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Development and Inheritance
Embryology Atlas

Chapter 20: Human Development

by John F. Neas

The period of prenatal development can be subdivided into preembryonic, embryonic, and fetal periods. The preembryonic period begins with the fertilization of a secondary oocyte and continues through cleavage (an initial series of cells divisions) and implantation (the movement of the preembryo into the uterine lining). The preembryonic period is followed by the embryonic period that extends from implantation, typically occurring on the ninth or tenth day after fertilization, and continuing to the end of the eighth developmental week during which time the organ systems develop. The fetal period begins at the start of the ninth developmental week and culminates in parturition, or birth.

Preembryonic Period

The first two weeks of development, the preembryonic stage, is a period of cell division and differentiation. The events of this stage include fertilization, transportation of the zygote through the uterine tube, mitotic cell divisions (cleavage), formation of embryonic tissue and extraembryonic membranes (amnion, chorion, allantois, placenta, and umbilical cord), and the beginning of implantation of the blastocyst into the uterine wall. The term conceptus refers to all the products of conception including all structures that develop from the fertilized ovum (zygote), including the embryo and its extraembryonic membranes. The developing conceptus during the preembryonic period is self-sustaining. The embryo, however, is not self-supporting and must derive sustenance and protection from the mother through the extraembryonic membranes.

Preembryonic forms are the zygote (fertilized egg), morula (a solid ball of cells), blastocyst (hollow ball with a single germ layer), and bilaminar embryonic disc (with two germ layers).

First Week—Fertilization, Cleavage, Blastulation

Fertilization

The term fertilization refers to the penetration of an ovum by a spermatozoon and the subsequent fusion of the haploid gametes (sperm and eggs have 23 chromosomes in human beings) into a diploid zygote with the normal somatic number of chromosomes (46 in human beings).

The spermatozoon and ovum have very different functional roles and contributions. The spermatozoon merely delivers paternal chromosomes to the site of fertilization, but the ovum provides all the nourishment and genetic programming to support embryonic development for almost a week after conception. The volume of the ovum, therefore, is much greater than that of the spermatozoon.

Gamete Transport

Fertilization normally occurs in the ampulla of the uterine (Fallopian) tube and usually within 24 hours after ovulation. Peristaltic contractions and ciliary action transport the secondary oocyte a few centimeters through the uterine tube. The spermatozoa, however, must travel the distance between the vagina and the fertilization site in the ampulla. Transit time for the spermatozoa may be from 30 minutes to 2 hours. Several factors apparently accelerate the movement of spermatozoa in their passage. Sperm probably swim up the female reproductive tract by using whip-like movements of their flagella. In addition, the acrosome of sperm produces an enzyme called acrosin that stimulates sperm motility and migration within the female reproductive tract. Finally, contractions of the uterine musculature and ciliary currents in the uterine tubes probably help transport the sperm.

During coitus (sexual intercourse), a male ejaculates between 100 million and 500 million sperm into the vagina (typically about 200 million). This tremendous number is needed because of the high rate of sperm fatality. Very few, perhaps only several hundred to several thousand, enter the uterine tube and fewer than 100 survive to reach the ampulla. Therefore, males are functionally sterile if they have a sperm count below 20 million/ml because too few spermatozoa survive to reach the secondary oocyte. One or two spermatozoa cannot complete fertilization because of the condition of the secondary oocyte at ovulation.

Secondary Oocyte at Ovulation

A woman usually ovulates one secondary oocyte each month, totaling about four hundred during her reproductive years. Ovulation occurs before completion of oocyte maturation, and the secondary oocyte that leaves the follicle is arrested in metaphase of the second meiotic division during which time metabolism has been discontinued. To develop further, the secondary oocyte must await stimulation by fertilization.

Fertilization is complicated by the fact that the ovulated secondary oocyte is surrounded by intercellular materials, including a thin transparent gelatinous layer of protein and polysaccharides called the zona pellucida and several layers of cells called the corona radiata, the innermost of which are follicle (granulosa) cells. The corona radiata protects the secondary oocyte as it passes through the ruptured follicular wall and into the infundibulum of the uterine tube. The process of fertilization requires only a single sperm to contact the oocyte membrane, but that spermatozoon must first penetrate the corona radiata.

Besides assisting in the transport of sperm, the female reproductive tract also confers on sperm the capacity to fertilize a secondary oocyte. Sperm undergo maturation in the epididymis and are motile upon arrival in the vagina. Experiments have shown, however, that freshly ejaculated sperm are infertile and must remain in the acidic environment of the female reproductive tract for at least seven hours before they gain the ability to fertilize a secondary oocyte. The functional changes that sperm undergo in the female reproductive tract that enable them to fertilize a secondary oocyte are known as capacitation. The sperm cell has an organelle called an acrosome that forms a cap over the head. Capacitation is not fully understood but, during this process, the acrosome presumably secretes a trypsin-like enzyme that digests protein (proteinase) and hyaluronidase that digests hyaluronic acid, which is an important constituent of connective tissue

Acrosome Reaction

When a sperm encounters a secondary oocyte in the uterine tube, an acrosomal reaction occurs that exposes the digestive enzymes of the acrosome and allows a sperm to penetrate the corona radiata and zona pellucida. Dozens of spermatozoa must release hyaluronidase before the intercellular cement between the follicular cells in the corona radiata break down sufficiently to permit fertilization.

Oocyte Activation; Prevention of Polyspermy

Regardless of how many spermatozoa make their way through the zona pellucida and corona radiata, only a single spermatozoon will accomplish fertilization and activate the oocyte.

As the first sperm penetrates the zona pellucida and contacts the secondary oocyte, the plasma membranes of the gametes fuse, and the sperm enters the ooplasm, or cytoplasm of the oocyte. When the cell membranes of the sperm and secondary oocyte merge, the secondary oocyte becomes an ovum. The process of membrane fusion triggers oocyte activation—a series of changes in the metabolic activity of the secondary oocyte, including a sudden rise in metabolic rate. Furthermore, the cell membrane of the oocyte undergoes immediate electrical changes that block the entry of other sperm, and enzymes produced by the fertilized ovum alter receptor sites so that sperm already bound are detached and others are prevented from binding. Therefore, only one sperm can fertilize a secondary oocyte. Normal development cannot occur if more than one sperm penetrates the oocyte membrane, an event called polyspermy.

