sequence of the expansion of this epithelium over structures that are
membrane. In the folded embryo, this region becomes superior to the
enlarging rapidly as development proceeds. After the surface ectoderm
cloacal membrane and corresponds to the ectoderm associated with the
has completed a number of early interactions it forms the periderm,
external genitalia, particularly the genital tubercle and urogenital swell
which remains throughout fetal life and differentiates into epidermis.
ings, where it influences the internal and external descent of the testis
and the formation of the inguinal canal.
Ectodermal ring and ectodermal placodes
The ectoderm on the head and lateral borders of the embryo shows a Neural ectoderm
zone of epithelial thickening, the ectodermal ring, which can be dis The neuroepithelium at the time of primary neurulation is pseudos
cerned from stage 10 and is completed by stage 12. Rostrally, it contains tratified. It has a midline hinge region, which, with concomitant
populations of neuroectoderm that remain in the ectoderm after wedging of the cells in the lateral wall of the neural groove, promotes
primary neurulation and are termed ectodermal placodes; these pla neural tube formation. The processes of the neuroepithelium abut on
codes may be considered to be neuroepithelial cells that remain within to internal and external limiting membranes. This epithelium prolifer
the surface ectoderm until central nervous system development has ates to form all the cell lines of the central nervous system and, via the
progressed sufficiently for their inclusion into sensory epithelia and production of neural crest, all the cell lines of the peripheral nervous
cranial nerve ganglia. The neuronal placodes may invaginate in toto to system.
form a vesicle, or remain as a neuronal layer, or contribute individually
Notochord
to neuronal structures with cells of other origins. The midline ectoder
mal thickening, the adenohypophysial placode, invaginates as Rathke’s During stage 10, the notochordal plate undergoes a process that is
pouch and forms a vesicle immediately rostral to the buccopharyngeal similar to, but a mirror image of, neurulation, and forms an epithelial


membrane. The ectodermal ring then passes bilaterally to encompass tube from caudal to rostral, ending with the pharynx. The notochordal
the olfactory and optic placodes, which give rise to the olfactory sensory plate forms a deep groove, the vertical edges of the groove move medi
epithelium and the lens of the eye, respectively. It then overlays the ally and touch, and then the endodermal epithelium from each side
pharyngeal arches, where it gives rise to epibranchial placodes; these fuses ventral to the notochord. The cells swell and develop an internal
remove themselves individually from the ectoderm at stage 10–11 and pressure (turgor) that confers rigidity on the notochord. The notochord
become associated with the neural crest cells within the cranial sensory is surrounded by a basal lamina, which is initially referred to as a peri
ganglia supplying the arches. It also forms specializations of the ecto notochordal sheath; this term is subsequently applied to mesenchymal
derm on the frontonasal, maxillary and mandibular processes, which populations that surround the notochord. After stage 11, the tubular
give rise to the tooth buds and the outer coating of the teeth. The paired notochord is in contact with the neural tube dorsally and the endoderm
otic placodes overlying the rhombencephalon at the lateral portion of ventrally. It is not a proliferative epithelium, but it has inductive effects
the second pharyngeal arch invaginate to form the otic vesicles, which on the overlying neural tube and the adjacent somites, and later pro
give rise to the membranous labyrinth of the ear. The ectodermal ring vides a focus for sclerotomal migration.


embryonic cell populations at the start of organogenesis
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A
Buccopharyngeal membrane
Prechordal mesenchyme
Unsegmented paraxial
mesenchyme C
Lateral plate mesenchyme Notochord (i)
Neural crest mesenchyme
Aorta
Unsegmented paraxial mesenchyme
Cloacal membrane Gut
Proliferative coelomic epithelium Endocardium
Pericardial cavity Developing myocardium
B
(ii)
Neural crest mesenchyme Notochordal plate
Paraxial mesenchyme
Aorta
(i)
Pericardial Neural tube Prolifer ca oti ev le o mso icm ea pto ithp ele lu iur mic Gut
cavity Pericardioperitoneal canal
Pharynx
(ii) Endothelium of sinus venosus
Amnion Septum transversum
mesenchyme
Pericardio-
(iii)
peritoneal
canal
(iii)
Somite Epithelial somite Neural crest mesenchyme
Yolk sac wall
Aorta
Notochordal plate
En pt er ra icn ac re d t ioo - (iv) Proliferative Pericardioperitoneal canal
splanchnopleuric
peritoneal canal
epithelium
Left Gut
umbilical vein
Midgut
(iv)
Neural crest mesenchyme Notochordal plate
Epithelial somite Aorta
Umbilical cord Region of intermediate Proliferative somatopleuric
mesenchyme coelomic epithelium
Gut
Proliferative splanchnopleuric
Intraembryonic coelom
coelomic epithelium
(peritoneal cavity)
Fig. 12.2 A, Mesoblast populations within the early embryonic disc. B, A stage 11 embryo, showing the position of the intraembryonic coelom
(contained by the walls coloured blue) and the positions of the sections (i)–(iv) shown in C. C, Transverse sections, arranged cranial to caudal, from a
stage 11 embryo; the populations of mesenchyme and the sites of mesenchymal proliferation are indicated.
Endoderm Somites


The craniocaudal progression of development means that the endo Somites are discrete epithelial spheres formed by the transformation of
derm of the early stomodeum develops ahead of other portions of the paraxial mesoblast cells to epithelium once their migration is complete.
endodermal epithelium. The development of the pharyngeal arches and Specific regions of the somitic epithelium form local proliferative
pouches (Ch. 36) is closely associated with the development of the centres and, like neural and coelomic epithelium, it produces cells
neural ectoderm and proliferation of the neural crest. The respiratory destined for different fates, at different developmental times. Somites
diverticulum arises slightly later, when the postpharyngeal gut may can be seen on each side of the fusing neural tube in the human embryo
also be distinguished. The endoderm gives rise to the epithelial lining from stage 9. Development proceeds in a craniocaudal direction. The
of the respiratory and gastrointestinal tracts, the biliary system, and the original epithelial somites form the base of the skull, and the vertebral
bladder and urethra. column and ribs; the dorsolateral portion, the dermomyotome, gives
rise to the majority of the skeletal muscle of the body, including that
Coelomic epithelium in the limbs.
The relative dispositions of the neural, endodermal and coelomic
The coelomic epithelium lines the intraembryonic coelom, which is
epithelia are shown in Figure 12.1.
subdivided into a midline pericardial cavity, two bilateral pericardio
peritoneal canals, and the initially bilateral peritoneal cavities; the
Mesenchymal populations in the embryo
latter are continuous with the extraembryonic coelom. The coelomic
epithelium is a germinal epithelium. It produces the myocardium
and connective tissue populations for the viscera, and also gives rise to In the stage 10 embryo, the major mesenchymal populations are in
the supporting cells for the germ cells, the epithelial lining of the uro place. Mesoblast is still being generated at the primitive streak and


genital tracts, and the mesothelial lining of the pericardial, pleural and moving into the presomitic mesenchymal population adjacent to the
peritoneal cavities. notochord. Some mesoblast is also contributing to the lateral regions


Cell populations at the start of organogenesis
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2
noitCes
Endoderm epithelium Coelomic wall epithelium Mesenchyme
Primitive gut Walls of intraembryonic coelom Paraxial mesenchyme
(somites and somitomeres)
Foregut – recesses, diverticula and glands of the Primitive pericardium – myocardium, parietal Sclerotome – vertebrae and portions of the
pharynx. pericardium. neurocranium, axial skeleton.
Pericardioperitoneal canals – visceral, parietal Myotome – all voluntary muscles of the head, trunk
General mucous glandular and duct-lining cells and and mediastinal pleura, pleuroperitoneal and limbs.
the main follicular cells of the thyroid. membranes contributing to diaphragm. Dermatome – dermis of skin over dorsal regions.
Intermediate mesenchyme – connective tissue of
Epithelium of pharyngeal pouches (tonsil, middle Splanchnopleuric epithelium – visceral peritoneum gonads, mesonephric and metanephric nephrons,
ear cavity, thymus, parathyroids 3 and 4, C cells of of stomach, peritoneum of lesser and greater smooth muscle and connective tissues of the
thyroid), adenoids, epithelial lining of the auditory omenta, falciform ligament, lienorenal and reproductive tracts.
tube, tympanic cavity, tympanic antrum, internal gastrosplenic ligaments. Septum transversum – epicardium, fibrous
lamina of the tympanic membrane.
Somatopleuric epithelium – parietal peritoneum. pericardium, portion of diaphragm, oesophageal
mesentery, sinusoids of liver, tissue within lesser
Respiratory tract – epithelial lining, secretory and Primitive peritoneal cavity omentum and falciform ligament.
duct-lining cells of the trachea, bronchi, bronchioles
Splanchnopleuric epithelium – visceral peritoneal
and alveolar sacs. Lateral plate mesenchyme
covering of mid- and hindgut, the mesentery, Splanchnopleuric layer – smooth muscle and


Epithelial lining, secretory and duct-lining cells of transverse and sigmoid mesocolon. connective tissues of respiratory tract and
the oesophagus, stomach and duodenum. Pronephros, epithelial lining of mesonephric ducts, associated glands.
vas deferens, epididymis, seminal vesicles, Smooth muscle and connective tissues of intestinal
Hepatocytes of liver, biliary tract, exocrine and ejaculatory duct, ureters, vesical trigone. tract, associated glands and abdominal mesenteries.
endocrine cells of the pancreas.
Müllerian ducts, epithelial lining of uterine tubes, Smooth muscle and connective tissue of blood
Midgut – epithelial lining, glandular and duct-lining body and cervix of uterus, vagina, broad ligament of vessels (also see below).
cells of the duodenum, jejunum, appendix, caecum, uterus. Somatopleuric layer – appendicular skeleton,
part of transverse colon. connective tissue of limbs and trunk, including
Germinal epithelium of gonad (note the germ cells cartilage, ligaments and tendons.
are not included on this chart because of their early
Hindgut – epithelial lining, glandular and sequestration into the extraembryonic tissues). Dermis of ventral body wall and limbs.
duct-lining cells of part of the transverse, Mesenchyme of external genitalia.
descending and sigmoid colon, rectum, upper part Germinal epithelium forming cortex of suprarenal
Angiogenic mesenchyme
of anal canal. gland.
Endocardium of heart, endothelium of blood and
Allantois – urinary bladder, vagina, urethra, Somatopleuric epithelium – parietal peritoneum, lymphatic vessels, vessels of choroid plexus,
secretory cells of the prostate and urethral glands. tunica vaginalis of testis. sinusoids of liver and spleen, circulating blood cells,
microglia, tissue macrophages.
Surface ectoderm epithelium Neural plate epithelium Neural crest
Ectodermal placodes CNS – Brain and spinal cord Neural derivatives
Adenohypophysis. Neurohypophysis. Sensory neurones of the cranial ganglia V, VII, VIII, IX, X.
Sensory neurones of the spinal dorsal root ganglia and


