a whitish appearance are present because of excessive fibrinoid form ation and infarction of a group of Intervillous lakes. pressure decreases, blood flows back from the chorionic píate toward the decidua, where it enters the endometrial veins (Fig. 8.13). Henee, blood from the intervillous lakes drains back into the maternal circulation through the endo metrial veins. Collectively, the intervillous spaces o f a mature placenta contain approximately 150 mL o f blood, which is replenished about three or four times per minute. This blood moves along the chorionic viUi, which have a surface area o f 4 to 14 m^. Placental exchange does not take place in all villi, however, only in those that have fetal vessels in intímate contact with the covering syncytial membrane. In these villi, the syncytium often has a brush border consisting o f numerous microvilli, which greatly increases the surface area and consequently the exchange rate between maternal and fetal circulations (Fig. 8.8D). The placental m em brane, which Clinical Correlates Erythroblastosis Fetalis and Fetal Hydrops Because som e fe ta l blood cells escape across th e placental barrier, th e re is a p o te n tia l fo r these cells to e lic it an a n tib o d y response by th e m o th e r’s im m une system. The basis fo r th is response is th e fa c t th a t m ore than 4 0 0 red blood cell antig e n s have been id entified, and alth o u g h m o st do n o t cause problem s during pregnancy, som e can s tim u la te a m ate rna l an tib o d y response aga in st fe ta l blood cells. This process is an exam ple o f isoim m unization, separates maternal and fetal blood, is initially composed o f four layers: (1) the endothelial lining o f fetal vessels, (2) the connective tissue in the vlllus core, (3) the cytotrophoblastic layer, and (4) the syncytium (Fig. 8.8C). From the fourth month on, the placental membrane thins because the endothelial lining o f the ves sels comes in intímate contact with the syncy tial membrane, gready increasing the rate o f exchange (Fig. 8.8D). Sometimes called the placental barrier, the placental membrane is not a true barrier, as many substances pass through it freely. Because the maternal blood in the intervillous spaces is separated from the fetal blood by a chorionic derivative, the human placenta is considered to be o f the hem ochorial type. Normally, there is no mixing o f maternal and fetal blood. However, small numbers o f fetal blood cells occasionally escape across microscopic defects in the placental membrane. w and if th e m ate rna l response is s u ffic ie n t, the antib odies w ill a tta c k and hem olyze fe ta l red blood cells, resultíng in hem olytic disease o f th e fetu s and newborn. Previously, the disease w as called erythroblastosis fetalis because in som e cases severe hem olysis s tim u la te d an increase in p roductio n o f fetal blood cells called erythroblasts. H owever, th is s e v e rity o f anem ia occurs o nly in a fe w cases such th a t h e m o ly tic disease o f th e fe tu s and [continued} Part I General Embryology n ew born is a m ore app ro p ria te term in o lo g y. In rare cases, th e anem ia becom es so severe th a t feta l hydrops [edem a and effu sio n s in to th e body cavities) occurs, leading to fe ta l death (Fig. 8.15]. M ost severe cases are caused by antig e n s fro m th e CDE (Rhesus) blood g ro u p system. The D or Rh antigen is th e m o s t dangerous because im m u n iza tio n can re su lt fro m a single e xposure and occurs earlie r and w ith greater s e ve rity w ith each succeeding pregnancy. The m ate rna l a n tib o d y response occurs in cases w hen th e fe tu s is D (R h]-p os¡tive and the m o th e r is D (R h)-negative and is elicited w hen fe ta l red blood cells e n te r th e m ate rna l system because o f sm all areas o f bleeding a t th e su rface o f placental villi or a t b irth. This cond itio n can be prevented by screening w o m en a t th e ir fir s t prenatal v is it fo r Rh blood ty p e and fo r the presence o f a n ti-D a ntib odies to determ ine if she has been sensitized previousiy. In Rhneg ative w o m en w ith o u t a n ti-D antibodies, re com m en dations include tre a tm e n t w ith Rh im m uno g lo b u lin a t 28 w e eks’ gesta tio n ; fo llow ing tim e s w hen fe ta l-m a te rn a l m ixing of blood m ay have occurred (e.g., a fte r a m nio centesis or pregnancy loss]¡ and a fte r delivery if th e new born is fou n d to be Rh-positive. Since th e in tro d u ctio n o f Rh im m uno g lo b u lin in 1968, he m o lytic disease in th e fe tu s and new born in th e United S tates has a lm o st been elim inated. A n tig e n s fro m th e ABO blood group can aiso e lic it an a n tib o d y response, b u t th e e ffe c ts Function of the Placenta Main functions o f the placenta are (1) exchange o f m etabolic and gaseous producís between maternal and fetal bloodstreams and (2) production o f hormones. Exchange o f Gases Exchange o f gases— such as oxygen, carbón dioxide, and carbón monoxide—is accomplished by simple difFusion. At term, the fetus extracts 20 to 30 mL of oxygen per minute from the maternal circulation, and even a short-term interruption o f the oxygen supply is fatal to the fetus. Placental blood flow is critical to oxygen supply, as the amount of oxygen reaching the fetus primarily depends on delivery, not difFusion. Exchange o f N utrients and Electrolytes Exchange o f nutrients and electrolytes, such as amino acids, free fatty acids, carbohydrates, and are m uch m ild e r th a n th o s e produce d by th e CDE group. A b o u t 2 0 % o f all in fa n ts have an ABO m ate rn a l in c o m p a tib ility , b u t o niy 5% w ill be c lin ic a lly affe c te d. These can be e ffe c tiv e ly tre a te d postn a ta lly. FIGURE 8.15 Fetal hydrops caused by the accum