Completion of Meiosis

The fertilization of a secondary oocyte by a sperm in the uterine tube stimulates the ovum to complete its second meiotic division and form a diploid zygote. Like the first meiotic division, the second produces a large mature ovum that contains all the cytoplasm and the second polar body that, like the first polar body, ultimately fragments and disintegrates.

Pronucleus Formation and Amphimixis

At fertilization, the entire sperm enters the cytoplasm of the much larger ovum, the tail is shed, and the nucleus in the head develops into a structure called the male pronucleus. After oocyte activation and completion of meiosis, the nuclear material remaining within the ovum reorganizes as the female pronucleus. The male pronucleus migrates toward the center of the cell, and the two pronuclei fuse in a process called amphimixis to produce a segmentation nucleus that contains 23 chromosomes from the male pronucleus and 23 chromosomes from the female pronucleus. Within twelve hours, the nuclear membrane in the ovum disappears, and the haploid number of chromosomes (23) in the ovum joins the haploid number of chromosomes from the sperm. Thus, a fertilized egg, or zygote, is formed that contains the diploid number of chromosomes (46). The fertilized ovum, or zygote, consisting of a segmentation nucleus, cytoplasm, and enveloping membrane, prepares to begin mitotic divisions called cleavage that will ultimately produce billions of specialized cells.

Gamete Viability

A secondary oocyte that is ovulated but not fertilized does not complete its second meiotic division. Rather, it disintegrates twelve to twenty-four hours after ovulation without completing meiosis. Therefore, fertilization cannot occur if intercourse occurs beyond one day following ovulation. Sperm, however, can survive up to three days in the female reproductive tract. Thus, fertilization can occur if coitus occurs within three days before the day of ovulation.

Cleavage

Fertilization initiates cleavage, a series of rapid mitotic divisions that subdivides the cytoplasm of the zygote into smaller, essentially equipotential cells called blastomeres contained by the zona pellucida. Cleavage generates a multicellular system essential for further differentiation and morphogenesis. Cleavage increases the number of cells, but it does not result in an increase in the size of the developing organism. Cleavage begins immediately after fertilization and ends when the developing structure first contacts the uterine wall. During the period of cleavage, the zygote becomes a preembryo that develops into a multicellular complex called a blastocyst.

The first cleavage division results in the formation of a preembryo consisting of two identical blastomeres. The first cleavage is completed approximately 30 hours after fertilization, and each succeeding division takes slightly less time, occurring at 10- to 12-hour intervals. All of the blastomeres undergo mitosis simultaneously during the initial cleavage divisions, but the timing becomes less predictable as the number of blastomeres increases. The second cleavage is completed by the second day after conception. There are 16 blastomeres by the end of the third day.

Morula

Several cleavage divisions occur as the structure moves down the uterine tube toward the uterus. By the third day, successive divisions increase the number of blastomeres to about sixteen, forming a solid ball called a morula ("mulberry") consisting of an inner and an outer cell mass. The morula has the first evident segregation of materials and potencies. The morula enters the uterus on the third or fourth day. The morula has undergone several mitotic divisions, but it is about the same size as the original zygote because additional nutrients necessary for growth have not entered the cells.

Blastocyst Formation (Blastulation)

As the number of cells increases, the structure moves from the original site of fertilization down through the ciliated uterine tube toward the uterus and enters the uterine cavity on about the third day. The developing structure remains unattached in the uterine cavity for about three days during which time the center of the morula fills with fluid passing in from the uterine cavity. The fluid-filled spaces that form between the blastomeres of the morula coalesce by the fourth or fifth day into a large blastocyst cavity (blastocoel, or primary yolk sac). The morula is now a blastocyst. The blastocyst cavity separates a single spherical outer layer of trophoblast cells (trophectoderm) that form the wall of the blastocyst from a small, inner aggregation of cells called the inner cell mass, or embryoblast, that will become the embryo proper. The trophoblast will later combine with mesoderm to form the chorion that will become the fetal portion of the placenta.

The relatively independent conceptus floats freely in endometrial gland secretions as it passes down the uterine tubes into the uterus where it implants between the fifth and ninth days after ovulation.

The inner cell mass has little visible organization in the early blastocyst stage. At seven days, the conceptus is a blastocyst that enlarges, loses its zona pellucida and, during the following four days, becomes implanted in the uterine mucosa. During those four days, the inner cell mass begins to separate from the trophoblast. The separation gradually increases, producing a fluid-filled chamber called the amniotic cavity. At this stage the cells of the inner cell mass are organized into an oval sheet called a bilaminar embryonic disc (blastodisc) that initially consists of two epithelial layers—the epiblast (ectoderm) facing the amniotic cavity and the hypoblast (endoderm) exposed to the fluid contents of the blastocoel.

The trophoblast differentiates from the superficial layer of cells of the morula. The trophoblast differentiates into an actively invading, superficial layer, the syncytiotrophoblast, and a deep stratum, the cytotrophoblast. The cytotrophoblast and syncytiotrophoblast form the chorion and ultimately the definitive placenta. Cytotrophoblast also produces mesoblast that forms extraembryonic blood vessels.

Splanchnic mesoderm (lateral plate, hypomere) and hindgut endoderm produce the yolk sac and allantois. Splanchnic mesoderm also produces mesoderm of the amnion, the lining of which develops from surface ectoderm

Second Week—Implantation

It takes about 4 days after fertilization for the zygote to reach the uterus. The zygote arrives in the uterine cavity as a morula, and over the next 2–3 days, blastocyst (blastula) formation occurs. The blastocyst remains free within the uterine cavity for 2–4 days before it attaches to the uterine wall. During this period, the cells absorb nutrients rich in glycogen from secretions of the endometrial glands sometimes called uterine milk.

The process of implantation, or nidation, begins between the seventh and eighth days after fertilization. Implantation begins with the attachment of the blastocyst to the endometrium and continues as the blastocyst invades the uterine wall. As implantation proceeds, several other important events occur that set the stage for the formation of vital embryonic structures.

Implantation begins as the surface of the blastocyst closest to the inner cell contacts and adheres to the endometrial lining, usually upon the posterior wall of the fundus or body of the uterus. The endometrium at this time is in its postovulatory phase. The trophoblast (trophectoderm) below the implanting blastocyst divides rapidly, producing several layers of cells. Near the endometrial wall, the cell membranes that separate the trophoblast cells disappear, forming a layer of cytoplasm called the syncytiotrophoblast that contains multiple nuclei (Day 8). This outer layer begins to secrete the proteolytic enzyme hyaluronidase that digests and liquefies the intercellular cement between adjacent endometrial cells. The action of the enzyme erodes a gap and depression in the uterine epithelium that enables the blastocyst to penetrate the uterine lining. The migration and division of nearby endometrial cells soon repair the surface and cover the defect. When the repairs are completed, the blastocyst loses contact with the uterine cavity and becomes completely embedded within the endometrium. The blastocyst becomes oriented with the inner cell mass toward the endometrium. Subsequent development occurs entirely within the functional zone of the endometrium.