Sensory neurones of the cranial ganglia V, VII, VIII, IX, X. Prosencephalon (telencephalon and diencephalon) their peripheral sensory receptors.
Olfactory receptor cells and olfactory epithelium. – cerebral hemispheres, basal nuclei. Satellite cells in all sensory ganglia.
Epithelial walls of the membranous labyrinth, the Mesencephalon – cerebral peduncles, tectum, Sympathetic ganglia and plexuses: neurones and
cochlear organ of Corti. tegmentum. satellite cells.
Lens of the eye. Rhombencephalon (metencephalon and P saa tr ea ls lity em cp ea llt sh .etic ganglia and plexuses: neurones and
Enamel organs of the teeth. myelencephalon) – cerebellum, pons, medulla
oblongata. Enteric plexuses: neurones and glial cells.
Cranial structures Schwann cells of all the peripheral nerves.
Secretory and duct-lining cells of the lacrimal, Spinal cord. Medulla of the suprarenal gland. Chromaffin cells.
nasal, labial, palatine, oral and salivary glands.
Carotid body type I cells (and type II, satellite type cells).
Epithelia of the cornea and conjunctiva. All cranial and spinal motor nerves. Calcitonin-producing cells (C cells).
Epithelial lining of the external acoustic meatus and All CNS neurones, including preganglionic efferent Melanocytes.
external epithelium of the tympanic membrane. neurones, with somata within the CNS. Mesenchymal derivatives in the head
Frontal, parietal, squamous temporal, nasal, vomer,
Epithelial lining of the lacrimal canaliculi and Astrocytes and oligodendrocytes. palatine bones, maxillae and mandible.
nasolacrimal duct. Meninges.
Ependyma lining the cerebral ventricles, aqueduct Choroid and sclera of eye.
Epithelial lining of the paranasal sinuses, lips, and central canal of brain and spinal cord,
cheeks, gums and palate. tanycytes, cells covering the choroid plexuses, Connective tissue of lacrimal, nasal, labial, palatine,


circumventricular cells. oral and salivary glands.
Epidermal structures Dentine of teeth.
Most of the cutaneous epidermal cells, the Retina and optic nerve (II), epithelium of the iris, Connective tissues of head, including cartilage,
secretory, duct-lining and myoepithelial cells of the ciliary body and processes. ligaments and tendons.
sweat, sebaceous and mammary glands.
Connective tissues of thyroid gland and of the
Hair and nails. pharyngeal pouches, i.e. parathyroid glands, thymus.
Tunica media of the outflow tract of the heart and the
Proctodeal epithelium and epithelium of the
great vessels.
terminal male urethra.
Fig. 12.3 Structures that will be derived from specific epithelial and mesenchymal populations in the early embryo. Abbreviation: CNS, central nervous
system.


embryonic cell populations at the start of organogenesis
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21
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of the embryo. The different mesenchymal populations within the the primitive streak, none of the cells that arise from the neural crest
embryo from stage 10 onwards are described below. The relative become arranged as epithelia. The development and fate of head and
dispositions of the early mesenchymal populations are shown in trunk neural crest cells are very different and therefore they will be
Figure 12.2. considered separately.
Axial mesenchyme head neural crest
The first epiblast cells to ingress through the primitive streak form the Head neural crest migrates before the neural tube closes. Two popula
endoderm and notochord, and initially occupy a midline position. The tions of crest cells develop. Some retain a neuronal lineage and con
earliest population of endodermal cells rostral to the notochordal plate tribute to the somatic sensory and parasympathetic ganglia in the head
is termed the prechordal plate. The notochordal cells remain medially and neck. Others produce extensive mesenchymal populations; the
and the endodermal cells subsequently flatten and spread laterally. The crest cell population arising from the head is larger than that found at
population of cells that remain mesenchymal in contact with the floor any trunk level. Each brain region has its own crest population that
of the neural groove, just rostral to the notochordal plate, is termed migrates dorsolaterally around the sides of the neural tube to reach the
prechordal mesenchyme (Fig. 12.4). These axial mesenchyme cells are ventral side of the head. Crest cells surround the prosencephalic and
tightly packed, unlike the more lateral paraxial cells but, unlike the optic vesicles, and occupy each of the pharyngeal arches (Ch. 36). They
notochord, they are not contained in an extracellular sheath. They are provide mesenchyme cells that will produce the connective tissue in
displaced laterally at the time of head flexion and form bilateral pre parts of the neuro and viscerocrania. All cartilage, bone, ligament,
mandibular mesenchymal condensations. They become associated with tendon, dermal components and glandular stroma in the head are


the local paraxial mesenchyme. Orthotopic grafting has demonstrated derived from the head neural crest. Head neural crest also contributes
that these cells leave the edges of the prechordal mesenchyme and to the tunica media of the aortic arch arteries.
migrate laterally into the periocular mesenchyme, where they give rise
to all of the extrinsic ocular muscles. trunk neural crest
Unlike its counterpart in the head, trunk neural crest is formed as the
Paraxial mesenchyme neural tube closes craniocaudally, which means that various stages of
Paraxial mesoblast is a transient structure that forms somites at its crest development can be found in the more caudal regions of an
cranial end, whilst unsegmented mesoblast is added caudally by the embryo. As the neural tube begins to fuse dorsally in the midline, the
primitive streak. Epiblast cells that migrate through the primitive node neural crest cells lose their epithelial characteristics and junctional con
and rostral primitive streak during gastrulation form mesoblast cells nections, and form a band of loosely arranged mesenchyme cells imme
that migrate to a position lateral to the notochord and beneath the diately dorsal to the neural tube and beneath the ectoderm. Initially,
developing neural plate. Cells that ingress through the primitive node most of the crest cells lie with their long axes perpendicular to the long
form the medial part of this paraxial mesoblast, and cells that ingress axis of the neural tube. Later, the cell population expands laterally and
through the rostral streak form the lateral part (see Fig. 10.3). The around the neural tube as a sheet. Trunk neural crest cells move from
paraxial mesoblast extends cranially from the primitive streak to the their position dorsal to the neural tube via three routes (see Fig. 17.11):
prechordal plate, which is immediately rostral to the notochord. Before dorsolaterally, to form dorsal root ganglia throughout the trunk; ven
somite formation, this mesenchymal tissue is also termed presomitic trally, to form sympathetic ganglia, enteric nerves and the suprarenal
or unsegmented mesenchyme in mammals (analogous to the segmen medulla; and rostrocaudally, along the aorta, to form the preaortic


tal plate in birds). Paraxial mesoblast rostral to the otic vesicle was ganglia. In a second migration route, crest cells pass dorsolaterally
previously believed not to segment. between the ectoderm and the epithelial plate of the somite into the
Caudal to the otic vesicle, the paraxial mesoblast on each side of the somatopleure, where they eventually form melanocytes in the skin.
rhombencephalon segments into somites as the neural folds elevate
Lateral plate
and neurulation begins; somites are therefore postotic. During somito
genesis, mesoblastic cells show changes in shape and in cell–cell adhe Lateral plate is the term for the early unsegmented mesoblast popula
sion, and become organized into epithelial somites; this process begins tion lateral to the paraxial mesenchyme. Mesoblastic cells, which arise
at the eighth somitomere, just caudal to the midpoint of the noto from the middle of the primitive streak (primary mesenchyme), migrate
chordal plate. Somite one is also termed the first occipital somite. The cranially, laterally and caudally to reach their destinations, where they
post otic paraxial cell population is termed paraxial mesoderm in con revert to epithelium and form a continuous layer that adheres to the
temporary literature. ectoderm dorsally and the endoderm ventrally. The epithelium faces a
Skeletal muscle throughout the body is derived from paraxial new intraembryonic cavity, the intraembryonic coelom, which becomes
mesoblastderived somatic epithelium, which proliferates to form confluent with the extraembryonic coelom and provides a route for the
myoblastic populations that migrate to the head, body and limbs. circulation of coelomic fluid through the embryo. Once formed, the
intraembryonic coelomic wall becomes a proliferative epithelium that
Septum transversum produces new populations of mesenchymal cells. The mesenchymal
Early mesenchyme that invaginates through the middle part of the population subjacent to the ectoderm is termed somatopleuric mesen


primitive streak comes to lie rostral to the buccopharyngeal membrane, chyme and is produced by the somatopleuric coelomic epithelium. The
where the cells form the epithelial wall of the pericardial coelom. As mesenchymal population surrounding the endoderm is termed splanch
this epithelium proliferates, the visceral pericardial wall gives rise to nopleuric mesenchyme and is produced by the splanchnopleuric coel
myocardium. The parietal pericardial wall forms mesenchyme, initially omic epithelium (see Fig. 12.2).
termed precardiac, or cardiac, mesenchyme, which is able to induce It is important to note that these terms are relevant only caudal to
proliferation of hepatic endodermal epithelium. With further prolifera the third pharyngeal arch. Rostral to this, there is a sparse mesenchymal
tion, the precardiac mesenchyme forms a ventral mass caudal to the population between the pharynx and the surface ectoderm prior to
heart, the septum transversum, separating the foregut endoderm from migration of the head neural crest, and there are no landmarks with
the pericardial coelom (see Fig. 12.2). By stage 11, the septum transver which to demarcate lateral from paraxial mesenchyme. This unsplit
sum extends dorsally on each side of the developing gut and becomes lateral plate is believed to contribute to the cricoid and arytenoid car
continuous with the mesenchymal populations that proliferate from tilages, the tracheal rings and the associated connective tissue.
the walls of the pericardioperitoneal canals. Cells of the septum trans
versum give rise to the sinusoids of the liver, the central portions of the somatopleuric mesenchyme
diaphragm and the epicardium. Somatopleuric mesenchyme produces a mixed population of connec
tive tissues and has a significant organizing effect at the level of the
Neural crest
developing limbs. The pattern of limb development is controlled by


The neural crest is unique: it gives rise to neural populations in the information contained in the somatopleuric mesenchyme. Regions of
head and trunk, and also provides an extensive mesenchymal popula the limb are specified by interaction between the surface ectoderm
tion in the head with attributes similar, in terms of patterning, to (apical ectodermal ridge) and underlying somatopleuric mesenchyme;
somatopleuric mesenchyme. Neural crest cells arise from cells that lie together, these tissues form the progress zone of the limb. The somato
initially at the outermost edges of the neural plate, between the pre pleuric mesenchyme in the limb bud also specifies the postaxial border
sumptive epidermis and the neural tube, and are committed to a neural of the developing limb. Somatopleuric mesenchyme gives rise to the
crest lineage before the neural plate begins to fold. After neurulation, connective tissue elements of the appendicular skeleton, including the
neural crest cells form a transient axial population and then disperse, pectoral and pelvic girdles and the bones and cartilage of the limbs,
in some cases migrating over considerable distances, to a variety of dif and their associated ligaments and tendons. It also gives rise to the
ferent developmental fates. Unlike mesoblast, which is produced from dermis of the skin of the ventral and lateral body walls and of the limbs.