ulation o f fluid In fetal tissues. vitamins, is rapid and increases as pregnancy advances. Transmission o f M aternal Antibodies Immunological competence begins to develop late in the first trimester, by which time the fetus makes all o f the components o f complement. Immunoglobulins consist almost entirely o f m aternal immunoglobulin G (IgG), which begins to be transported from m other to fetus at approximately 14 weeks. In this manner, the fetus gains passive immunity against various infectious diseases. Newborns begin to produce their own IgG, but adult levels are not attained until the age o f 3 years. Hormone Production By the end o f the fourth m onth, the placenta produces progesterone in suflicient amounts to maintain pregnancy if the corpus luteum Chapter 8 Third Month to Birth: The Fetus and Placenta _Ba Clinical Correlates The Placental Barrier M aternal ste ro id a l horm ones readily cross th e placenta. O th e r horm ones, such as th y ro x in e , do so o n iy a t a slo w rate. Some s y n th e tic prog estin s ra pid ly cross th e placenta and m ay m asculinize fe m a le fetuse s. Even m ore dan gerous w a s th e use o f th e s y n th e tic estro gen diethyistilb estro l (DES], w h ic h easily crosses th e placenta. This com poun d produced c le arcell c a rc in o m a o f th e vagina and a b n o rm a litie s o f th e ce rvix and ute ru s in fem a les and in th e te s te s o f m ales in in dividuáis w h o w e re e xposed to th e com poun d durin g th e ir in tra u te rine life (see C hapter 9]. is removed or fails to function properly. In all probability, all hormones are synthesized in the syncytial trophoblast. In addition to progesterone, the placenta produces increasing amounts o f estrogenic hormones, predominantly estriol, until just before the end o f pregnancy, when a máximum level is reached. These high levels o f estrogens stimulate uterine growth and development o f the mammary glands. During the first 2 m onths o f pregnancy, the syncytiotrophoblast also produces hum an chorionic gonadotropín (hCG), which maintains the corpus luteum. This horm one is excreted by the m other in the uriñe, and in the early stages o f gestation, its presence is used as an indicator o f pregnancy. Another horm one produced by the placenta is som atom am m otropin (form erly placental lactogen). It is a growth h orm one-like substance that gives the fetus priority on m aternal blood glucose and makes the m other somewhat diabetogenic. It also promotes breast development for milk production. AMNION AND UMBILICAL CORD The oval line o f reflection between the amnion and embryonic ectoderm (am nio-ectoderm al junction) is the primitive umbilical ring. At the fifth week o f development, the following structures pass through the ring (Fig. 8.16A,C): (1) the connecting stalk, containing the allantois and the umbilical vessels, consisting o f two A lth o u g h th e placental ba rrie r is fre q u e n tly considered to a c t as a p ro te c tiv e m echanism aga in st dam aging fa c to rs , m any v iru s e s such as rubella, cytom e g a lo v iru s , coxsackie, v arióla, varicella, m easles, and p o lio m y e litis v iru s -tra v e rs e th e placenta w ith o u t d iffic u lty. Once in th e fe tu s , som e v iruses cause in fections, w h ich m ay re s u lt in cell death and birth de fe cts (see C hapter 9]. U nfortunately, m ost drugs and drug m etabolites traverse th e placenta w ith o u t diffic u lty , and m any cause serious dam age to th e em bryo (see C hapter 9]. In addition, m aternal use o f heroin and cocaine can cause hab ituation in th e fetus. arteries and one vein; (2) the yolk stalk (vitelline duct), accompanied by the vitelline vessels; and (3) the canal connecting the intraem bryonic and extraem bryonic cavities (Fig. 8.16C). The yolk sac proper occupies a space in the chorionic cavity, that is, the space between the amnion and chorionic píate (Fig. 8.16B). During further development, the amniotic cavity enlarges rapidly at the expense o f the cho rionic cavity, and the amnion begins to envelop the connecting and yolk sac stalks, crowding them together and giving rise to the primitive umbilical cord (Fig. 8.16B). Distally, the cord contains the yolk sac stalk and umbilical ves sels. M ore proximally, it contains some intes tinal loops and the remnant o f the allantois (Fig. 8.16B,D). The yolk sac, found in the cho rionic cavity, is connected to the umbilical cord by its stalk. At the end o f the third m onth, the amnion has expanded so that it comes in con ta d with the chorion, obliterating the chorionic cavity (Fig. 8.IOS). The yolk sac then usually shrinks and is gradually obliterated. The abdominal cavity is temporarily too small for the rapidly developing intestinal loops, and some o f them are pushed into the extraem bryonic space in the umbilical cord. These extruding intestinal loops form a physiological umbilical hernia (see Chapter 15). At approximately the end o f the third m onth, the loops are withdrawn into the body o f the embryo, and the cavity in the cord is obliterated. W hen the allantois and the vitelline duct and its vessels are ^ n i _ P art I General Embryology Chorionic cavity Amnion / - \ Chorion Chorionic píate Allantois FIGURE 8.16 A. A 5-week embryo showing structures passing through the primitive umbilical ring. B. The primitive umbilical cord of a 10-week embryo. C. Transverse section through the structures at the level of the umbilical ring. D. Transverse section through the primitive umbilical cord showing intestinal loops protruding in the cord. also obliterated, all that remains in the cord are the umbilical vessels surrounded by W harton jelly. This tissue, which is rich in proteoglycans, functions as a protective layer for the blood ves sels. The walls o f the arteries