As implantation progresses, the syncytiotrophoblast continues to enlarge and expand into the surrounding endometrium (Day 9), resulting in disruption and enzymatic digestion of uterine glands. The nutrients released are absorbed by the syncytiotrophoblast and distributed by diffusion across the underlying cytotrophoblast to the inner cell mass. The fluid and nutrients provide the additional nourishment needed to support the early stages of embryo formation, especially during the first week after implantation. Trophoblastic extensions grow around endometrial capillaries and, as the capillary walls are destroyed, maternal blood begins to percolate through trophoblastic channels called lacunae. Finger-like projections called primary villi extend from the trophoblast into the surrounding endometrium. Each primary villus consists of an extension of syncytiotrophoblast with a core of cytotrophoblast. Over the next few days, the trophoblast begins to break down larger endometrial veins and arteries, and blood flow through the lacunae increases. Nutrients are eventually delivered through the placenta for the growth and development of the embryo and fetus.

Embryonic Period

The embryonic period is the period of organogenesis during which all the major organs and systems of the body differentiate from germ layer derivatives. Consequently, this is the time of greatest vulnerability to teratogens (including drugs, viruses and radiation) that interfere with development. The major features of external body form also establish at this time and the body grows rapidly.

Major processes during the embryonic period include formation of three germ layers ("gastrulation"), neurulation (formation of the neural tube), notochord and somite formation, and folding (establishment of body form). Gastrulation involves the development of three germ layers (in triploblastic organisms, like the human), formation of the primitive gut, and establishment of axial symmetry. The cardiovascular system is especially precocious and circulation begins early in the fourth week.

With their branchial (pharyngeal) arches and tail, vertebrate embryos look much alike for the first few weeks. The human embryo has less resemblance to other vertebrate embryos after the seventh week when the head begins to look more human and the tail regresses. Folding of the embryo and formation of the brain, heart, pharynx, somites, pharynx, liver, limbs, eyes, ears, and nose also greatly affect the external appearance of the embryo.

Formation of Germ Layers ("Gastrulation")

Primitive Streak

Following implantation, the inner cell mass of the blastocyst begins to differentiate into three primary germ layers, the embryonic tissues that will produce all tissues and organs of the body.

Before implantation, a layer of ectoderm (trophectoderm) already has developed around the blastocoel. The trophectoderm will form a portion of the chorion, one of the fetal membranes. As the blastocyst completes implantation during the second week, the inner cell mass undergoes marked differentiation. Within 8 days after fertilization, the upper layer of cells of the inner cell mass proliferates and produces another fetal membrane called the amnion and a slit-like space, the amniotic (amnionic) cavity, develops between the inner cell mass and the invading trophoblast.

Striking changes occur at about the twelfth day after fertilization. The inner cell mass below the amniotic cavity flattens into an embryonic disc that will form the embryo. At this stage, the embryonic disc consists of an upper ectodermal layer called the epiblast, which is closer to the amniotic cavity, and a lower endodermal layer called the hypoblast that borders the blastocyst cavity; mesodermal cells are scattered external to the embryonic disc.

At about the fourteenth day, epiblastic cells migrate toward and proliferate at the dorsal midline of the embryonic disc (blastodisc), forming a thick linear band of cells called the primitive streak. The primitive streak establishes a structural foundation for morphogenesis along the longitudinal axis of the embryo. Cells of the epiblast continue to proliferate and migrate to the center of the embryonic disc.

The primitive streak lengthens by addition of cells to its caudal end. As the primitive streak elongates, its cranial end enlarges to form the primitive knot. Cells from the primitive knot invaginate through a pit (blastopore). The primitive streak produces loose embryonic connective tissue called mesenchyme (mesoblast). The mesenchymal cells migrate inward (invaginate) and then move laterally and cranially between the epiblast and hypoblast. There they form a new cell layer between the epiblast and hypoblast called intraembryonic mesoderm. These cells establish contact with the extraembryonic mesoderm covering the amnion and yolk sac. Some mesoblastic cells invade the hypoblast and displace most or all of the hypoblastic cells laterally. This new germ layer is the intraembryonic (embryonic) endoderm. The cells that remain in the epiblast create the intraembryonic (embryonic) ectoderm, or neuroectoderm.

After arrival at the primitive streak, the cells migrate to the interior, between the epiblast and hypoblast to form embryonic mesoblast and endoderm. This movement, inaccurately called "gastrulation," produces three distinct embryonic layers with markedly different fates. (The term gastrulation is inappropriate because no "gastrula" is formed.) After this process begins, the upper layer that remains in contact with the amniotic cavity is the ectoderm, the lower hypoblast becomes the endoderm, and the middle intervening layer is mesoderm. These three layers are the primary germ layers. After they appear at the end of the second week, the preembryonic stage is complete and the embryonic stage begins. The mesoderm in the disc soon split into two layers, and the space between the layers becomes the extraembryonic coelom.

Mesenchyme from the primitive streak also differentiates into all the various kinds of connective tissue found in the adult and the mesodermal structures of the head.

The primary germ layers are important because they produce the various cells and tissues of the body. As the embryo develops, the ectodermal cells develop into the nervous system, the outer layer of skin (epidermis) including hair, nails, and skin glands, and portions of the sensory organs. Mesodermal cells form the peritoneum, muscle, bone, reproductive organs, dermis of the skin, blood and other connective tissue. Endodermal cells produce the epithelial lining of the of the digestive tract (digestive organs), respiratory tract (trachea, bronchi, and lungs), the urinary bladder, and the urethra. (See Chapter 3 for additional details.)

Notochordal (Head) Process

Mesenchymal cells that migrate through the blastopore produce a tubular midline structure, the notochordal (head) process that later becomes the notochord. The notochord provides a midline axis to provide support to the embryo and becomes the basis of the embryonic axial skeleton.