Cell populations at the start of organogenesis
198
2
noitCes
PATTERNS OF GENE EXPRESSION
HOX-b5
HOX-b4
HOX-b3 Engrailed-2
HOX-b2
HOX-b1
HOX-a1
CRABP
RAR-β Krox 20
Wnt-1
Wnt-2
AXIAL STRUCTURES
Rhombencephalon
Otic vesicle
Rhombomeres
Mesencephalon
Spinal cord 7 6 5 4 3 2 1
Notochord Prechordal mesenchyme
Prosencephalon
Optic cup
MIGRATION OF NEURAL CREST MESENCHYME
Maxillary
Otic vesicle
Mandibular
Pharyngeal arches: 4th 3rd 2nd 1st
Frontonasal
PARAXIAL MESENCHYME
3 2 1 7 6 5 4 3 2
4
5 Somites Somitomeres 1
BRAIN AND CRANIAL MOTOR NERVES
7 6 5 4 3 2 1
XII VI IV
X IX VII V III
4th 3rd 2nd 1st
CRANIAL SENSORY AND PARASYMPATHETIC GANGLIA Neural crest shown in green and
Proximal VII (root)
ectodermal placodes in grey
Proximal X (jugular) Ciliary
Proximal IX (superior) V (trigeminal)
VIII (vestibulocochlear)
Pterygopalatine
Distal X (nodose)
Distal VII (geniculate)
Distal IX (petrosal)
Otic Submandibular
SUGGESTED ORIGIN OF STRIATED MUSCLES Prechordal mesenchyme migrates
FROM PARAXIAL MESENCHYME to form extraocular muscles
3 2 1 7 6 5 4 3 2 Lateral rectus
4 1
5 Inferior rectus
3rd arch Eye
2nd arch (hyoid) Superior rectus
Laryngeal Inferior oblique
Glossal Superior oblique
1st arch (mandibular) Medial rectus


PHARYNGEAL ARCH ARTERIES Neural crest shown in
green around great vessels
Descending aorta
4 3 2 1
Ductus arteriosus Internal carotid artery
Pulmonary artery
Pharyngeal arch arteries
Ascending aorta
ENDODERMAL PHARYNGEAL POUCHES Neural crest shown in green
around pharyngeal pouches
Inferior parathyroid
Superior parathyroid 4 3 2 1
Tubotympanic recess
Oesophagus
Thyroid
Ultimobranchial body
Pharyngeal tonsil
Lung bud
Thymus
Fig. 12.4 The organization of the head and pharynx in an embryo at about stage 14. The individual tissue components have been separated but are
aligned in register through the numbered zones.


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Key references
splanchnopleuric mesenchyme endodermal tissues are necessary for endothelial differentiation, par
Splanchnopleuric mesenchyme surrounds the developing gut and res ticularly the early foregut. Angioblastic mesenchyme forms early in
piratory tubes, contributing connective tissue cells to the lamina propria the third week of development from extraembryonic mesenchyme in
and submucosa, and smooth muscle cells to the muscularis mucosae the splanchno pleure of the yolk sac, in the body stalk (containing the
and muscularis externa. It plays a patterning role in endodermal devel allantois), and in the somatopleure of the chorion. The peripheral cells
opment, specifying the region and villus type in the gut, and the branch flatten as a vascular endothelium, whereas the central cells transform
ing pattern in the respiratory tract. into primitive red blood corpuscles. Later, contiguous islands merge,
forming a continuous network of fine vessels. Intraembryonic blood
Intermediate mesenchyme vessels are first seen at the endoderm–mesenchyme interface within the
Intermediate mesenchyme is a loose collection of cells found between lateral splanchnic mesenchyme at the caudolateral margins of the
the somites and the lateral plate (see Fig. 12.2). Its development is cranial intestinal portal. Angioblastic competence has been demon
closely related to the progress of differentiation of the somites and the strated within the ventral (splanchnopleuric) mesenchymes with which
proliferating coelomic epithelium from which it is derived. Intermedi the endoderm interacts. However, the notochord and prechordal plate
ate mesenchyme is not present before somitogenesis or the formation do not contain angiogenic cells. Similarly, ectodermal tissues do not
of the eighth somite. In embryos with 8–10 somites, it is present lateral appear to give rise to angiogenic cells. Somites, derived from paraxial
to the sixth somite but does not extend cranially. The mesenchyme cells mesenchyme, have been shown to be a source of angioblasts that either


are arranged as layers, one continuous with the dorsal side of the par differentiate with the somite derivatives, or migrate to the neural tube,
axial mesenchyme and the somatopleure, the other with the ventral side ventrolateral body wall, limb buds, mesonephros and the dorsal part
of the paraxial mesenchyme and the splanchnopleure. of the aorta.
As development proceeds, the intermediate mesenchyme forms a The earliest angiogenic mesenchymal cells form blood vessels by
loosely packed dorsolateral cord of cells, which lengthens at the caudal vasculogenesis, a process in which new vessels (e.g. endothelial heart
end and ultimately joins the cloaca. It gives rise to the nephric system, tubes, dorsal aortae, umbilical and early vitelline vessels) develop in situ
gonads and reproductive ducts. (Ch. 13). Later vessels develop by angiogenesis, sprouting and branch
ing from the endothelium of preexisting vessels; this process is the
Angioblastic mesenchyme
means by which most other vessels develop. The ultimate pattern of
Mesenchymal cells, which give rise to the cellular elements of the vessels is controlled by the surrounding, nonangiogenic mesenchyme;
blood, the endothelium and the mesenchymal layers of the tunica vessels become morphologically specific for the organ in which they
externa and adventitia of blood and lymphatic vessels, arise from develop, and also immunologically specific, expressing organspecific
extraembryonic and intraembryonic sources. Evidence suggests that proteins.
KEY REFERENCES
O’Rahilly R, Müller F 1985 The origin of the ectodermal ring in staged Richardson MK, Keuck G 2002 Haeckel’s ABC of evolution and develop
human embryos of the first 5 weeks. Acta Anat 122:145–57. ment. Biol Rev Camb Philos Soc 77:495–528.


Cell populations at the start of organogenesis
199.e1
21
retpahC
REFERENCES
O’Rahilly R, Müller F 1985 The origin of the ectodermal ring in staged Richardson MK, Keuck G 2002 Haeckel’s ABC of evolution and develop
human embryos of the first 5 weeks. Acta Anat 122:145–57. ment. Biol Rev Camb Philos Soc 77:495–528.


CHAPTER
13
Early embryonic circulation
The early embryonic circulation is symmetrical (Fig. 13.1). It is modi- guidance, where the distal tip cell extends supported by proximal stalk
fied throughout development to produce a functioning fetal circulation cells that may divide; sprout elongation in response to cues from the
that is connected to the placenta, and changes rapidly at birth to accom- extracellular matrix; lumen formation, which is initially by the conflu-
modate disconnection from the placenta and the start of gaseous ence of intracellular vacuoles, followed by establishment of apical basal
exchange in the lungs. Major restructuring of early vessels occurs as polarity of the cells of the endothelial sprout; and fusion of the tip cell
the embryo grows; anastomoses form and then disappear, capillaries to another sprout tip with confluence of the two lumina established
fuse and give rise to arteries or veins, and the direction of blood flow (Chappell et al 2012, Kuijper et al 2007). The developmental processes
may reverse several times before the final arrangement of vessels is of angiogenesis are similar to those seen in both neoplasia and acute
completed. inflammation in adult tissue. The scientific literature on angiogenesis
is extensive and the process will not be considered in detail here; the
interested reader is directed to Senger and Davis (2011), Beets et al
ANGIOGENESIS
(2013), Herbert and Stainier (2011) and Eichmann and Pardanaud
(2014).
The earliest circulatory components develop by vasculogenesis in the Studies have considered the development of capillary beds within
extraembryonic tissues. The endothelial heart tubes, dorsal aortae, the surrounding mesenchymal tissues destined to become laminae pro-
umbilical and early vitelline vessels arise by vasculogenesis within the priae, but few have looked at how capillary beds form within tissues
embryo. Further vessel development occurs by a process of angiogenesis undergoing morphogenetic movements. Czirok et al (2011) discussed
in which angioblasts, arising in splanchnic and somitic tissues, add the temporal imperative for free-living embryos to develop rapidly in
endothelial sprouts and branches to earlier vessels. None of the main contrast to amniote embryos, which do not have to fend for themselves.


vessels of the adult arises as a single trunk in the embryo. A capillary They concluded that amniote vascular patterns of development, prior
network is first laid down along the course of each vessel; the larger to the establishment of a circulation, are not predetermined by a
arteries and veins are defined by selection and enlargement of definite network of patterning genes and cell signalling pathways, but rather that
paths in this network. Lymphatic vessels develop after the main arteries the tissue movements during organogenesis and the realignment and
and veins are formed; they arise initially by angiogenesis from the car- tension that develop within extracellular matrix fibres may guide cell
dinal veins and subsequently by proliferation of lymphangioblasts to migration and the position of early vessels.
form lymphatic capillaries. Extracellular matrix plays a critical role in angiogenesis and vessel
Five stages have been described during angiogenesis: endothelial tip stabilization in the embryo and in the adult; differences in the composi-
cell specification and sprout initiation; sprout elongation and local tion and abundance of specific extracellular matrix components between
A B C Aortic sac First aortic arch
Rudiment of second
aortic arch
Left first aortic arch Left precardinal vein Otic placode
Primitive head vein
Pericardial cavity
Left common cardinal vein
Right atrium
Atrium Ventricle
Ventricle
Sinus venosus
Rudiment of common
cardinal vein
Septum transversum
Dorsal aorta
Vitelline plexus
Rudiments of
postcardinal vein
Yolk stalk (cut)
Dorsal aorta
Umbilical arteries
Left postcardinal vein
Left umbilical vein
Left umbilical artery
Fig. 13.1 The early, symmetrical blood vascular system. A, Ventrolateral view of the endothelial profile of the heart, the first aortic arch arteries and the
dorsal aorta shown in relation to the major epithelial populations. B, Ventrolateral view of the main venous channels shown in relation to the major
epithelial populations. C, Left lateral view of the blood vascular system of a stage 11 human embryo; only the endothelial lining of the heart tube is
200 shown. At this stage, the arteries and veins are in the process of development and no true circulation is yet established.