are muscular and contain many elastic fibers, which contribute to a rapid constriction and contraction o f the um bilical vessels after the cord is tied off. PLACEN TAL C H AN CES A T THE END OF PREGNANCY________________ At the end o f pregnancy, a number o f changes that occur in the placenta may indícate reduced exchange between the two circulations. These changes include (1) an increase in fibrous tissue in the core o f the villus, (2) thickening o f basem ent membranes in fetal capillaries, (3) obliterative changes in small capillaries o f the villi, and (4) deposition of fibrinoid on the surface o f the villi in the junctional zone and in the chorionic píate. Excessive fibrinoid formation frequently causes infarction o f an intervillous lake or sometimes o f an entire cotyledon. The cotyledon then assumes a whitish appearance. AMNIOTIC FLUID The am niotic cavity is filled with a clear, watery fluid that is produced in part by am niotic cells but is derived primarily from maternal blood. The amount o f fluid increases from approximately 30 mL at 10 weeks o f gestation to 450 mL at 20 weeks to 800 to 1,000 mL at 37 weeks. During the early months o f pregnancy, the em bryo is suspended by its umbilical cord in this fluid, which serves as a protective cushion. The fluid (1) absorbs jolts, (2) prevents adherence o f the embryo to the am nion, and (3) allows for fetal movements. The volume o f am niotic fluid is replaced every 3 hours. From the beginning o f the flfth month, the fetus swallows its own am niotic fluid, and it is estimated that it drinks about 400 mL a day, about h alf o f the total amount. Fetal uriñe is added daily to the am niotic fluid in the flfth m onth, but this uriñe is m ostly water because the placenta is functioning as an exchange for metabolic wastes. During childbirth, the am niochorionic membrane forms a hydrostatic wedge that helps to dilate the cervical canal. Chapter 8 Third Month to Birth: The Fetus and Placenta Clinical Correlates Um bilical Cord A bnorm alities A m niotic Fluid A t b irth, th e um bilical cord is a p p ro x im a te ly 1 to 2 cm in diam e ter and 50 to 60 cm long. It is to rtu o u s , causing false knots. Length o f a cord re fle cts th e a m o u n t o f in tra u te rin e m o vem ent o f th e fe tu s, and shortened cords have been observed in fe ta l m o ve m e n t disorders and w ith in tra u te rin e constra in t. An e x tre m e ly long cord m ay encircle th e neck o f th e fe tu s , usually w ith o u t increased risk, w hereas a s h o rt one m ay cause d iffic u ltie s durin g deliv e ry by pulling th e placenta fro m its a tta c h m e n t in th e uterus. N orm ally, there are tw o arte ries and one vein in th e um bilical cord. In 1 in 2 0 0 new borns, how ever, oniy a single umbilical arte ry is present, and these babies have app ro x im a te ly 20% chance o f having cardiac and o th e r vascular defects. The m issing a rte ry eithe r fa ils to fo rm [agenesis] or degenerates early in developm ent. Hydramnios or polyhydramnios is the term used to describe an excess o f am niotic fluid (1,500 to 2,000 mL), whereas oligohydramnios refers to a decreased am o u n t ( < 4 0 0 mL]. Both conditions are associated w ith an increase in th e incidence o f birth defects. Prim ary causes o f hydram nios include idiopathic causes (35%), m aternal diabetes (25%], and congenital m alform ations, including central nervous system disorders (e.g., anencephaly] and gastrointestinal defects (atresias, e.g., esophageal) th a t prevent the infa n t from swailow ing the fluid. O ligohydram nios is a rare occurrence th a t m ay result from renal agenesis. The lack o f fluid in the am niotic cavity m ay constrict the fe tu s or there m ay be too littie fluid fo r th e fetus to “ breathe” into its lungs resulting in lung hypoplasia. Prem atura rupture of the m embranes (PROM) refers to rupture o f th e m em branes before uterine contractions begin and occurs in 10% o f pregnancies. Preterm PROM occurs before 37 com pleted weeks o f pregnancy, occurs in 3% of pregnancies, and is a com m on cause o f preterm labor. Causes o f preterm PROM are unknown, bu t risk factors include a previous pregnancy affected by p rem atu rity or PROM, black race, sm oking, infections, and severe polyhydram nios. Am niotic Bands O ccasionally, te a rs in th e a m nio n re s u lt in am niotic bands th a t m ay encircle p a rt o f th e fe tu s, p a rtic u la rly th e lim bs and digits. A m p u ta tio n s, ring constrictions, and o th e r abn orm a litie s, in cluding cranio facial d e fo rm a tions, m ay re s u lt (Fig. 8.17). O rigin o f th e bands is unknow n. FIGURE 8.17 Limb abnorm alities causad by am niotic bands. A. Limb constriction ring. B. Digit am putation (big toe) and ring constriction (second toe]. Part I General Embryology FETAL M EM BR AN ESIN TW IN S The frequency o f múltiple gestation (e.g., twins, triplets) has increased substantiaUy in recent years and now accounts for over 3% of aUlive births in the United States. The rate of twin births has increased to a high o f 32.6 per 1,000 births in 2008. The reasons for this increase are twofold: the increasing age o f mothers at the time of their infants’ birth and the increasing use o f fertility treatments, including assisted reproductive technologies (ART). Dizygotic Twins Approximately 90% of twins are dizygotic, or fraternal, and their incidence increases with ma ternal age (doubling at age 35) and with fertility procedures, including ART. They result from simultaneous shedding o f two oocytes and fertilization by different spermatozoa. Because the two zygotes have totally diíferent genetic constitutions, the twins have no more resemblance than any other brothers or sisters. They may or may not be o f different sex. The zygotes implant