As the notochordal process lengthens, the primitive streak shortens. The notochordal process continues to grow cranially between the ectoderm and endoderm until its tip reaches the prochordal plate, the site of the future mouth. The prochordal plate firmly attaches to the overlying ectoderm, forming the oropharyngeal membrane. The oropharyngeal membrane prevents further cranial extension of the notochordal process. The cloacal membrane, the future site of the anus, is at the caudal end of the primitive streak.

Neurulation

The neural plate is initially rather narrow in the cervical region and somewhat wider in the cephalic region of the embryo. It gradually expands toward the primitive streak.

About the 18th day, the neural plate invaginates along its midline axis to form a neural groove with paired elevations on either side of the midline called neural folds. The neural groove between the neural folds deepens. The cranial end of the neural plate markedly expands and will later produce the vesicles of the brain. The more slender part of the neural tube caudal to the large cerebral region will become the spinal cord.

Fusion of the neural folds progresses rapidly toward the head and tail, but the anterior and posterior neuropores remain widely open for a while.

Somite Formation

Late in the third week, thick longitudinal bands of tissue on both sides of the midline produce intraembryonic mesoderm (paraxial mesoderm, or epimere). The intraembryonic mesoderm also organizes into intermediate mesoderm (mesomere—the primordia of the genitourinary system) and lateral plate mesoderm (hypomere—that will produce the somatic and splanchnic linings of the coelomic cavities).

The epimeres become segmented into somites that are the primordia of the axial skeleton (vertebral column, ribs, sternum, and skull), the voluntary muscles of the trunk, and the adjacent dermis of the skin. The appearance of somites is an indication of the metamerism (segmentation) of the body.

The first pair of somites develops a short distance caudal to the cranial end of the notochord. Subsequent pairs form in a craniocaudal sequence. About 38 pairs of somites form during the somite period (days 20 to 30), an average of two or three pairs per day. Eventually 42–44 pairs develop. The numbers of somites are one of the criteria used for determining the age of an embryo. By the time the caudal somites appear, the cranial ones differentiate. Therefore, at no time are all the somites visible.

Folding

Shortly after gastrulation begins, folding and differential growth of the embryonic disc produce a bulge known as the head fold that projects into the amniotic cavity. Similar movements produce a tail fold. The embryo is now physically and developmentally separated from the rest of the blastodisc and the extraembryonic membranes. The embryo now has dorsal and ventral surfaces and left and right sides.

Extraembryonic Membranes, Umbilical Cord, Multiple Pregnancy

While the germ layers are forming many intraembryonic structures and organs, the germ layers also produce a complex system of extraembryonic membranes that extend outside the embryonic body. The extraembryonic membranes include (1) the yolk sac (endoderm and mesoderm), (2) amnion (ectoderm and mesoderm), (3) allantois (endoderm and mesoderm), and (4) chorion (mesoderm and trophoblast). The extraembryonic membranes support embryonic and fetal development by maintaining a stable environment and by providing protection, respiration, excretion, and nutrition of the embryo and, later, the fetus. The placenta, umbilical cord, and extraembryonic membranes separate from the fetus at parturition and are expelled from the uterus as the afterbirth. Despite their importance during prenatal development, the extraembryonic membranes leave few traces in the adult.

When implantation first occurs, the nutrients absorbed by the trophoblast can easily reach the blastodisc by simple diffusion. As the embryo and the trophoblastic complex enlarge, however, the distance that separates the two increases and diffusion can not keep pace with the demands of the developing embryo. The chorion solves this problem, for blood vessels that develop within the mesoderm provide rapid transport between the embryo and trophoblast. Circulation through the chorionic vessels begins early in the third week of development when the heart begins to pump blood.

Amnion

Ectodermal cells spread over the inner surface of the amniotic cavity and mesodermal cells soon follow. The combination of ectoderm and mesoderm produces a thin extraembryonic membrane called the amnion. Amniotic development begins by the eighth day following fertilization, at which time its margin is attached around the free edge of the embryonic disc. The amnion later loosely surrounds the embryo, forming an amniotic sac filled with amniotic fluid. As the embryo and fetus enlarge, the amnion expands and contacts the chorion, increasing the size of the amniotic cavity. As the amniotic sac enlarges during the late embryonic period (about eight weeks), the amnion gradually ensheathes the developing umbilical cord with an epithelial covering.

Amniotic fluid is a buoyant medium that performs four functions for the embryo and fetus. Amniotic fluid (1) permits symmetrical development and growth; (2) cushions and protects by absorbing shocks that the mother may receive; (3) helps maintain constant pressure and temperature; and (4) enables freedom of fetal development, important for musculoskeletal development and blood flow.

Amniotic fluid first forms as an isotonic fluid absorbed from the maternal blood in the endometrium that surrounds the developing embryo. The volume later increases and the concentration changes by urine excreted from the fetus into the amniotic sac. The fetus normally swallows amniotic fluid, which becomes absorbed in the gastrointestinal tract. Amniotic fluid contains cells sloughed from the fetus, placenta, and amniotic sac. All of these cells develop from the same fertilized egg and have the same genetic composition. Thus, many genetic abnormalities can be detected through amniocentesis in which the amniotic fluid is aspirated and the cells obtained are examined.

The amnion usually ruptures naturally or surgically just before birth and the amniotic fluid ("bag of waters") is released.

Yolk sac

The yolk sac is the first extraembryonic membrane to develop. The yolk sac develops from migrating hypoblast cells that spread out around the outer edges of the blastocoel to form a complete pouch (exocoelomic membrane) suspended below the blastodisc. This pouch is visible 10 days after fertilization. As gastrulation continues, mesodermal cells migrate around the endodermal pouch and complete the formation of the yolk sac. Blood vessels soon appear within the mesoderm.

The yolk sac provides the primary or exclusive source of nutrition for the embryo in many species of vertebrates. The human embryo, however, receives its nourishment from the endometrium. The yolk sac in human embryos contains no nutritive yolk and remains small. Nevertheless, the yolk sac in humans is an essential structure during early embryonic development. The yolk sac is attached to the underside of the embryonic disc, where it produces early blood cells for the embryo until the liver develops during the sixth week. The dorsal portion of the yolk sac contributes to formation of the primitive gut. Furthermore, primordial germ cells develop in the wall of the yolk sac and migrate during the fourth week to the developing gonads where they become primitive germ cells (spermatogonia or oogonia).

The stalk of the yolk sac usually separates from the gut by the sixth week, and the yolk sac gradually shrinks as pregnancy advances. During an early stage of development, the yolk sac becomes a very small nonfunctional part of the umbilical cord, and it serves no additional developmental functions.