Angiogenesis
201
31
RETPAHC
A
Second aortic arch Otocyst
Third aortic arch Primary head vein
Internal carotid artery
Right atrium
Precardinal vein
Somite IV B
Second aortic arch
Right common Internal carotid artery Third aortic arch
cardinal vein
Optic Aorta
vesicle
Aorta
Truncus Truncus arteriosus Lung bud
arteriosus Right atrium
Left common
Right ventricle Left atrium cardinal vein
Left ventricle
Left ventricle Left
Developing liver sinusoids umbilical vein
in septum transversum
Right sinus horn
Right umbilical artery Left
Hepatocardiac Right vitelline vein vitelline vein
channel
Caudal Vitelline artery
Upper limb bud plexus
Primary plexus
Postcardinal vein
to intestine
Right umbilical vein
Hindgut
0.2 cm 0.2 cm
Left umbilical artery
Fig. 13.2 Profile reconstructions of the blood vascular system of a stage 13 human embryo. The early circulation is now asymmetrical; the venous
vessels are enlarging on the right and diminishing on the left. A, Seen from the right side, showing the main venous channels to the heart. B, Seen from
the left side, showing the aortic arch arteries, the main vessels arising from the dorsal aorta and umbilical arteries. Note that only the endothelial lining of
the heart chambers is shown and, because the muscular wall has been omitted, the pericardial cavity appears much larger than the contained heart.
the embryo and adult mean that there are likely to be significant dif- As the heart muscle thickens, compacts and strengthens, the cardiac
ferences in the process at different ages. Fibronectin is required for orifices become both relatively and absolutely reduced in size, the valves
normal vascular development; its deposition is related to interactions increase their efficiency, and the large arteries acquire their muscular
between endothelial cells and pericytes, and local tensional forces that walls and undergo a relative reduction in size. From this time onwards,
occur between blood vessel basement membrane and local extracellular the embryo is dependent for its nourishment on the expanding capillary


matrix assembly (Davis and Senger 2005; Senger and Davis 2011). Early beds, and the function of the larger arteries becomes restricted to that
blood vessels are initially surrounded by a fibronectin-rich matrix that of controllable distribution channels to keep the embryonic tissues
is later incorporated into the endothelial basal lamina along with constantly and appropriately supplied.
laminin, a particularly early constituent. Several layers of fibronectin- The heart starts to beat early, before the development of the conduc-
expressing cells are seen around larger vessels, such as the dorsal aortae. tion system, and a circulation is established before a competent valvular
The endothelium does not synthesize a basal lamina in those regions mechanism has formed. Cardiac output increases in proportion with
where remodelling and angiogenesis are active, and the mesenchyme the weight of the embryo and cardiac rate increases with development.
around such endothelium does not express α-actin or laminin until However, most of the increase in cardiac output results from a geomet-
branching has stopped and differentiation of the tunica media begins ric increase in stroke volume. When dorsal aortic blood flow is matched
(after a stable vascular pattern has formed). It is not known how dif- to embryonic weight, blood flow remains constant over a more than
ferentiation of pericytes and smooth muscle cells is induced; the major- 150-fold change in mass of the embryo.
ity of arteries accumulate medial smooth muscle from the surrounding After head folding, the embryo has bilateral primitive aortae, each
mesenchyme. consisting of ventral and dorsal parts that are continuous through the
Although studies have elucidated the genes involved in vasculogen- first embryonic aortic arches (Ch. 36). The ventral aortae are fused and
esis and angiogenesis, the drivers that lead to development of asym- form a dilated aortic sac. The dorsal aortae run caudally, one on each
metric vessels from an early symmetrical pattern and the specification side of the notochord. In the fourth week, they fuse from about the
of the position of particular arteries, veins and lymphatic vessels are still level of the fourth thoracic to that of the fourth lumbar segment to


not clear. In early development, the arteries of the embryo are dispro- form a single definitive descending aorta (see Fig. 13.1A,C; Fig. 13.2B).
portionately large and their walls consist of little more than a single In general, more mature endothelial channels are seen in the rostral,
layer of endothelium. The cardiac orifices are also relatively large and more advanced regions of the embryo whereas, more caudally, a
the force of the cardiac contraction is weak; consequently, the circula- changing capillary plexus constantly remodels until it becomes conflu-
tion is sluggish, despite the rapid rate of contraction of the developing ent with the vascular channels of the connecting stalk. The dorsal
heart. However, the tissues are able to draw nourishment not only from continuation of the primitive dorsal aortae directs blood into an anas-
the capillaries but also from the large arteries and the intraembryonic tomosing network around the allantois, which will form the umbilical
coelomic fluid. arteries. Blood is channelled back to the developing heart from the
It has been suggested that the rapidly expanding cardiovascular allantois via umbilical veins, from anastomoses in the primitive yolk
system is filled with plasma by the movement of fluid from the intra- sac via the vitelline veins, and from the body via pre- and postcardinal
embryonic coelom to the veins. In general, the wall of the intraembry- veins that join to form the common cardinal veins (see Figs 13.1B,C,
onic coelom is composed of proliferating cells that produce the 13.2A).
splanchnopleuric and somatopleuric mesenchymal populations. How-
ever, the walls of a portion of the pericardioperitoneal canals are thin- Vascular anomalies Localized defects of vascular development,
ner, and possibly more permeable to coelomic fluid, at the time when characterized by focal increases in the number of vessels that are abnor-
the canals surround the hepatocardiac channels (veins). The latter mally tortuous and enlarged, have been shown to have genetic causes
lie between the hepatic plexus and the sinus venosus; the hepatocar- and mapped to the predisposing gene and chromosomal locus (Boon


diac channel on the right side is more developed and on the left it is et al 2011). It has been suggested that a range of capillary malforma-
more plexiform, with only a transitory connection to the sinus veno- tions, venous malformations, telangiectasia and lymphatic malforma-
sus. The differentiation of this specific coelomic region occurs just in tions, including lymphoedema, is associated with factors identified in
advance of the expansion and filling of the right and left atria, at about the early formation of blood and lymphatic vessels (Brouillard and
stage 12. Vikkula 2007, Boon et al 2011).


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Spinal branch Intersegmental somatic artery renal artery arises from the most caudal. Additional renal arteries are
frequently present and may be regarded as branches of persistent lateral
Dorsal aorta Dorsal branch of splanchnic arteries.
somatic artery
Kidney Ventral splanchnic arteries
Ventral
branch of
somatic The ventral splanchnic arteries are originally paired vessels distributed
artery
Ventral to the capillary plexus in the wall of the yolk sac. After fusion of the
splanchnic dorsal aortae, they merge as unpaired trunks that are distributed to the
artery Lateral increasingly defined and lengthening primitive digestive tube. Longitu-
branch dinal anastomotic channels connect these branches along the dorsal
and ventral aspects of the tube, forming dorsal and ventral splanchnic
Lateral anastomoses (see Fig. 13.3). These vessels obviate the need for so many
splanchnic ‘subdiaphragmatic’ ventral splanchnic arteries, and these are reduced to
artery three: the coeliac trunk and the superior and inferior mesenteric arter-
ies. As the viscera supplied descend into the abdomen, their origins
Gut Anterior branch migrate caudally by differential growth: the origin of the coeliac artery
is transferred from the level of the seventh cervical segment to the level
Fig. 13.3 The segmental and intersegmental arteries. The small red of the twelfth thoracic; the superior mesenteric from the second thoracic
dilations indicate the positions of the longitudinal anastomoses. to the first lumbar segment; and the inferior mesenteric from the twelfth
thoracic to the third lumbar segment. However, above the diaphragm,
a variable number of ventral splanchnic arteries persist, usually four or
five, and supply the thoracic oesophagus. The dorsal splanchnic anas-
EMBRYONIC ARTERIES
tomosis persists in the gastroepiploic, pancreaticoduodenal and primary
branches of the colic arteries, whereas the ventral splanchnic anasto-
Initially, the dorsal aortae are the only longitudinal vessels present. mosis forms the right and left gastric and the hepatic arteries.


Their branches all run at right angles to the long axis of the embryo.
Later, these transverse arteries become connected by longitudinal anas-
tomosing channels that persist in part, forming arteries such as the EMBRYONIC VEINS
vertebral, internal thoracic, superior and inferior epigastric, and gastro-
epiploic. Each primitive dorsal aorta gives off somatic arteries (interseg-
The early embryonic veins are often segregated into two groups, visceral
mental branches to the body wall), a caudal continuation that passes
and somatic, for convenience and apparent simplicity. The visceral
into the body stalk (the umbilical arteries), lateral splanchnic arteries
group contains the derivatives of the vitelline and umbilical veins, and
(paired segmental branches to the mesonephric ridge), and ventral
the somatic group includes all remaining veins. It should be noted that,
splanchnic arteries (paired segmental branches to the digestive tube).
with time, embryonic veins change the principal tissues they drain. They
may receive radicles from obviously parietal tissues, which become
Somatic arteries
confluent with drainage channels that are clearly visceral, and so form
a compound vessel. The arrangement of the early embryonic veins is
The somatic arteries are intersegmental in position. They persist, almost initially symmetrical. The primitive tubular symmetric heart receives its
unchanged, in the thoracic and lumbar regions, as the posterior inter- venous return through the right and left sinual horns, which are initially
costal, subcostal and lumbar arteries. Each gives off a dorsal ramus, embedded in the mesenchyme of the septum transversum. Each horn
which passes backwards in the intersegmental interval and divides into receives, most medially, the termination of the principal vitelline vein;
medial and lateral branches to supply the muscles and superficial more laterally, the umbilical vein; and, most laterally, having encircled
tissues of the back (Fig. 13.3). The dorsal ramus also gives off a spinal the pleuroperitoneal canal, the common cardinal vein. This symmetric
branch, which enters the vertebral canal and divides into a series of pattern changes as the heart and gut develop and the cardiac return is


branches that supply the walls and joints of the osteoligamentous canal, diverted to the right side of the heart.
and neural branches to the spinal cord and spinal nerve roots. After
giving off its dorsal ramus, each intersegmental artery runs ventrally in Vitelline veins
the body wall, gives off a lateral branch and terminates in muscular and
cutaneous rami.
The vitelline veins drain capillary plexuses that develop in the splanch-
nopleuric mesenchyme of the secondary yolk sac. With head, tail and
Early umbilical arteries
lateral fold formation, the upper recesses of the yolk sac are enclosed
within the embryo as the splanchnopleuric gut tube, which extends
Initially, the umbilical arteries are the direct caudal continuation of the from the stomodeal buccopharyngeal membrane to the proctodeal
primitive dorsal aortae. They are present in the body stalk before any cloacal membrane. Derivatives from all these levels possess a venous
vitelline or visceral branches emerge, indicating the dominance of the drainage that is originally vitelline.
allantoic over the vitelline circulation in the human embryo. (On a
comparative basis, the umbilical vessels are chorio-allantoic and there- Early umbilical veins
fore ‘somatovisceral’.) After the dorsal aortae fuse, the umbilical arteries
arise from their ventrolateral aspects and pass medial to the primary
The umbilical veins form by the convergence of venules that drain the
excretory duct to the umbilicus. Later, the proximal part of each umbili-
splanchnopleure of the extraembryonic allantois. The human endoder-
cal artery is joined by a new vessel that leaves the aorta at its termination
mal allantois is very small; it projects into the embryonic end of the
and passes lateral to the primary excretory duct. This, possibly the fifth
connecting stalk, which is therefore regarded as precociously formed
lumbar intersegmental artery, constitutes the dorsal root of the umbili-
allantoic mesenchyme, whereas the umbilical vessels are considered to
cal artery (the original stem, the ventral root). The dorsal root gives off
be allantoic. The peripheral venules drain the mesenchymal cores of the


the axial artery of the lower limb, branches to the pelvic viscera and,
chorionic villous stems and terminal villi (extraembryonic somatopleu-
more proximally, the external iliac artery. The ventral root disappears
ric structures). These are the radicles of the vena umbilicalis impar
entirely, and the umbilical artery now arises from that part of its dorsal
(usually single), which traverses the compacting mixed mesenchyme of
root distal to the external iliac artery, i.e. the internal iliac artery.
the umbilical cord to reach the caudal rim of the umbilicus. Here, the
single cordal vein divides into primitive right and left umbilical veins.
Lateral splanchnic arteries
Each curves rostrally in the somatopleuric lateral border of the umbili-
cus, i.e. where intraembryonic and extraembryonic or amniotic somato-
The lateral splanchnic arteries supply, on each side, the mesonephros, pleure are continuous, lying lateral to the communication between
metanephros, testis or ovary, and the suprarenal gland. All these struc- both the intraembryonic and the extraembryonic coeloms. Rostrolateral
tures develop, in whole or in part, from the intermediate mesenchyme, to the umbilicus, the two umbilical veins reach, enter and traverse the
later termed the aorta-gonad-mesonephros region. One testicular or junctional mesenchyme of the septum transversum and connect with
ovarian artery and three suprarenal arteries persist on each side. The septal capillary plexuses. They then continue, entering their correspond-
phrenic artery branches from the most cranial suprarenal artery, and the ing cardiac sinual horns lateral to the terminations of the vitelline veins.