individually in the uterus, and usually each develops its own placenta, amnion, and chorionic sac (Fig. 8.18A). Sometimes, however, the two placentas are so cióse together that they fuse. Similarly, the walls o f the chorionic sacs may also come into cióse apposition and fuse (Fig. 8.185). Occasionally, each dizygotic twin possesses red blood cells o f two dif ferent types (erythrocyte mosaicism), indicating that fusión o f the two placentas was so intimate that red cells were exchanged. Monozygotic Twins The second type o f twins, which develops from a single fertilized ovum, is monozygotic, or identical, twins. The rate for monozygotic twins is 3 to 4 per 1,000. They result from splitting o f the zygote at various stages o f development. The earliest separation is believed to occur at the twocell stage, in which case two separate zygotes develop. The blastocysts implant separately, and each embryo has its own placenta and chorionic sac (Fig. 8.19A). Although the arrangement o f the membranes o f these twins resembles that o f dizygotic twins, the two can be recognized as partners of a monozygotic pair by their strong re semblance in blood groups, fingerprints, sex, and external appearance, such as eye and hair color. Splitting o f the zygote usually occurs at the early blastocyst stage. The inner cell mass splits into two separate groups o f cells within the same blastocyst cavity (Fig. 8.19B). The two embryos have a common placenta and a common chorionic cavity but separate amniotic cavities (Fig. 8.19B). In rare cases, the separation occurs at the bilaminar germ disc stage, just before the appearance of the primitive stieak (Fig. 8.19C). This method o f splitting results in formation o f two partners with a single placenta and a common chorionic and amniotic sac. Although the twins have a common placenta, blood supply is usually well balanced. Although triplets are rare (about 1 per 7,600 pregnancies), birth o f quadruplets, quintuplets, and so forth is rarer. In recent years, múltiple births have occurred more frequently in mothers given gonadotiopins (fertility drugs) forovulatoryfailure. PARTURITION (BIRTH)___________ For the first 34 to 38 weeks o f gestation, the uterine myometrium does not respond to signáis for parturition (birth). During the last 2 to 4 weeks o f pregnancy, however, this tissue undergoes a transitional phase in preparation for the onset of labor. Ultimately, this phase ends with a thickening o f the myometrium in the upper región o f the uterus and a softening and thinning o f the lower región and cervix. Labor itself is divided into three stages: (1) eífacement (thinning and shortening) and dilatation o f the cervix (this stage ends when the cervix is fully dilated), (2) delivery o f the fetus, and (3) delivery o f the placenta and fetal m em branes. Stage 1 is produced by uterine contractions that forcé the amniotic sac against the cervical canal like a wedge, or if the membranes have ruptured, then pressure will be exerted by the presenting part o f the fetus, usually the head. Stage 2 is also assisted by uterine contractions, but the most important forcé is provided by increased intra-abdominal pressure from contraction o f abdominal muscles. Stage 3 requires uterine contractions and is aided by increasing intra-abdominal pressure. As the uterus contracts, the upper part retracts, creating a smaller and smaller lumen, while the lower part expands, thereby producing direction to the forcé. Contractions usually begin about 10 minutes apart; then, during the second stage o f labor, they may occur < 1 m in ute apart and last from 30 to 90 seconds. Their occurrence in pulses is essential to fetal survival, as they are o f sufRcient forcé to compromise uteroplacental blood flow to the fetus. Chapter 8 Third Month to Birth: The Fetus and Placenta _ E r Two-cell stage zygotes Inner cell mass Trophoblast Amniotic cavity Separata placenta and chorion Fusión of placenta and chorion FIGURE 8.18 Development of dizygotic twins. Normally, each embryo has its own amnion, chorion, and pla centa (A), but sometimes the placentas are fused (B). Each embryo usually receives the appropriate am ount of blood, but on occasion, large anastomoses shunt more blood to one of the partners than to the other. Part I General Embryology O ] 2-cell-stage zygote ooo o A ,,.'' ár , ^ 1^. Inner celk Blastocyst cavity \ Common / chorionic cavity Common amniotic cavity FIGURE 8.19 Possible relations of fetal membranes in m onozygotic twins. A. Spiltting occurs a t the tw o cel! stage, and each em bryo has Its own placenta, am niotic cavity, and chorionic cavity. B. Spiltting of the inner cell mass into tw o com pletely separated groups. The tw o em bryos have a common placenta and a com mon chorionic sac but separate am niotic cavities. C. Spiltting of the inner cell mass a t a late stage of developm ent. The em bryos have a common placenta, a com mon am niotic cavity, and a com mon chorionic cavity. Clinical Correlatas A bnorm alities Associated w ith Tw ins Tw in pre g n a n cie s have a high in cidence o f p e rin a ta l m o rta lity and m o rb id ity and an in crea sed risk fo r p re te rm delivery. A p p ro x im a te ly 6 0 % o f tw in s are born p re te rm and aiso have a high in ciden ce o f being LBW. B o th o f th e se fa c to rs p u t tw in p re g n a n cies a t g re a t risk and tw in p re gna ncies have an in fa n t m o rta lity ra te th re e tim e s hig h e r th a n th a t fo r sin g le to n s. The in cidence o f tw in n in g m ay be m uch h ig h e r th a n th e n u m b e r o b se rved a t b irth because tw in s are c once ived m ore o fte n th a n th e y are born. M any tw in s die b efore birth , Chapter 8 Third Month to Birth: The Fetus and Placenta and som e stu d ie s in díca te t h a t o n iy 2 9 % o f w