Allantois

The allantois, a small, vascularized sac of endoderm and mesoderm, forms during the third week as a small outpouching, or diverticulum, of the endoderm near the caudal wall of the yolk sac. The free endodermal tip grows toward the wall of the blastocyst, surrounded by a mass of mesodermal cells.

The allantois remains small but is involved in the formation of blood cells and its blood vessels—the umbilical arteries and vein—serve as connections in the placenta between mother and fetus. The base of the allantois later becomes the urinary bladder.

The extraembryonic segment of the allantois degenerates during the second month, but the intraembryonic portion involutes to form a thick urinary tube called the urachus. After delivery, the urachus becomes a fibrous cord called the median umbilical ligament that attaches to the urinary bladder.

Chorion

The chorion is the highly specialized outermost extraembryonic membrane. The mesoderm associated with the allantois spreads until it completely extends around the inside of the trophoblast (trophectoderm), forming a mesodermal layer beneath the trophoblast. The chorion develops from this combination of trophoblast and associated mesoderm.

Numerous, small, finger-like extensions called villi develop from the chorion and penetrate deeply into the uterine tissue. Initially, villi cover the entire surface of the chorion. Those villi on the surface toward the uterine cavity, however, gradually degenerate and produce a smooth, bare area called the smooth chorion. As this occurs, the villi associated with the uterine wall rapidly increase in number and branch, forming the portion of the chorion called the villous chorion. The villous chorion becomes highly vascular, and as the embryonic heart begins to function, blood is pumped close to the uterine wall.

Thus, the chorion eventually becomes the principal embryonic part of the placenta, the structure through which materials are exchanged between mother and fetus. The amnion also surrounds the embryo and, later, the fetus and eventually fuses to the inner layer of the chorion.

Placenta and Umbilical Cord

The placenta is a vascular structure that provides a vital link between maternal and embryonic systems. The placenta provides respiratory and nutritional support essential for further prenatal development, and it secretes hormones necessary to maintain pregnancy. The placenta forms from maternal and embryonic tissues. The embryonic portion of the placenta consists of the villi of the chorion frondosum; the maternal portion consists of the area of the endometrium called the decidua basalis into which the villi penetrate. Blood does not flow directly between the maternal and embryonic portions of the placenta but, because of the close membranous proximity, certain substances diffuse readily.

The first step in formation of a functional placenta, or placentation, is the appearance of blood vessels in the chorion. By the third week of development, mesoderm extends along the core of each of the trophoblastic villi, forming finger-like projections of the chorion called chorionic villi in contact with maternal tissues. These villi continue to enlarge and branch, forming an intricate network that grows into the decidua basalis of the endometrium. The villi will contain fetal blood vessels of the allantois. Maternal blood vessels continue to erode, and maternal blood slowly percolates through lacunae lined by syncytiotrophoblast. Lacunae fuse into increasingly larger lacunar networks, the primordia of the intervillous spaces of the placenta. Endometrial capillaries dilate into maternal sinusoids. The syncytiotrophoblast erodes some of them, causing maternal blood to seep into the lacunar networks and establish a primitive uteroplacental circulation. Diffusion occurs between the maternal blood flowing through the lacunae and fetal blood flowing through vessels within the chorionic villi.

Initially chorionic villi surround the entire blastocyst. The chorion continues to enlarge within the endometrium. By the fourth week, the embryo, amnion, and yolk sac are suspended within an expansive, fluid-filled chamber. The connection between the embryo and chorion, called the body stalk, contains the distal portions of the allantois and blood vessels that convey blood to and from the placenta. The yolk stalk is the narrow connection between the endoderm of the embryo and the yolk sac.

If implantation occurs, a portion of the endometrium becomes modified as the decidua that includes all but the deepest layer of the endometrium and is shed when the fetus is delivered. Regional differences in placental organization develop as placental expansion forms a prominent bulge in the endometrial surface. The names of the different regions of the decidua, all areas of the stratum functionalis, reflect their positions with respect to the site of the implanted ovum. The decidua capsularis is the relatively thin portion of the endometrium that covers the embryo and separates it from the uterine cavity; this layer does not participate in nutrient exchange and the chorionic villi disappear in this region. Placental functions are now concentrated in a disc-shaped area in the deepest portion of the endometrium called the decidua basalis between the chorion and the stratum basalis of the uterus; the decidua basalis becomes the maternal part of the placenta. The portion of the modified endometrium that lines the entire pregnant uterus, except for the area where the placenta is forming, is the decidua parietalis; the decidua parietalis has no contact with the chorion.

Development of the placenta is completed by the third month of pregnancy. As the end of the first trimester approaches, the fetus moves farther from the placenta, but it remains connected by the umbilical cord, or umbilical stalk, that contains the allantois, placental blood vessels, and yolk stalk.

Chapter 28: Human Development

by John F. Neas

The period of prenatal development can be subdivided into preembryonic, embryonic, and fetal periods. The preembryonic period begins with the fertilization of a secondary oocyte and continues through cleavage (an initial series of cells divisions) and implantation (the movement of the preembryo into the uterine lining). The preembryonic period is followed by the embryonic period that extends from implantation, typically occurring on the ninth or tenth day after fertilization, and continuing to the end of the eighth developmental week during which time the organ systems develop. The fetal period begins at the start of the ninth developmental week and culminates in parturition, or birth.

Preembryonic Period

The first two weeks of development, the preembryonic stage, is a period of cell division and differentiation. The events of this stage include fertilization, transportation of the zygote through the uterine tube, mitotic cell divisions (cleavage), formation of embryonic tissue and extraembryonic membranes (amnion, chorion, allantois, placenta, and umbilical cord), and the beginning of implantation of the blastocyst into the uterine wall. The term conceptus refers to all the products of conception including all structures that develop from the fertilized ovum (zygote), including the embryo and its extraembryonic membranes. The developing conceptus during the preembryonic period is self-sustaining. The embryo, however, is not self-supporting and must derive sustenance and protection from the mother through the extraembryonic membranes.

Preembryonic forms are the zygote (fertilized egg), morula (a solid ball of cells), blastocyst (hollow ball with a single germ layer), and bilaminar embryonic disc (with two germ layers).

First Week—Fertilization, Cleavage, Blastulation

Fertilization

The term fertilization refers to the penetration of an ovum by a spermatozoon and the subsequent fusion of the haploid gametes (sperm and eggs have 23 chromosomes in human beings) into a diploid zygote with the normal somatic number of chromosomes (46 in human beings).