Embryonic veins
203
31
RETPAHC
A Postcardinal vein
Supracardinal vein (thoracolumbar line vein)
Azygos line vein (medial sympathetic line vein)
Subcardinal vein
Subcentral vein
Hepatic segment of inferior vena cava
(and right vitelline vein)
Subhepatic segment of IVC
B (i) Precardinal veins (iii) Internal
Common cardinal vein jugular veins
Sinus venosus
Hepatocardiac veins
Subcardinal veins
Postcardinal vein Postcardinal
vein
Brachiocephalic veins
(iv) Superior
intercostal vein
Oblique vein
Superior
and ligament
vena cava
of left atrium
Azygos vein IVC hepatic
segment
IVC subhepatic
segment
(ii)
Hemiazygos vein
Oblique
interprecardinal
anastomosis IVC subcardinal
segment
Azygos line vein
Left suprarenal vein
Left renal vein
Intersubcardinal Left gonadal vein
anastomosis
(renal collar) IVC supracardinal
segment
Supracardinal vein
Common iliac veins
Interpostcardinal
anastomosis
Early symmetrical Progressive asymmetry; right-sided dominance; Maturation and tributaries of superior vena
disposition of veins some channels enlarge; others retrogress cava; segments of definitive inferior vena cava
Fig. 13.4 Somatic venous development. A, A schematic section through the embryonic trunk. Principal longitudinal veins are colour-coded.
Interconnections and intersegmental veins are uncoloured. B, The development of the principal somatic veins, from the early symmetric state, through
states of increasing asymmetry, to the definitive arrangement. Abbreviations: IVC, inferior vena cava.
This early symmetric disposition of the vitelline veins and anastomoses, mented by a range of bilateral longitudinal channels that anastomose
umbilical and common cardinal veins, and the locus of the hepatic with the posterior cardinal system and with each other. These channels
primordial complex are summarized in Figures 13.1B and 13.2A. For are the subcardinal, supracardinal, azygos line, subcentral and precostal


further development of the vitelline and umbilical veins, see Chapter veins (Fig. 13.4).
60 (Figs 60.8–60.10).
Subcardinal veins
Cardinal veins and somatic Subcardinal veins form in the ventromedial parts of the mesonephric
ridges and become connected to the postcardinal veins by a number of
venous complexes
vessels traversing the medial part of the ridges. The subcardinal veins
assume the drainage of the mesonephros and intercommunicate by a
The initial venous channels in the early embryo have traditionally been pre-aortic anastomotic plexus, which later constitutes the part of the
termed cardinal because of their importance at this stage. The cardinal left renal vein that crosses anterior to the abdominal aorta.
venous complexes are first represented by two large vessels on each side,
the precardinal portion being rostral and the postcardinal being caudal Supracardinal veins
to the heart. The two veins on each side unite to form a short common Supracardinal veins form dorsolateral to the aorta and lateral to the
cardinal vein, which passes ventrally, lateral to the pleuropericardial sympathetic trunk and take over the intersegmental venous drainage
canal, to open into the corresponding horn of the sinus venosus (see from the posterior cardinal vein. The supracardinal veins are also
Figs 13.1B and 13.2A; Fig. 13.4B). The precardinal veins undergo referred to as the thoracolumbar line or lateral sympathetic line veins.
remodelling as the head develops. The postcardinal veins, which, in the
Azygos line veins
early embryo, drain the body wall, are insufficient channels for venous
return from the developing mesonephros and gonads and for the Azygos line veins form dorsolateral to the aorta and medial to the
growing body wall. As the embryo increases in size, they are supple- sympathetic trunk. These channels, also referred to as the medial


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noiTCES
sympathetic line veins, gradually take over the intersegmental venous Internal jugular vein
drainage from the supracardinal veins. The intersegmental veins now
External jugular vein
reach their longitudinal channel by passing medial to the autonomic Jugular lymph sac
trunk, a relationship that the lumbar and intercostal veins subsequently Right brachiocephalic vein Left brachiocephalic vein
maintain. Cranially, the azygos lines join the persistent cranial ends of Left common cardinal vein
the posterior cardinal veins.
Superior vena cava
Subcentral veins
Left postcardinal vein
Subcentral veins form directly dorsal to the aorta in the interval between
the origins of the paired intersegmental arteries. These veins communi-
cate freely with each other and with the azygos line veins; these con- Prerenal part of
nections ultimately form the retro-aortic parts of the left lumbar veins inferior vena cava
Left suprarenal vein
and of the hemiazygos veins.
Left renal vein
Precostal or lumbocostal venous line Retroperitoneal lymph sac
Postrenal part of
A precostal or lumbocostal venous line, anterior to the vertebrocostal
inferior vena cava
element and posterior to the supracardinal, is recognized by some
authorities. A possible derivative is the ascending lumbar vein. Left suprarenal vein
Cisterna chyli
Retroperitoneal lymph sac
Further development of the somatic veins
Posterior lymph sac Left renal vein
The supracardinal veins lie lateral to the aorta and the sympathetic
Fig. 13.5 Relative positions of the primary lymph sacs (as originally
trunks, which therefore intervene between them and the azygos lines
determined by Sabin (1912) ).
(see Fig. 13.4). They communicate caudally with the iliac veins and
cranially with the subcardinal veins in the neighbourhood of the pre-
aortic intersubcardinal anastomosis. The supracardinal veins also com-
municate freely with each other through the medium of the azygos lines
and the subcentral veins. The most cranial of these connections, together mechanotransduction with lymphatic endothelial cells elongating as a


with the supracardinal–subcardinal and the intersubcardinal anasto- consequence of high interstitial fluid volume (Planas-Paz et al 2012).
moses, complete a venous ring around the aorta below the origin of the For more details on the morphogenesis of lymphatic vessels, see Tatin
superior mesenteric artery, termed the ‘renal collar’. and Makinen (2014).
The ultimate arrangement of these embryonic abdominal and thor- The formation of jugular lymph sacs and their normal remodelling
acic longitudinal cardinal veins may be summarized as follows. The as the lymphatic system develops are of particular interest because delay
terminal part of the left postcardinal vein forms the distal part of the or disruption is noted in aneuploidic fetuses. Increased accumulation
left superior intercostal vein. On the right side, its cranial end persists of tissue fluid between the skin and soft tissues, posterior to the forming
as the terminal part of the azygos vein. The caudal part of the subcar- cervical spine – termed nuchal translucency – can be identified on
dinal vein is, in part, incorporated in the testicular or ovarian vein and ultrasound examination between 10 and 14 weeks’ gestation. Approxi-
partly disappears. The cranial end of the right subcardinal vein is incor- mately 75% of trisomy 21 fetuses show an increased distance of nuchal
porated into the inferior vena cava and also forms the right suprarenal translucency at this time (see Fig. 14.4). In the majority of cases, early
vein. The left subcardinal vein, cranial to the intersubcardinal anasto- nuchal fluid accumulation resolves for normal and chromosomally
mosis, is incorporated into the left suprarenal vein. The renal and tes- abnormal fetuses between 14 and 20 weeks, and is thought to reflect
ticular or ovarian veins on both sides join the supracardinal–subcardinal increased lymphatic system development, the onset of urine production
anastomosis. On the left side, this is connected directly to the part of by the metanephric kidneys and a decrease in placental resistance
the inferior vena cava that is of subcardinal status via an intersubcardi- (Nafziger and Vilensky 2014).


nal anastomosis. The right supracardinal vein forms much of the post- In the fetus, lymphatic flow rates appear to be higher than in the
renal (caudal) segment of the inferior vena cava. The left supracardinal neonate, which, in turn, are higher than in the adult; overall fetal lymph
vein disappears entirely. The right azygos line persists in its thoracic part flow is thought to be five times greater than in adults (Bellini et al
to form all but the terminal part of the azygos vein. Its lumbar part can 2006). The production of pulmonary fluid secreted into the amniotic
usually be identified as a small vessel that leaves the vena azygos on the cavity is related to the lymphatic drainage of the lungs. In the neonate,
body of the twelfth thoracic vertebra and descends on the vertebral pulmonary ventilation is important in regulating lymphatic flow in the
column, deep to the right crus of the diaphragm, to join the posterior lungs. The process of parturition causes significant changes in the dis-
aspect of the inferior vena cava at the upper end of its postrenal segment. tribution of body water in the neonate, including movement of blood
The left azygos line forms the hemiazygos veins. The subcentral veins from the placenta to the fetus and a temporary shift of fluid from the
give rise to the retro-aortic parts of the left lumbar veins and of the intravascular compartment to the interstitial compartment; restoration
hemiazygos veins (see Fig. 13.4). of fluid balance between intravascular, lymphatic and interstitial com-
partments occurs concomitant with an increase in postnatal oxygena-
tion (Bellini et al 2006).
LYMPHATIC VESSELS
LYMPH NODES AND LYMPHOID TISSUES
The earliest lymphatic vessels arise from budding of lymphatic endothe-
lial cells from the cardinal veins to form lymph sacs (Eichmann et al
2005). Six early lymph sacs can be identified; two are paired (the jugular Lymph vessels can be seen in the embryo in the cervical region from
and the posterior lymph sacs) and two are unpaired (the retroperitoneal stage 16. Lymph nodes, which provide regional proliferative foci for


sac and the cisterna chyli). In lower mammals, an additional pair (sub- lymphocytes, have been identified from week 9. Early lymph sacs
clavian) is present, but in the human embryo, these are merely exten- become infiltrated by lymphoid cells, and the outer portion of each sac
sions of the jugular sacs. becomes the subcapsular sinus of the lymph node. Morphological dif-
The jugular lymph sac is the first to appear, at the junction of the ferentiation of medullary and cortical compartments has not been
subclavian vein with the precardinal vein, with later prolongations observed until the end of week 10 (Tonar et al 2001). At the same time
along the internal and external jugular veins. The posterior lymph sac as these early lymph nodes are developing, the nasopharyngeal wall is
encircles the left common iliac vein. The retroperitoneal sac appears in infiltrated by lymphoid cells that are believed to herald the early devel-
the root of the mesentery near the suprarenal glands. The cisterna chyli opment of the tubal and pharyngeal tonsils.
appears opposite the third and fourth lumbar vertebrae (Fig. 13.5). The In the neonate, a considerable proportion of the total amount of
lymph vessels bud out from the lymph sacs along lines that correspond lymphoid tissue is localized in lymph nodes; the subsequent increase
more or less closely with the course of embryonic blood vessels (most in the amount of lymphoid tissues that occurs during childhood reflects
commonly, veins); many also arise de novo in the mesenchyme and the growth of these nodes. Definitive follicles with germinal centres are
establish connections with existing vessels. In the body wall and the formed during the first postnatal year. The pharyngeal tonsil reaches its
wall of the intestine, the deeper plexuses are the first to be developed; maximal development at 6 years and its subsequent involution is com-
the vessels in the superficial layers are gradually formed by continued pleted by puberty. Details of the development of gut-associated lym-
growth. Lymph vessel expansion appears to be influenced by local phoid tissue are given in Chapter 60.