o m e n p re g n a n t w ith tw in s a c tu a lly give b irth to tw o in fa n ts. The te rm vanishing twin re fe rs to th e dea th o f one fe tu s. This disappearance, w h ich o ccurs in th e fir s t trim e s te r or th e ea rly second trim e s te r, m ay re s u lt fro m re s o rp tio n o r fo rm a tio n o f a fe tu s pap yrace us [Fig. 8.20], A n o th e r probiem leading to increased m o rt a lity am ong tw in s is tw in -tw in tra n s fu s ió n syndrom e, w h ich occurs in 15% o f m onocho rionic m o n o zyg o tic pregnancies. In th is c ond itio n , placental vascular ana stom oses, w h ich occur in a balanced a rra n g e m e n t in m ost m on o ch o rio n ic placentas, are form ed, so th a t one tw in receives m o st o f th e blood flow , and flo w to th e o th e r is com prom ised. As a result, one tw in is la rge r th a n th e o th e r (Fig. 8.21). The ou tco m e is poor, w ith th e dea th o f bo th tw in s occurring in 5 0 % to 70% o f cases. A t la te r stages o f d eve lopm ent, partial s p iittin g o f th e p rim itiv e node and s tre a k m ay re s u lt in fo rm a tio n o f conjoin ed tw in s. These FIGURE 8.20 Fetus papyraceus. One tw in is larger, and the other has been compressed and mummified, henee, the term papyraceus. _isr tw in s are classified according to th e nature and degree o f th e ir unión (Figs. 8.22 and 8.23). O ccasionally, m o n o z y g o tic tw in s are conn ected o niy by a com m o n skin bridg e or by a com m o n liver bridge. The ty p e o f tw in s fo rm e d depends on w hen and to w h a t e x te n t a b n o rm a litie s o f th e node and s tre a k occurred. M isexpression o f genes, such as GOOSECOID, m ay aiso re s u lt in conjoin ed tw in s. M any co n jo in e d tw in s have survived , in cluding th e m ost fa m o u s pair, Chang and Eng, w h o w e re jo ined a t th e abd om e n and w h o tra v e le d to England and th e United S tates on e x h ib itio n s in th e m id-1800 s. Finally s e ttíin g in N orth Carolina, th e y fa rm e d and fa th e re d 21 c hildren w ith th e ir tw o wives. In b ro th e r-s is te r pairs o f d iz y g o tic tw in s , te s to s te ro n e fro m th e m ale tw in can a ffe c t d e v e lo p m e n t o f th e fem ale. Thus, fem a les in such pairs te n d to have squa re jaw s, la rge r te e th , p e rfo rm b e tte r on s p a c ia l-a b ility te s ts and have b e tte r ball skills th a n m o s t giris. They are 15% less likely to g e t m arried and th e y have fe rtility problem s, producing 25% fe w e r children. FIGURE 8.21 Monozygotic tw ins w ith tw in transfusión syndrome. Placental vascular anastom oses produced unbalanced blood flow to the two fetuses. (continued) 1 2 I _ P art I General Embryology Pygopagus Craniopagus FIGURE 8.22 Thoracopagus, pygopagus, and craniopagus tw ins [pagus; fastened], Conjoined tw ins can be separated oniy if they have no vital parts in common. FIGURE 8.23 Examples o f conjoined twins. A. Dicephalus (two heads). B. Craniopagus Ooined a tth e head). Clinical Correlates P reterm Birth Factors in itia tin g la bor are n o t know n and m ay in volve “re tre a t fro m m aintenance of pregnancy," in w h ich p re g n a n c y -s u p p o rtin g fa c to rs (e.g., horm ones) are w ith d ra w n , or active induction caused by s tim u la to ry fa c to rs ta rg e tin g th e uterus. Probably, c o m p o n e n ts o f both phenom ena are involved. U n fo rtu n a te ly , a lack o f know led ge a b o u t these fa c to rs has res tric te d progress in pre ve n tin g preterm birth. P reterm b irth (delivery b efore 37 c om ple ted weeks) o f prem atu re in fa n ts occurs in app ro x im a te ly 12% o f b irth s in th e United S tates and is a leading cause o f in fa n t m o rta lity and aiso c o n trib u te s s ig n ific a n tly to m o rb id ity. It is caused by p re te rm PROM, p re m a tu re onse t o f labor, or pregna ncy c o m p lic a tio n s requiring p re m a tu re delivery. Risk fa c to rs in clude p revious p re te rm birth ; black race; m ú ltip le ge sta tions; in fe ctio n s, such as p e rio d o n ta l disease and bacterial vaginosis; and lo w m aternal b od y m ass Índex. Chapter 8 Third Month to Birth: The Fetus and Placenta SUMMARY The fetal period extends from the nínth week o f gestation until birth and is characterized by rapid growth o f the body and maturation o f organ systems. Growth in length is particularly striking during the third, fourth, and fifth months (approximately 5 cm per m onth), whereas increase in weight is m ost striking during the last 2 months o f gestation (approximately 700 g per month) (Table 8.1, p. 105). M ost babies weigh between 2,700 and 4,000 g (6 to 9 Ib) at birth. Those babies weighing < 2 ,5 0 0 g (5 Ib 8 oz) are considered lew birth weight; those below 1,500 g (3 Ib 5 oz) are considered very low birth weight. lU G R is a term applied to babies who do not achieve their genetically determined potential size and are pathologically small. This group is distinct from babies that are healthy but are below the lOth percentile in weight for their gestational age and are classified as SGA. A striking change is the relative slowdown in the growth o f the head. In the third month, it is about half the size o f the CRL. By the fifth month, the size o f the head is about one third o f the CHL, and at birth, it is one quarter o f the CHL (Fig. 8.2). During the fifth m onth, fetal movements are clearly recognized by the mother, and the fetus is covered with fine, small hair. A fetus born during the sixth or the beginning of the seventh month has difficulty surviving, mainly because the respiratory and central nervous systems have not differentiated suíficiently. In general, the length of pregnancy for a fuUterm fetus is considered to be 280 days, or 40 weeks after onset of the last menstruation, or, more