The spermatozoon and ovum have very different functional roles and contributions. The spermatozoon merely delivers paternal chromosomes to the site of fertilization, but the ovum provides all the nourishment and genetic programming to support embryonic development for almost a week after conception. The volume of the ovum, therefore, is much greater than that of the spermatozoon.

Gamete Transport

Fertilization normally occurs in the ampulla of the uterine (Fallopian) tube and usually within 24 hours after ovulation. Peristaltic contractions and ciliary action transport the secondary oocyte a few centimeters through the uterine tube. The spermatozoa, however, must travel the distance between the vagina and the fertilization site in the ampulla. Transit time for the spermatozoa may be from 30 minutes to 2 hours. Several factors apparently accelerate the movement of spermatozoa in their passage. Sperm probably swim up the female reproductive tract by using whip-like movements of their flagella. In addition, the acrosome of sperm produces an enzyme called acrosin that stimulates sperm motility and migration within the female reproductive tract. Finally, contractions of the uterine musculature and ciliary currents in the uterine tubes probably help transport the sperm.

During coitus (sexual intercourse), a male ejaculates between 100 million and 500 million sperm into the vagina (typically about 200 million). This tremendous number is needed because of the high rate of sperm fatality. Very few, perhaps only several hundred to several thousand, enter the uterine tube and fewer than 100 survive to reach the ampulla. Therefore, males are functionally sterile if they have a sperm count below 20 million/ml because too few spermatozoa survive to reach the secondary oocyte. One or two spermatozoa cannot complete fertilization because of the condition of the secondary oocyte at ovulation.

Secondary Oocyte at Ovulation

A woman usually ovulates one secondary oocyte each month, totaling about four hundred during her reproductive years. Ovulation occurs before completion of oocyte maturation, and the secondary oocyte that leaves the follicle is arrested in metaphase of the second meiotic division during which time metabolism has been discontinued. To develop further, the secondary oocyte must await stimulation by fertilization.

Fertilization is complicated by the fact that the ovulated secondary oocyte is surrounded by intercellular materials, including a thin transparent gelatinous layer of protein and polysaccharides called the zona pellucida and several layers of cells called the corona radiata, the innermost of which are follicle (granulosa) cells. The corona radiata protects the secondary oocyte as it passes through the ruptured follicular wall and into the infundibulum of the uterine tube. The process of fertilization requires only a single sperm to contact the oocyte membrane, but that spermatozoon must first penetrate the corona radiata.

Besides assisting in the transport of sperm, the female reproductive tract also confers on sperm the capacity to fertilize a secondary oocyte. Sperm undergo maturation in the epididymis and are motile upon arrival in the vagina. Experiments have shown, however, that freshly ejaculated sperm are infertile and must remain in the acidic environment of the female reproductive tract for at least seven hours before they gain the ability to fertilize a secondary oocyte. The functional changes that sperm undergo in the female reproductive tract that enable them to fertilize a secondary oocyte are known as capacitation. The sperm cell has an organelle called an acrosome that forms a cap over the head. Capacitation is not fully understood but, during this process, the acrosome presumably secretes a trypsin-like enzyme that digests protein (proteinase) and hyaluronidase that digests hyaluronic acid, which is an important constituent of connective tissue

Acrosome Reaction

When a sperm encounters a secondary oocyte in the uterine tube, an acrosomal reaction occurs that exposes the digestive enzymes of the acrosome and allows a sperm to penetrate the corona radiata and zona pellucida. Dozens of spermatozoa must release hyaluronidase before the intercellular cement between the follicular cells in the corona radiata break down sufficiently to permit fertilization.

Oocyte Activation; Prevention of Polyspermy

Regardless of how many spermatozoa make their way through the zona pellucida and corona radiata, only a single spermatozoon will accomplish fertilization and activate the oocyte.

As the first sperm penetrates the zona pellucida and contacts the secondary oocyte, the plasma membranes of the gametes fuse, and the sperm enters the ooplasm, or cytoplasm of the oocyte. When the cell membranes of the sperm and secondary oocyte merge, the secondary oocyte becomes an ovum. The process of membrane fusion triggers oocyte activation—a series of changes in the metabolic activity of the secondary oocyte, including a sudden rise in metabolic rate. Furthermore, the cell membrane of the oocyte undergoes immediate electrical changes that block the entry of other sperm, and enzymes produced by the fertilized ovum alter receptor sites so that sperm already bound are detached and others are prevented from binding. Therefore, only one sperm can fertilize a secondary oocyte. Normal development cannot occur if more than one sperm penetrates the oocyte membrane, an event called polyspermy.

Completion of Meiosis

The fertilization of a secondary oocyte by a sperm in the uterine tube stimulates the ovum to complete its second meiotic division and form a diploid zygote. Like the first meiotic division, the second produces a large mature ovum that contains all the cytoplasm and the second polar body that, like the first polar body, ultimately fragments and disintegrates.

Pronucleus Formation and Amphimixis

At fertilization, the entire sperm enters the cytoplasm of the much larger ovum, the tail is shed, and the nucleus in the head develops into a structure called the male pronucleus. After oocyte activation and completion of meiosis, the nuclear material remaining within the ovum reorganizes as the female pronucleus. The male pronucleus migrates toward the center of the cell, and the two pronuclei fuse in a process called amphimixis to produce a segmentation nucleus that contains 23 chromosomes from the male pronucleus and 23 chromosomes from the female pronucleus. Within twelve hours, the nuclear membrane in the ovum disappears, and the haploid number of chromosomes (23) in the ovum joins the haploid number of chromosomes from the sperm. Thus, a fertilized egg, or zygote, is formed that contains the diploid number of chromosomes (46). The fertilized ovum, or zygote, consisting of a segmentation nucleus, cytoplasm, and enveloping membrane, prepares to begin mitotic divisions called cleavage that will ultimately produce billions of specialized cells.

Gamete Viability

A secondary oocyte that is ovulated but not fertilized does not complete its second meiotic division. Rather, it disintegrates twelve to twenty-four hours after ovulation without completing meiosis. Therefore, fertilization cannot occur if intercourse occurs beyond one day following ovulation. Sperm, however, can survive up to three days in the female reproductive tract. Thus, fertilization can occur if coitus occurs within three days before the day of ovulation.