Early embryonic circulation
204.e1
31
RETPAHC
Lymphatic endothelial cells in lymphatic capillaries display a dis-
continuous basal lamina and basement membrane. They are held by
anchoring filaments to the surrounding extracellular matrix. Their dif-
ferentiation in the mouse starts with expression of Sox-18 and Prox-1,
a Prospero homeobox transcription factor, in a subset of cardinal veins
(Park et al 2011, Zhou et al 2010). Prox-1 is the most specific and func-
tional lymphatic marker: its disruption leads to failure of lymphatic
vessel development. Abnormal or absent lymphatic development is also
seen with lack of vascular endothelial growth factor 3 (VEGFR3) and
lack of angiopoietin 1, respectively (Yamashita 2007). Abnormalities of
development and of remodelling of primary lymphatic vessels also
occur if Akt, a serine/theonine protein kinase, is absent, possibly due
to insufficient recruitment of smooth muscle cells to larger lymphatic
vessels (Zhou et al 2010).


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Springer-Verlag France; Ch. 1, pp. 3–23. Yamashita JK 2007 Differentiation of arterial, venous and lymphatic
Eichmann A, Yuan Li, Moyon D et al 2005 Vascular development: from endothelial cells from vascular progenitors. Trends Cardiovasc Med
precursor cells to branched arterial and venous networks. Int J Dev Biol 17:59–63.
49:259–67. Zhou F, Chang Z, Zhang L et al 2010 Akt/protein kinase B is required for
Herbert SP, Stainier D 2011 Molecular control of endothelial cell behaviour lymphatic network formation, remodelling and valve development. Am
during blood vessel morphogenesis. Nat Rev Mol Cell Biol 12:551–64. J Pathol 177:2124–33.
Kuijper S, Turner CJ, Adams RH 2007 Regulation of angiogenesis by Eph-
Ephrin interactions. Trends Cardiovasc Med 17:145–51.


CHAPTER
14
Pre- and postnatal development
related to early embryonic stages, and once the number of somites is
PRENATAL STAGES
too great to count with accuracy, the degree of development of the
pharyngeal arches is often used. External staging becomes more obvious
The absolute size of an embryo or fetus does not afford a reliable indi- when the limb buds appear. The upper limb bud is clearly visible at
cation of either its chronological age or the stage of structural organiza- stage 13 and, by stage 16, the acquisition of a distal paddle on the upper
tion, even though graphs based on large numbers of observations have limb bud is characteristic. At stage 18, the lower limb bud now has a
been constructed to provide averages. All such data suffer from the dif- distal paddle, whereas the upper limb bud has digit rays that are begin-
ficulty of timing the moment of conception in humans. It has long ning to separate. By stage 23, the embryo has a head that is almost erect
been customary to compute the age, whether in a normal birth or an and rounded, and eyelids are beginning to form. The limbs look far
abortion, from the first day of the last menstrual period of the mother more in proportion and fingers and toes are separate. At this stage, the
but, as ovulation usually occurs near the fourteenth day of a menstrual external genitalia are well developed, although they may not be suffi-
cycle, this ‘menstrual age’ is an overestimate of about 2 weeks. Where a ciently developed for the accurate determination of the sex.
single coitus can be held to be responsible for conception, a ‘coital age’ Historically, the onset of bone marrow formation in the humerus
can be established, and the ‘fertilization age’ cannot be much less than was used by Streeter to indicate the end of the embryonic and the begin-
this because of the limited viability of both gametes. It is usually held ning of the fetal period of prenatal life. The fetal period occupies the
that the difference may be several days, which is a highly significant remainder of intrauterine life; growth is accentuated, although differ-
interval in the earlier stages of embryonic development. Even if the entiative processes continue up to and beyond birth. Overall, the fetus


time of ovulation and coitus were known in instances of spontaneous increases in length from 30 mm to 500 mm, and increases in weight
abortion, not only would some uncertainty still persist with regard to from 2–3 g to more than 3000 g.
the time of fertilization, but also there would remain an indefinable
period between the cessation of development and the actual recovery
Fetal staging
of the conceptus.
To overcome these difficulties, early embryos have been graded or
classified into developmental stages or ‘horizons’, on the basis of both Currently, there is no satisfactory system of morphological staging of
internal and external features. The study of the Carnegie collection of the fetal period of development, and the terminology used to describe
embryos by Streeter (1942, 1945, 1948), and the continuation of this this time period reflects this confusion. The terms ‘gestation’, ‘gesta-
work by O’Rahilly and Müller (1987), provided, and continues to tional age’ and ‘gestational weeks’ are considered ambiguous by
provide, a sound foundation for embryonic study and a means of com- O’Rahilly and Müller (2000), who recommend that they should be
paring stages of human development with those of the animals rou- avoided. However, they are widely used colloquially within obstetric
tinely used for experimental study, namely: the chick, mouse and rat. practice. Staging of fetal development and growth is based on an esti-
Recent use of ultrasound for the examination of human embryos and mate of the duration of a pregnancy. Whereas development of a human
fetuses in utero has confirmed much of the staging data. from fertilization to full term averages 266 days, or 9.5 lunar months
The development of a human from fertilization to birth is divided (28 day units), the start of pregnancy is traditionally determined clini-
into two periods: embryonic and fetal. The embryonic period has been cally by counting days from the last menstrual period; estimated in this
defined by Streeter as 8 weeks post fertilization, or 56 days. This time- manner, pregnancy averages 280 days, or 10 lunar months (40 weeks).
scale is divided into 23 Carnegie stages, a term introduced by O’Rahilly Figure 14.3 shows the embryonic timescale used in all descriptions of


and Müller (1987) to replace developmental ‘horizons’. The designation embryonic development and the obstetric timescale used to gauge the
of stage is based on external and internal morphological criteria and stage of pregnancy.
not on length or age. The predicted date of full term and delivery is revised after routine
ultrasound examination of the fetus. Early ultrasound estimation of
Embryonic staging gestation increases the rate of reported preterm delivery (delivery at
<37 weeks) compared with estimation based on the date of the last
menstrual period (Yang et al 2002), possibly because delayed ovulation
Embryonic stages 1–10 are shown in detail in Figure 8.1. Estimations
is more frequent than early ovulation; the predicted age of a fetus esti-
of embryonic length may be 1–5 mm less than equivalent in vivo esti-
mated from the date of the last menstrual period may differ by more
mates, reflecting the shrinkage caused by the fixation procedures that
than 2 weeks from estimates of postfertilization days.
are inevitably used in embryological studies. O’Rahilly and Müller
(2000, 2010) have revised some of the ages that were previously assigned
Obstetric staging
to early embryonic stages, pointing out that interembryonic variation
may be greater than had been thought and that, consequently, some
ages may have been underestimated. They note that, as a guide, the age In obstetric practice, the duration of the period of gestation is regarded
of an embryo can reasonably be estimated from the embryonic length as 9 calendar months, which is approximately 270 days. The period of
within the range 3–30 mm, by adding 29 to the length. Correlating the pregnancy is divided into thirds, termed trimesters. The first and second
age of any stage of development to an approximate day may be unreli- trimesters each cover a period of 12 weeks, and the third trimester covers
able, and a generalization using the number of weeks of development the period from 24 weeks to delivery. Although the expected date of
might now be more appropriate. delivery is computed at 40 weeks of pregnancy, the term of the preg-
The stages of development encompass all aspects of internal and nancy, i.e. its completion resulting in delivery, is considered normal


external morphogenetic change that occur within the embryo within between 37 and 42 weeks. Neonates delivered before 37 weeks are called
the duration of the stage. They are used to convey a snapshot of the preterm (or premature); those delivered after 42 weeks are post-term.
status of the development of all body systems within a particular time- The period from the end of week 24 and up to 7 days after birth is
frame. Figure 14.1 shows the external appearance of embryos from termed the perinatal period. Fetuses that are delivered and die before
stage 6 to stage 23, with details of their size and age in days. The correl- 24 weeks are considered to be miscarriages of pregnancy, although tech-
ation of external appearance of the embryo with internal development nological advances in neonatal care can now assist the delivery and
is shown in Figure 14.2. support of infants younger than 24 weeks. Infants born after 24 weeks
Obvious external features provide some guidance to the changes of pregnancy who subsequently die are classed as stillborn and contrib-
occurring within embryos during successive stages. Somite number is ute to the statistics of perinatal mortality. Studies that discuss fetal 205


Pre- and Postnatal develoPment
206
2
noItCes
Neurulation First pharyngeal arch Mandibular Maxillary Pinna Eyelids
process process
Optic
Pericardial Otic vesicle vesicle
cavity
and heart
Somites Cerebral
hemisphere
Yolk
Hand
sac
Upper limb Connecting Connecting Umbilical
Lower limb
Connecting bud stalk stalk cord
bud
stalk
Stage 10 Stage 13 Stage 16 Stage 18
Reflection of amnion
Epiblast population
Primitive node
Primitive streak
Connecting stalk
Stage 6
Embryonic stage 6 10 13 16 18 20 23
Size (mm) 0.4 1.5–3 4–6 8–11 13–17 21–23 28–30
Approximate age 16–18 26–29 30–33 35–40 41–45 46–50 53–58
(days)
Fig. 14.1 The external appearance and size of embryos between stages 6 and 23. Early in development, external features are used to describe the
stage, e.g. somites, pharyngeal arches or limb buds. (Adapted with permission from Rodeck CH, Whittle MJ 1999 Fetal Medicine. London: Churchill
Livingstone.)
development and the gestational age of neonates, particularly those defects, lung immaturity, renal agenesis, polyhydramnios and defects of
born before 40 weeks’ gestation, use the obstetric estimated stages and the anterior abdominal wall (gastroschisis and exomphalos). Estima-
age (menstrual age), unless they specifically correct for this. If a fetal tions are made of the following: biparietal skull diameter, taken through
ageing system is used, it is important to remember that the age of the a plane of section that traverses the third ventricle and thalami; head
fetus may be 2 weeks more than a comparable fetus that has been aged circumference through a plane that traverses the third ventricle and
from postovulatory days. thalami plus the cavum septi pellucidi anteriorly and the tentorial
hiatus posteriorly; abdominal circumference through a plane where the