accurately, 266 days or 38 weeks after fertilization. The placenta consists o f two components: (1) a fetal portion, derived from the chorion frondosum or viUous chorion, and (2) a maternal portion, de rived fi'om the decidua basalis. The space between the chorionic and decidual plates is filled with intervillous lakes of maternal blood. Villous trees (fetal tissue) grow into the maternal blood lakes and are bathed in them. The fetal circulation is at all times separated from the maternal circulation by (1) a syncytial membrane (a chorion derivative) and (2) endothelial cells from fetal capillaries. Henee, the human placenta is of the hemochorial type. Intervillous lakes o f the fuUy grown placenta contain approximately 150 mL of maternal blood, which is renewed three or four times per minute. The villous area varíes from 4 to 14 m^, facilitating exchange between mother and child. JE l Main functions o f the placenta are (1) exchange o f gases; (2) exchange o f nutrients and electrolytes; (3) transmission o f maternal antibodies, providing the fetus with passive immunity; (4) production o f hormones, such as progesterone, estradiol, and estrogen (in addition, it produces hCG and somatomammotropin); and (5) detoxification o f some drugs. The amnion is a large sac containing amniotic fluid in which the fetus is suspended by its umbili cal cord. The fluid (1) absorbs jolts, (2) allows for fetal movements, and (3) prevents adherence o f the embryo to surrounding tissues. The fetus swallows amniotic fluid, which is absorbed through its gut and cleared by the placenta. The fetus adds uriñe to the amniotic fluid, but this is mostly water. An excessive amount o f amniotic fluid (hydramnios) is associated with anencephaly and esophageal atresia, whereas an insufficient amount (oligohydramnios) is related to renal agenesis. The umbilical cord, surrounded by the am nion, contains (1) two umbilical arteries, (2) one umbilical vein, and (3) W harton jelly, which serves as a protective cushion for the vessels. Fetal membranes in twins vary according to their origin and time o f formation. Two thirds o f twins are dizygotic, or fraternal; they have two amnions, two chorions, and two placentas, which sometimes are fused. Monozygotic twins usually have two amnions, one chorion, and one placenta. In cases o f conjoined twins, in which the fetuses are not entirely split from each other, there is one amnion, one chorion, and one placenta. Signáis initiating parturition (birth) are not clear, but preparation for labor usually begins between 34 and 38 weeks. Labor itself consists o f three stages: (1) effacement and dilatation o f the cervix, (2) delivery o f the fetus, and (3) delivery o f the placenta and fetal membranes. Problems to Solve 1. An ultrasound at 7 m onths’ gestation shows too much space (fluid accumulation) in the amniotic cavity. W hat is this condition called, and what are its causes? 2. Later in her pregnancy, a woman realizes that she was probably exposed to toluene in the workplace during the third week o f gestation but tells a fellow worker that she is not con cerned about her baby because the placenta protects her infant from toxic factors by acting as a barrier. Is she correct? CHAPTER Birth Defects and Prenatal Diagnosis BIRTH DEFECTS B irth defect, congenital m alform ation, and congenital anom aly are synonymous terms used to describe structural, behavioral, ftinctional, and metabolic disorders present at birth. Terms used to describe the study o f these dis orders are teratology (Gr. teratos; monster) and dysmorphology. Dysmorphologists are usually within a department o f chnical genetics. M ajor structural anomalies occur in approximately 3% o f liveborn infants and birth defects are a leading cause o f infant mortaUty, accounting for approximately 25% o f infant deaths. They are the fifth leading cause o f years o f potential life lost prior to age 65 and a m ajor contributor to disabilities. They are also nondiscriminatory; the frequencies o f birth defects are the same for Asians, African Americans, Latin Americans, Whites, and Native Americans. The causes o f birth defects fall into three categories: those that are caused by environmental FIGURE 9.1 Pie chart showing the contributions of various fac tors to the causes of birth defects. Approxim ately 15% will have purely environmental causes, such as drugs, environmental pollutants, infectious diseases, and maternal diseases, such as diabetes, phenylketonuria, obesity, etc.; 30% v^ill be purely genetic, including chromosomal abnorm alities and single gene m utations; and 55% w ill be m ultifactorial and will involve gene teratogen interactions. This latter group also includes birth defects of unknown origin. factors (15% ), those caused by genetic factors (30% ), and those caused by an interaction o f the environment with a person’s genetic susceptibility. M ost birth defects fall into this last category (55% ), and for most o f these congenital malformations, details o f their origin are unknown (F ig.9.1). M in o r an om alies occur in approxim ately 15% o f newborns. These structural abnorm alities, such as m icrotia (sm all ears), pigmented spots, and short palpebral fissures, are n ot themselves detrim ental to health but, in some cases, are associated with m ajor de fects. For example, infants with one m inor anomaly have a 3% chance o f having a m ajor m alform ation; those with two m inor anom a lies have a 10% chance; and those with three or m ore m inor anom alies have a 20% chance. Therefore, m inor anom alies serve as clues for diagnosing m ore serious underlying defects. In particular, ear anom alies are easily recognizable indicators o f other defects and are Chapter 9 Birth Defects and Prenatal Diagnosis jn i Risk of Birth Defects Being