Cleavage

Fertilization initiates cleavage, a series of rapid mitotic divisions that subdivides the cytoplasm of the zygote into smaller, essentially equipotential cells called blastomeres contained by the zona pellucida. Cleavage generates a multicellular system essential for further differentiation and morphogenesis. Cleavage increases the number of cells, but it does not result in an increase in the size of the developing organism. Cleavage begins immediately after fertilization and ends when the developing structure first contacts the uterine wall. During the period of cleavage, the zygote becomes a preembryo that develops into a multicellular complex called a blastocyst.

The first cleavage division results in the formation of a preembryo consisting of two identical blastomeres. The first cleavage is completed approximately 30 hours after fertilization, and each succeeding division takes slightly less time, occurring at 10- to 12-hour intervals. All of the blastomeres undergo mitosis simultaneously during the initial cleavage divisions, but the timing becomes less predictable as the number of blastomeres increases. The second cleavage is completed by the second day after conception. There are 16 blastomeres by the end of the third day.

Morula

Several cleavage divisions occur as the structure moves down the uterine tube toward the uterus. By the third day, successive divisions increase the number of blastomeres to about sixteen, forming a solid ball called a morula ("mulberry") consisting of an inner and an outer cell mass. The morula has the first evident segregation of materials and potencies. The morula enters the uterus on the third or fourth day. The morula has undergone several mitotic divisions, but it is about the same size as the original zygote because additional nutrients necessary for growth have not entered the cells.

Blastocyst Formation (Blastulation)

As the number of cells increases, the structure moves from the original site of fertilization down through the ciliated uterine tube toward the uterus and enters the uterine cavity on about the third day. The developing structure remains unattached in the uterine cavity for about three days during which time the center of the morula fills with fluid passing in from the uterine cavity. The fluid-filled spaces that form between the blastomeres of the morula coalesce by the fourth or fifth day into a large blastocyst cavity (blastocoel, or primary yolk sac). The morula is now a blastocyst. The blastocyst cavity separates a single spherical outer layer of trophoblast cells (trophectoderm) that form the wall of the blastocyst from a small, inner aggregation of cells called the inner cell mass, or embryoblast, that will become the embryo proper. The trophoblast will later combine with mesoderm to form the chorion that will become the fetal portion of the placenta.

The relatively independent conceptus floats freely in endometrial gland secretions as it passes down the uterine tubes into the uterus where it implants between the fifth and ninth days after ovulation.

The inner cell mass has little visible organization in the early blastocyst stage. At seven days, the conceptus is a blastocyst that enlarges, loses its zona pellucida and, during the following four days, becomes implanted in the uterine mucosa. During those four days, the inner cell mass begins to separate from the trophoblast. The separation gradually increases, producing a fluid-filled chamber called the amniotic cavity. At this stage the cells of the inner cell mass are organized into an oval sheet called a bilaminar embryonic disc (blastodisc) that initially consists of two epithelial layers—the epiblast (ectoderm) facing the amniotic cavity and the hypoblast (endoderm) exposed to the fluid contents of the blastocoel.

The trophoblast differentiates from the superficial layer of cells of the morula. The trophoblast differentiates into an actively invading, superficial layer, the syncytiotrophoblast, and a deep stratum, the cytotrophoblast. The cytotrophoblast and syncytiotrophoblast form the chorion and ultimately the definitive placenta. Cytotrophoblast also produces mesoblast that forms extraembryonic blood vessels.

Splanchnic mesoderm (lateral plate, hypomere) and hindgut endoderm produce the yolk sac and allantois. Splanchnic mesoderm also produces mesoderm of the amnion, the lining of which develops from surface ectoderm

Second Week—Implantation

It takes about 4 days after fertilization for the zygote to reach the uterus. The zygote arrives in the uterine cavity as a morula, and over the next 2–3 days, blastocyst (blastula) formation occurs. The blastocyst remains free within the uterine cavity for 2–4 days before it attaches to the uterine wall. During this period, the cells absorb nutrients rich in glycogen from secretions of the endometrial glands sometimes called uterine milk.

The process of implantation, or nidation, begins between the seventh and eighth days after fertilization. Implantation begins with the attachment of the blastocyst to the endometrium and continues as the blastocyst invades the uterine wall. As implantation proceeds, several other important events occur that set the stage for the formation of vital embryonic structures.

Implantation begins as the surface of the blastocyst closest to the inner cell contacts and adheres to the endometrial lining, usually upon the posterior wall of the fundus or body of the uterus. The endometrium at this time is in its postovulatory phase. The trophoblast (trophectoderm) below the implanting blastocyst divides rapidly, producing several layers of cells. Near the endometrial wall, the cell membranes that separate the trophoblast cells disappear, forming a layer of cytoplasm called the syncytiotrophoblast that contains multiple nuclei (Day 8). This outer layer begins to secrete the proteolytic enzyme hyaluronidase that digests and liquefies the intercellular cement between adjacent endometrial cells. The action of the enzyme erodes a gap and depression in the uterine epithelium that enables the blastocyst to penetrate the uterine lining. The migration and division of nearby endometrial cells soon repair the surface and cover the defect. When the repairs are completed, the blastocyst loses contact with the uterine cavity and becomes completely embedded within the endometrium. The blastocyst becomes oriented with the inner cell mass toward the endometrium. Subsequent development occurs entirely within the functional zone of the endometrium.

As implantation progresses, the syncytiotrophoblast continues to enlarge and expand into the surrounding endometrium (Day 9), resulting in disruption and enzymatic digestion of uterine glands. The nutrients released are absorbed by the syncytiotrophoblast and distributed by diffusion across the underlying cytotrophoblast to the inner cell mass. The fluid and nutrients provide the additional nourishment needed to support the early stages of embryo formation, especially during the first week after implantation. Trophoblastic extensions grow around endometrial capillaries and, as the capillary walls are destroyed, maternal blood begins to percolate through trophoblastic channels called lacunae. Finger-like projections called primary villi extend from the trophoblast into the surrounding endometrium. Each primary villus consists of an extension of syncytiotrophoblast with a core of cytotrophoblast. Over the next few days, the trophoblast begins to break down larger endometrial veins and arteries, and blood flow through the lacunae increases. Nutrients are eventually delivered through the placenta for the growth and development of the embryo and fetus.