Ultrasound staging transverse diameter of the liver is greatest, the appearance of the lower
ribs is symmetrical and the junction of the left and right portal veins is
identified; and femoral length, which measures the ossified portions of
The difficulty of correlating the appearance of a chorionic sac, embryo
the diaphysis and metaphysis (Fig. 14.4).
or fetus on an ultrasound scan with age during the first trimester is
Between 15 and 28 weeks, the biparietal diameter is the most accu-
related to the specificity of reporting the age. An age reported as within
rate index of fetal menstrual age and the expected date of delivery. Other
a week of pregnancy, e.g. week 12, will cover a period of 6 days (12 weeks
measurements that may also be taken include transverse cerebellar
0 days up to 12 weeks 6 days). Therefore, it is recommended that sono-
diameter and foot length. The amount and type of fetal movement,
graphic estimation of age should be given as menstrual weeks and days
breathing movements and visceral functions, exemplified by bladder
(i.e. 12 weeks indicates 12 weeks 0 days) (Galan et al 2008).
emptying, peristaltic action and colonic echogenicity, are noted. Three-
First trimester scan An early ultrasound scan will detect implanta- and four-dimensional ultrasound scans are now routinely constructed
tion and viability of the embryo once a heart beat is detected, confirm (Video 14.1).
multiple pregnancy and estimate the date of delivery. Cardiac activity Gender can be identified later in development but this information
can be identified by the sixth menstrual week (Galan et al 2008). Crown– is not always routinely passed on to parents.
rump length measurement is the most accurate predictor of menstrual Constructions of ultrasound biometry charts for fetal aging now take
age of the embryo during the first trimester (Galan et al 2008). Nuchal into account the ethnic population under consideration; it is recom-
translucency is measured between 10 and 14 weeks to diagnose trisomy mended that locally developed charts specific to the population should
21. The development of three-dimensional ultrasound scanning has be used. The use of these charts means that factors that may influence
enabled early detection of many anomalies previously diagnosed in the fetal biometry, including maternal age and nutritional status, maternal


second trimester, including anencephaly, hydrocephalus and encepha- height, weight, parity and smoking habits, are noted, facilitating accu-
locele (Pretorius et al 2014). Normograms of fetal spine growth have rate prediction of small-for-date and growth-retarded fetuses. The World
been constructed for a Taiwan population, which show mean spine Health Organization (WHO) has published a protocol for the collec-
length increasing linearly between 11 and 14 weeks (Cheng et al 2010). tion of data for a multicentre study of fetal growth (Merialdi et al 2014).
The study also noted a tendency for spinal extension as early as 11 weeks. INTERGROWTH-21st, an international, multicentre project, also aims
to standardize protocols for collecting anthropometric measurements
Second trimester scan Routine scanning at 18–20 weeks (obstetric and constructing charts describing optimal fetal and preterm postnatal
staging) is used to confirm the delivery date, and assess not only the growth (Sarris et al 2013, Uauy et al 2013).
position of the placenta but also the presence of fetal anomalies that An outcome of routine ultrasound examination of embryos and
would require special intervention following delivery, such as cardiac fetuses for anomalies may be a change to the perinatal management,


Prenatal stages
207
41
retPaHC
Embryonic stages 6 7 8 9 10 1112131415 16 17 18 19 20 21 2223
Weeks post ovulation 1 2 3 4 5 6 7 8 9 10 11 12
Head and tail folding Upper lip Digits on hand Eyelids fuse
External appearance
Pharyngeal arches Palate External ear
Neurulation Anterior lobe Posterior lobe
Nervous First neural Otic vesicle pituitary pituitary
crest cells Optic cup Membranous labyrinth
Trachea
Respiratory Lung buds Further division of bronchi
Primary bronchi
Fore-, mid-,Thyroid Pharyngeal pouches Midgut loop
hindgut Liver dorsal and ventral Midgut loop rotating returns to
Gastrointestinal
Pancreas abdomen
Urorectal septum Rotation of stomach
Mesonephros
Urinary Mesonephric duct Metanephric nephrons Kidneys ascend
Ureteric bud Major calyces Minor calyces
Germ cells in allantois wall Müllerian ducts Uterus and uterine tubes Testis at inguinal canal
Reproductive Indifferent gonad Testis differentiating Vagina Prostate
External genitalia indifferent External genitalia differentiating
Primitive Septum primum Septation of ventricles
vascular
Cardiovascular Heart beats Spleen Septum secundum
system
Heart tube
Somite period Cartilaginous Membranous
20 days .................................. 30 days part of skull part of skull
Musculoskeletal
Forelimb bud Forelimb digit rays
Hindlimb bud
Fig. 14.2 A timetable of development of the body systems. The development of individual systems can be seen progressing from left to right. Embryonic
stages and weeks of development are shown. Embryonic stages are associated with external and internal morphological features rather than embryonic
length. To identify the systems and organs at risk at any time of development, follow a vertical progression from top to bottom.
Late neonatal period (7–28 days)
Implantation period Early neonatal period (birth–7 days)
Embryonic
Fetal period Perinatal period
stages


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 Age of embryo (weeks)
1 2 3 4 5 6 7 8 9 10 Age of embryo (months)
Implantation
Fertilization
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 Pregnancy (weeks)
1 2 3 4 5 6 7 8 9 10 Pregnancy (lunar months)
Last menstruation Estimated date of delivery
First trimester Second trimester Third trimester (of pregnancy)
Fig. 14.3 The two timescales used to depict human development. Embryonic development, in the upper scale, is counted from fertilization (or from
ovulation, i.e. in postovulatory days; see O’Rahilly and Müller (1987)). Throughout this book, times given for development are based on this scale. The
clinical estimation of pregnancy is counted from the last menstrual period and is shown on the lower scale; throughout this book, fetal ages relating to
neonatal anatomy and growth will have been derived from the lower scale. Note that there is a 2-week discrepancy between these scales. The perinatal
period is very long because it includes all preterm deliveries.


Pre- and Postnatal develoPment
208
2
noItCes
Ultrasound planes examined in 20-week scan
Nuchal translucency (A) Longitudinal spine (A)
Aortic arch (A)
Transventricular (B)
Midline
A 20-week scan biometry for
delivery date estimation
Transthalamic – biparietal diameter (C)
B
Posterior C
ventricle Midline
D
Transcerebellar (D) Thalami
Cerebellum
Cisterna
magna
Midline
Transthalamic – head circumference (C)
Midline
Heart - three-vessel view (E)
Thalami
Ao E
SVC PA
F
DA
G Abdominal circumference (G)
Spine
H
Heart - four-chamber view (F)
I LPV
DV
RPV
RV
LV
RA
LA Stomach
J Spine
Spine
Femur length (J)
Cord insertion (H) Bladder (I)
Cord
insertion
Cord
insertion
Bladder
Bowel
Spine
Spine
Fig. 14.4 Ultrasound planes examined in a routine second-trimester antenatal scan (left) and measurements taken to predict the estimated date of
delivery (right). The top three images are in the sagittal plane (A). The other planes are transverse, apart from J, which is longitudinal. Abbreviations:
Ao, aorta; DA, ductus arteriosus; DV, ductus venosus; LA, left atrium; LPV, left portal vein; LV, left ventricle; PA, pulmonary artery; RA, right atrium;
RPV, right portal vein; RV, right ventricle; SVC, superior vena cava.


Growth in utero
209
41
retPaHC
i.e. to the time, method and place of delivery of the fetus, or the parents still disproportionately large. (Although the rates of growth of the trunk
may choose to terminate the pregnancy to minimize concerns about and lower limbs increase during the remainder of intrauterine life, the
fetal and neonatal suffering and long-term disability. Termination may disproportion is present after birth and, to a diminishing degree, is
be chosen for severe, untreatable inherited metabolic disorders (e.g. retained throughout childhood and on into the years of puberty.) A
Tay–Sachs disease), severe chromosomal anomalies (e.g. trisomy 13), covering of primary hair, lanugo, appears. Towards the end of this
lethal bone dysplasias, lethal anomalies such as anencephaly and other period, sebaceous glands become active; the sebum that is secreted
extreme neurological defects, and bilateral renal agenesis (Cass 2011). blends with desquamated epidermal cells to form a cheesy covering
Improvements in prenatal screening and diagnosis have led to an over the skin, the vernix caseosa, which is usually considered to protect
overall increase in the prevalence of reported birth defects and overall the skin from maceration by the amniotic fluid. At about this time, the
lower perinatal mortality rates, reflecting increased early terminations mother becomes conscious of fetal movement, formerly termed
of pregnancy (Cass 2011). ‘quickening’.
In the sixth month, the lanugo darkens, the vernix caseosa is more
Magnetic resonance imaging abundant and the skin becomes markedly wrinkled. The eyelids and
eyebrows are now well developed. During the seventh month, the hair
of the scalp is lengthening and the eyebrow hairs and the eyelashes are
Advances in prenatal ultrafast magnetic resonance imaging (MRI) now
well developed. The eyelids themselves separate and the pupillary mem-
provide further ways to detect fetal anomalies, capturing particularly
brane disappears. The body becomes more plump and rounded in
clear images (Sepulveda et al 2012) (Fig. 14.5). MRI is considered a
contour and the skin loses its wrinkled appearance as a result of the
useful adjunct to ultrasound imaging at 20–22 weeks because it enables
increased deposition of subcutaneous fat. Fetal length has increased to


better management planning for known or suspected anomalies (Reddy
approximately 350 mm and weight to about 1.5 kg. Towards the end
et al 2014).
of this month, the fetus is viable; if born prematurely, it may be able
Fetal development to survive without the technological assistance found in neonatal inten-
sive care units and its postnatal development can proceed normally.
Throughout the remaining lunar months of normal gestation, the
Although accurate morphological stages are not available for the fetal
covering of vernix caseosa is prominent. There is a progressive loss of
period, the developmental progression is broadly clear. During the
lanugo, except for the hairs on the eyelids, eyebrows and scalp. The
fourth and fifth months, the fetus has a head and upper limbs that are
bodily shape becomes more infantile but, despite some acceleration in
their growth, the legs have not quite equalled the arms in length pro-
portionately, even at the time of birth. The thorax broadens relative to
the head, and the infra-umbilical abdominal wall shows a relative
increase in area, so that the umbilicus gradually becomes more centrally
situated. Average lengths and weights for the eighth, ninth and tenth
months are 40, 45 and 50 cm and 2, 2.5 and 3–3.5 kg, respectively. The
rate of fetal growth slows from 36 to 40 weeks in response to the physi-
cal limitation imposed by the maternal uterus. Birth weight thus reflects
the maternal environment more than the genotype of the child. This
slowing of the growth rate enables a genetically larger child developing
within a small mother to be delivered successfully. After birth, the
growth rate of the neonate increases; the rate of weight gain reaches a
peak some 2 months postnatally.
Just before birth, the lanugo almost disappears and the umbilicus is
central. The testes, which begin to descend with the processus vaginalis
of peritoneum during the seventh month and are approaching the
scrotum in the ninth month, are usually scrotal in position. The ovaries
are not yet in their final position at birth; although they have attained
their final relationship to the uterine folds, they are still above the level
of the pelvic brim.
A
Fetal surgery
The use of routine ultrasound examination and MRI of fetuses has led