Induced Embryonic Period W eeks G e s ta tio n FIGURE 9.2 Grapli showing tlie times in gestation versus the risl 2 5 ,0 0 0 lU ) is controversial, but the amount o f vitamin A typicaUy contained in multivitamins (2,000 to 8,000 lU ) is below these doses, unless an individual takes more than one multivitamin a day. Other drugs with teratogenic potential include the anticonvulsants diphenylhydantoin (phenytoin), valproic acid, and trimethadíone, which are used by women who have seizure disorders. Specifically, trimethadione and di phenylhydantoin produce a broad spectrum o f abnormalities that constitute distinct patterns o f dysmorphogenesis known as the trimethadione and fetal hydantoin syndromes. Facial clefts are particularly common in these syndromes. The anticonvulsant valproic acid increases the risk for several defects, including atrial septal defects, cleft palate, hypospadias, polydactyly, and craniosynostosis, but the highest risk is for the neural tube defect, spina bifida. The anticonvulsant carbamazepine also has been associated with an increased risk for neural tube defects and possibly other types o f malformations. Even newer anticonvulsant drugs like Topam ax (topiram ate) increase the risk for cleft lip and/or cleft palate. A confounding issue with these patients is the fact that they require these medications to prevent seizures. Because o f their teratogenic potential, however, the type o f drug employed and the dose should be considered to provide the best outcome for the m other and her child. Antipsychotic and antianxiety agents (m ajor and m inor tranquilizers, respectively) are suspected producers o f congenital malfor mations. The antipsychotics phenothiazine and lithium have been implicated as teratogens. Although evidence for the teratogenicity o f phenothiazines is conflicting, an association between lithium and congenital heart defects, especially Ebstein anomaly, is better documented, although the risk is small. Antidepressant drugs that work as selective serotonin reuptake inhibitors (SSRIs) including fluoxetine (Prozac), paroxetine (Paxil), sertraline (Zoloft), citalopram (Celexa), and escitalopram (Lexapro) have been linked by epidemiological studies to múltiple birth defects, presumably because o f serotonin’s role in estabhshing the leftright axis (laterality; see Chapter 5, p. 62). The heart is particularly sensitive because o f its complex laterality, and many types o f heart defects have been observed in infants born to mothers taking the drugs. Even malformations in the midline, such as neural tube defects, cleft palate, and anal atresia have been associated with exposure to these drugs, which animal studies have demonstrated may be due to disruption o f coordinated signaling essential to establishing the cranial-caudal and left-right axes o f the embryo (see Chapter 5, p. 59; Chapter 13, p. 175). Opioid medications such as codeine, hydrocodone, and oxycodone are used to treat severe pain, and both their use and abuse have been increasing in recent years. Epidemiology studies demónstrate an association with the use o f these drugs and neural tube defects, heart defects, and gastroschisis (an abdominal wall defect). Mycophenolate mofetU (MMF) is an immunosuppressant drug used to prevent rejection in organ transplant patients. Use o f the drug in pregnancy has resulted in spontaneous abortions and birth defects, including cleft lip and palate, m icrotia (small ears), microcephaly, and heart defects. The anticoagulant warfarin is teratogenic. Infants born to mothers with first trimester exposures typically have skeletal abnormalities, including nasal hypoplasia, abnormal epiphyses in their long bones, and limb hypoplasia. In contrast, the anticoagulant heparin does not appear to be teratogenic. Antihypertensive agents that inhibit angiotensin-converting enzyme (ACE inhibitors) produce growth retardation, renal dysfunction, fetal death, and oligohydramnios if exposures occur during the second or third trimester. EfFects o f exposure to these compounds in the ñrst trimester are less clear. Caution has also been expressed regarding a number o f other compounds that may damage the embryo or fetus. The most prominent among these are propylthiouracil and potassium iodide (goiter and intellectual disability), streptomycin (hearing loss), sulfonamides (kernicterus), the antidepressant imipramine (limb deformities), tetracyclines (bone and tooth anomalies), amphetamines (oral clefts and cardiovascular abnormalities), and quinine (hearing loss). Chapter 9 Birth Defects and Prenatal Diagnosis _ E E I lllicit Drugs, Alcohol, and Cigarettes One o f the problems in today’s society is the eífect o f m aternal use o f social drugs, such as lysergic acid diethylamide (LSD ), phencyclidine (PC P) or “ángel dust”, m arijuana, cocaine, alcohol, and tobáceo on em bryonic and fetal development. In the case o f LSD, lim b abnorm alities and m alform ations o f the central nervous system have been reported. A com prehensive review o f m ore than 100 pubhcations, however, led to the conclusión that puré LSD used in m oderate doses is not teratogenic and does not cause genetic damage. A similar lack o f conclusive evidence for teratogenicity has been described for m arijuana and PCP. Cocaine use has been linked to premature labor, intrauterine growth retardation, and spontaneous abortion. Also, m alformations o f the heart, genitourinary system, and brain have been observed in babies whose mothers used cocaine, and there may be long-term effects on behavior. One difíiculty in assessing the drug’s eífects is the fact that women who use cocaine often use other drugs as well, especially alcohol. There is a well-documented association between maternal alcohol ingestión and congeni tal abnormalities. Because