to the development of a number of prenatal surgical interventions: e.g.
to correct placental or membrane anomalies resulting in twin-to-twin
transfusion and the production of amniotic bands (Deprest et al 2014);
or to offer improved outcomes for meningomyelocele on the basis that
the neural tissue may become secondarily damaged due to exposure to
amniotic fluid and mechanical traumatic injury during gestation
(Adzick 2013, Danzer and Johnson 2014, Cohen et al 2014).
Bowel GROWTH IN UTERO
Alterations in the availability of nutrients to the fetus at particular stages
of pregnancy elicit adaptive responses by the fetus. These may ensure
Umbilical cord fetal coping but may also result in pathology in adult life; the nutri-
tional status of pregnant females is therefore of fundamental impor-
tance for the health of the next generation. Under- or overnutrition
during fetal life may lead to metabolic changes in childhood, adoles-
B cence and adulthood, and pass to successive generations. Poor nutrition
at critical stages of fetal life permanently alters the normal developmen-
tal pattern of a range of organs and tissues, e.g. the endocrine pancreas,
Fig. 14.5 MRI scans of fetal anomalies. A, Polyhydramnios may arise as
liver and blood vessels, resulting in their pathological responses to
a result of oesophageal compression, impaired swallowing and lack of
absorption of amniotic fluid from the gut. B, Gastroschisis with loops of certain conditions in later adult life (Barker et al 1993, Catalano and
bowel in the extracellular coelom (chorionic cavity) and normal insertion Hauguel-De Mouzon 2011). Maternal hyperglycaemia leads to changes
of the umbilical cord. (With permission from Sepulveda W, Ximenes R, in fetal metabolism and pathology in the child and adult (Pedersen
Wong AE, et al 2012 Fetal magnetic resonance imaging and three- 1952).
dimensional ultrasound in clinical practice: Applications in prenatal An increase in placental size occurs in pregnancy as an adaptive
diagnosis. Best Pract Res Clin Obstet Gynaecol 26:593–624.) response to both high altitude and mild undernutrition, particularly


Pre- and postnatal development
209.e1
41
retPaHC
Other conditions have also been treated prenatally with limited
improvement in mortality. Thus, congenital diaphragmatic hernia may
be treated by percutaneous fetoscopic endoluminal tracheal occlusion
from 25 to 33 weeks’ gestation to prevent loss of lung fluid and enhance
lung growth (Deprest et al 2004). Fetal airway patency has also been
preserved during birth through perinatal ex utero intrapartum (EXIT)
treatment, where a portion of the fetus is delivered through a hysterec-
tomy incision for surgery while the fetus remains attached to the utero-
placental circulation. After the airway procedure is completed, the fetus
is completely delivered (Deprest et al 2014).


Pre- and Postnatal develoPment
210
2
noItCes
during mid-pregnancy. However, although a larger placenta may be the rapid maturation of some systems and the compensatory growth of
better able to deliver the full nutritional requirements of the fetus, the others (in terms of responses to the effect of gravity or enteral feeding
perfusion of a larger placenta is not without problems. It may produce or exposure to microorganisms).
changes in fetal blood flow and placental enzymes, and in the normal Details of the relative positions of the viscera and the skeleton in a
structure of the fetal vessel wall or of its responses to circulating full-term neonate are shown in Figures 14.6–14.8. The newborn infant
trophins, e.g. catecholamines or angiotensin II, which will continue is not a miniature adult, and extremely preterm infants are not the same
into adult life. Undernutrition in later pregnancy does not produce the as full-term infants. There are immense differences in the relations of
same sequelae and placental enlargement does not occur. However, fetal some structures between the full-term neonate, child and adult, and
growth slows and fetal wasting may occur as oxygen, glucose and amino there are also major differences between the 20-week-gestation fetus
acids are redistributed to the placenta to maintain its function. and the 40-week fetus, just before birth. The study of fetal anatomy at
20, 25, 30 and 35 weeks is vital for the investigative and life-saving
Transition to extrauterine life procedures carried out on preterm infants today.
Neonatal measurements and period
The type of birth confers developmental outcomes on the neonate that
affect its subsequent growth. Caesarean section for preterm delivery of time in utero
appears not to be associated with improved neonatal outcomes but is
associated with increased risk of respiratory distress syndrome due to The tenth to ninetieth centile ranges for length of full-term neonates
slower postnatal movement of fluid out of the lungs (Werner et al 2012, are 48–53 cm (Fig. 14.9A). Length of the newborn is measured from
Bhatta and Keriakos 2011, Bellini et al 2006). The dramatic rise of this crown to heel. In utero, length has been estimated either from crown–


delivery method is not necessarily driven by improved neonatal out- rump length, i.e. the greatest distance between the vertex of the skull
comes because caesarean section has been shown to increase the odds and the ischial tuberosities, with the fetus in the natural curved posi-
of developing asthma and type 1 diabetes in later life by 20%. Meta- tion, or from the greatest length exclusive of the lower limbs. Greatest
analyses indicate that the endocrine milieu during caesarean section length is independent of fixed points and thus much simpler to measure;
may lead to epigenetic effects on hepatic and metabolic function and it is generally taken to be the sitting height in postnatal life, and is the
so affect immune function in adult life, leading, in some instances, to measurement recommended by O’Rahilly and Müller (2000) as the
food allergy and obesity (Steer and Modi 2009, Hyde and Modi 2012, standard in ultrasound examination.
Song et al 2013). At birth, weight reflects the maternal environment, the number of
Prior to birth, the gut is exposed to hundreds of proteins, metabo- conceptuses, the sex of the baby and the parity of the mother. Generally,
lites and cytokines that are swallowed in amniotic fluid; there is some full-term female babies are lighter than full-term males, twins are lighter
evidence for the presence of bacterial species in amniotic fluid prior than singletons, and later children tend to be heavier than the first-born.
to delivery. Establishment of the gut microbiota by exposure to mater- The tenth to ninetieth centile ranges for the weight of a full-term infant
nal vaginal and colonic bacteria during vaginal delivery leads to normal at parturition are 2700–3800 g (Fig. 14.9B), the average being 3400 g;
maturation of the gut wall. Gut colonization in preterm infants is 75–80% of this weight is body water and a further 15–28% is composed
delayed (Cilieborg et al 2012). Infants born via caesarean section may of adipose tissue.
have primary gut flora disturbance for up to 6 months after birth and Birth weight is noted against charts appropriate for ethnicity and


associated delay in postnatal immune development (Neu and Rushing categorized as low, normal and high. Low birth weight has been defined
2011, Neu and Mai 2012, Matamoros et al 2013). as less than 2500 g, very low birth weight as less than 1500 g, and
The establishment of enteral feeding has profound effects on early extremely low birth weight as less than 1000 g. Infants may weigh less
postnatal maturation. Human breast milk contains many bioactive sub- than 2500 g but not be premature by gestational age. Measurement of
stances that enhance gut maturity. It improves gastric emptying, encour- the range of weights that fetuses may attain before birth has led to the
ages the growth of the microbiotome and contains a range of proteins, production of weight charts, which allow babies to be described accord-
including large amounts of secretory immunoglobulin A and cytokines ing to how appropriate their birth weight is for their gestational age,
(e.g. interleukin (IL)-10) (Jakaitis and Denning 2014). Feeding preterm e.g. small for gestational age, appropriate for gestational age or large for
infants human milk is associated with less feeding intolerance and is gestational age (Fig. 14.10). Small-for-gestational-age infants, also
thought to provide protection against diabetes and obesity in later life termed ‘small-for-dates’, are often the outcome of intrauterine growth
(Valentine and Morrow 2012). The rate of growth of infants fed breast retardation.
milk for the first 6 months of postnatal life is different to that of For both premature and growth-retarded infants, an assessment of
formula-fed infants. Delivery of low-weight preterm babies, followed gestational age, which correlates closely with the stage of maturity, is
by parenteral feeding with no enteral nutrition, disrupts normal gut desirable. Gestational age at birth is predicted by its proximity to the
maturation and may lead to necrotizing enterocolitis (Wynn and Neu estimated date of delivery and the results of ultrasonographic examin-
2012). However, a balance with the gut microbiome is necessary; ations during pregnancy. It is currently assessed in the neonate by evalu-


although full-term neonates born in tropical countries have similar ation of a number of external physical and neuromuscular signs. Scoring
villous height to those born in temperate climates, villous length in the of these signs results in a cumulative score of maturity that is usually
small intestine shortens within 2–12 months of birth as a consequence within ±2 weeks of the true age of the infant. The scoring scheme has
of tropical enteropathy (Ramakrishna et al 2006). been devised and improved over many years.
The time of transition to extrauterine life is permanently recorded Estimation of large-for-dates infants is based on assessment of fetal
in the primary teeth and can be reliably demonstrated in forensic weight through ultrasound evaluation and some biometrical indices.
dental identification. The circadian growth rhythm of dentine and Assessment of anterior abdominal wall width is thought to predict
enamel deposition in tooth germs is temporarily blocked by the meta- large-for-gestational-age babies (Walsh and McAuliffe 2012). Fetal mac-
bolic stress of delivery; the resultant change in enamel prism deposi- rosomia is defined as an absolute birth weight greater than 4000 g,
tion is seen as a neonatal line or ring that can be detected in all 4500 g or 5000 g, or as a customized birth weight centile greater than
deciduous teeth and permanent first molar teeth of live births. The the ninetieth, ninety-fifth or ninety-seventh centile for the infant’s gesta-
thickness of the line is related to birth difficulties, being thinner in tion age (Walsh and McAuliffe 2012, Schwartz et al 2014). The precise
caesarean section and thicker in vaginal delivery (Sabel et al 2008, definition may not necessarily be helpful, as some at-risk infants, not
Canturk et al 2014). identified as large for dates from growth curve charts, might go unrec-
ognized (Larma and Landon 2011). There is a correlation between
macrosomia and short maternal stature; macrosomic fetuses are at risk
NEONATE of shoulder dystocia and brachial plexus injuries during vaginal
delivery.
The neonatal period extends from birth to 28 days postnatally; it is
divided into an early neonatal period from birth to 7 days, and a late