alcohol may induce a broad spectrum o f defects, ranging from intel e ctu a l disability to structural abnormalities o f the brain (microcephaly, holoprosencephaly), face, and heart, the term fetal alcohol spectrum dísorder (FASD) is used to refer to any alcohol-related defects. Fetal alcohol syndrome (FAS) represents the severe end o f the spec trum and includes structural defects, growth deficiency, and intellectual disability (Fig. 9.6). Alcohol-related neurodevelopm ental disorder (ARND) refers to cases with evidence o f involvement o f the central nervous system that do not meet the diagnostic criteria for FAS. The incidence o f FAS and ARND together has been estimated to be I in 100 live births. Furthermore, alcohol is the leading cause o f intellectual disability. It is n ot clear how much alcohol is necessary to cause a developmental problem. The dose and timing during gestation are both critical, but there is probably no “safe” level. Fven binge drinking ( > 5 drinks per sitting) at a critical stage o f development appears to increase the risk for birth defects, including orofacial clefts. FIGURE 9.6 Cliaractehstic features of a child w itli FAS, including an indistinct philtrum, thin upper lip, depressed nasal bridge, short nose, and fíat midface. Cigarette smoking has been linked to an increased risk for orofacial clefts (cleft lip and cleft palate). It also contributes to intrauterine growth retardation and premature delivery. Hormones A n d ro g e n ic A g ents In the past, synthetic progestins were frequently used during pregnancy to prevent abortion. The progestins ethisterone and norethisterone have considerable androgenic activity, and many cases o f masculinization o f the genitalia in female embryos have been reported. The abnor malities consist o f an enlarged clitoris associated with varying degrees o f fusión o f the labioscrotal folds. En d o c r in e D is r u p t e r s Endocrine disrupters are exogenous agents that interfere with the norm al regulatory actions o f horm ones controlling developmental processes. M ost commonly, these agents in terfere with the action o f estrogen through its receptor to cause developmental abnormalities o f the central nervous system and reproductive tract. For some tim e, it has been known that the synthetic estrogen diethylstUbestrol iES|_ Part I General Embroyology (D ES), which was used to prevent abortion, raised the incidence o f carcinom as o f the va gina and cervix in women exposed to the drug in Utero. Furtherm ore, a high percentage o f these women had reproductiva dysfunction caused in part by congenital malformations o f the uterus, uterine tubes, and upper vagina. Male embryos exposed in útero can also be aífected, as evidenced by an increase in m al form ations o f the testes and abnormal sperm analysis among these individuáis. In contrast to women, however, m en do not demónstrate an increased risk o f developing carcinom as o f the genital system. Today, environmental estrogens are a con cern, and numerous studies to determine their effects on the unborn are under way. Decreasing sperm counts and increasing incidences o f testicular cáncer, hypospadias, and other abnormalities o f the reproductiva tract in humans, together with documented central nervous sys tem abnormalities (masculinization o f female brains and feminization o f male brains) in other species with high environmental exposures, have raised awareness o f the possible harmful effects o f these agents. Many are formed from chemicals used for industrial purposes and from pesticides. O r a l Co n t r a c e p t iv e s Birth control pills, containing estrogens and progestogens, appear to have a low teratogenic potential. Because other hormones such as DES produce abnormalities, however, use o f oral contraceptives should be discontinued if pregnancy is suspected. CORTISONE Experimental work has repeatedly shown that cortisone injected into mice and rabbits at certain stages o f pregnancy causes a high percent age o f cleft palates in the oífspring. Some recent epidemiologic studies also suggest that women who take corticosteroids during pregnancy are at a modestly increased risk for having a child with an orofacial cleft. In Vitro Fertilization Evidence from several studies indicates that in v itro fertilization techniques are associated with an increase in birth defects and that these rates are higher with in tracy to plasm ic sperm injection (IC SI) procedures. Furtherm ore, any treatm ent for infertiUty, whether chem ical induction o f ovulation or in vitro fertiUzation, is associated with an in creased risk for stillbirths, low birth weight, and prematurity. M aternal Disease D iabetes Disturbances in carbohydrate metabolism dur ing pregnancy in diabetic mothers cause a high incidence o f stillbirths, neonatal deaths, abnormally large infants, and congenital malfor mations. The risk o f congenital anomahes in children born to mothers with pregestational diabetes (diabetes diagnosed before pregnancy; both type 1 [insulin dependent] and type 2 [non-insulin dependent]) is three to four times that for offspring o f nondiabetic mothers and has been reported to be as high as 80% in the offspring o f diabetics with long-standing dis ease. The increased risk is for a wide variety o f malformations, including neural tube defects and congenital heart defects. There is also a higher risk for caudal dysgenesis (sirenomelia: see Fig. 5.8, p. 65). Factors responsible for these abnormalities have not been delineated, although evidence suggests that altered glucose leveis play a role and that insulin is not teratogenic. In this respect, a significant correlation exists between the severity and duration o f the m other’s disease and the incide

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