Umbilical Cord

The umbilical cord forms as the yolk sac diminishes and the amnion expands to envelop the tissues beneath the embryo. The umbilical cord consists of an outer layer of amnion containing the two umbilical arteries, which carry deoxygenated blood toward the placenta, and one umbilical vein, which carries oxygenated blood from the placenta to the embryo. The umbilical vessels are surrounded by embryonic mucous connective tissue (Wharton’s jelly) from the allantois. The umbilical cord generally attaches near the center of the placenta. When fully formed, the umbilical cord is about 1–2 cm (0.5–1.0 in) in diameter and approximately 55 cm (2 ft) long. The umbilical cord has natural twists because the umbilical arteries are shorter than the umbilical vein.

At delivery, the placenta detaches from the uterus and as the afterbirth. At this time, the umbilical cord is severed, and the baby is on its own. The umbilicus (navel) is the scar that marks the site of the entry of the fetal umbilical cord into the abdomen.

Exchange of Molecules across the Placenta

The developing fetus completely depends on maternal organ systems for nourishment, respiration, and waste removal. The mother must absorb enough oxygen, nutrients, and vitamins for herself and her fetus, and she must eliminate all of the generated wastes. This is not a burden over the first weeks of gestation, but the demands upon the mother become significant in the second and third trimesters as the fetus grows.

Wastes leave the fetus through the umbilical arteries, pass into the capillaries of the villi of the chorion frondosum of the placenta, and diffuse into the maternal blood. Maternal blood is delivered to and drained from the cavities within the decidua basalis, which are located between the chorionic villi. The chorionic villi provide the surface area for active and passive exchange between the fetal and maternal circulatory systems. In this way, maternal and fetal blood is brought close together, but they normally never mix within the placenta. Oxygen and nutrients from the maternal blood diffuse into capillaries of the villi. From the capillaries, the nutrients and oxygen circulate to the fetus through the single umbilical vein.

Placental Functions

The placenta provides a site for the exchange of gases and other molecules between the maternal and fetal blood. Oxygen diffuses from mother to fetus, and carbon dioxide diffuses from the fetus to the mother. Nutrient molecules and waste products also pass between maternal and fetal blood.

The placenta, however, is not merely a passive conduit for exchange between maternal and fetal blood. The placenta has a very high metabolic rate and uses about a third of all the oxygen and glucose supplied by the maternal blood. The placenta has a higher rate of protein synthesis than the liver. Like the liver, the placenta produces many types of enzymes that can convert biologically active molecules (such as hormones and drugs) into less active, more water-soluble forms. Thus, the placenta prevents potentially dangerous molecules in the maternal blood from harming the fetus.

The placenta functions as an endocrine gland in secreting hormones that are important to maintain pregnancy and ensure optimal nutrition to the fetus. The placenta secretes glycoprotein hormones (hCG, hPL) that perform actions like those of some anterior pituitary hormones. In the later stages of gestation, the steroid hormones progesterone and estrogens stimulate the development of the mammary glands.

Multiple Pregnancy

The frequency of twins is about 1/85 pregnancies. Twins can develop in two ways. Dizygotic (fraternal) twins develop from the independent release of two oocytes in the same ovulatory cycle and the fertilization of each by different spermatozoa. Dizygotic twins are the same age and are in the uterus at the same time. Dizygotic twins may be of the same sex or different sexes and are as genetically dissimilar as any other siblings born at different times. Approximately two-thirds of twins are dizygotic. Dizygotic twins always have two chorions and two amnions, but the chorions and the placentas might be fused.

Monozygotic (identical) twins develop from a single fertilized oocyte (zygote) that divides at an early stage in development. Monozygotic twins are genetically identical and always the same sex. Any physical differences in monozygotic twins result from environmental factors during morphogenetic development (e.g., a differential vascular supply might cause expression of slight differences). Monozygotic twinning is usually initiated toward the end of the first week when the inner cell mass divides to produce two embryonic primordia. Monozygotic twins have two amnions but a single chorion and a common placenta. Conjoined (Siamese) twins may result if the inner cell mass fails to completely divide.

The frequency of triplets is about 1/7,600 pregnancies. Triplets may be (1) all from the same ovum and identical, (2) two identical twins and the third from another ovum, or (3) three zygotes from three different ova. Similar combinations occur in quadruplets, quintuplets, and so forth.

Chronological Changes of the Embryo

Third Week (15 to 21 Days)

These figures depict changes in external appearance of the embryo in dorsal and lateral views from the third through the eighth weeks. A discussion of the structural changes of the embryo by weeks follows.

The third week of development corresponds to the week following the first missed menstrual period. The embryo develops rapidly during this important period, beginning as a bilaminar (double-layered) embryonic disc, or embryoblast (inner cell mass), and ending as a trilaminar (three-layered) embryo.

At the beginning of the third week of development, the ectodermal germ layer forms a flat egg-shaped embryonic disc that is broadest in the cranial region. The conversion of the inner cell mass into a trilaminar embryonic disc ("gastrulation") begins at the end of the first week when hypoblast develops. The epiblast begins to develop during the second week and is complete during the third week when three germ layers develop.

During the first part of the third week, the primitive streak differentiates, neural folds appear, the allantoic duct begins to form, the yolk sac enlarges, and blood vessels begin to develop. The neural folds begin to unite, and the neurenteric canal is open. Primitive segments begin to form and the notochord develops. By the end of the third week, three basic germ layers develop that enable further tissue and organ differentiation.

By the fourth week following conception, a single layer of cuboidal ectodermal cells surrounds the embryo. Skin is one of the earliest formed organs. It develops to support and maintain homeostasis within the embryo.

Fourth Week (22 to 28 Days)

By the fourth week, most of the body systems are present in rudimentary form. These include the neural tube, that will form the eyes, brain, and spinal cord; the laryngotracheal groove and lung buds that become the respiratory system; and the esophagus, stomach, liver, and pancreatic buds of the gastrointestinal system. The thymus and thyroid glands begin to develop. The heart increases greatly in size, producing a prominent bulge in the branchial region. It begins to beat, pumping blood through a primitive circulatory system that connects capillary plexuses of the yolk sac and chorion to all parts of the embryo. The placenta starts to form and chorionic villi are highly developed. A connecting stalk, later involved in the formation of the umbilical cord, is established from the body of the embryo to the developing placenta.

During the fourth week the neural folds close, the somites increase in number, and the branchial arches appear. The yolk sac connection with the embryo becomes considerably narrowed so that the embryo develops a more definite form. The arm and leg buds appear as small swellings on the lateral body walls. The embryo increases to about 4 millimeters during the fourth week of development. The head and jaws become apparent.

Fifth Week (29 to 35 Days)

Most changes in body form are minor compared with the fourth week.

During the fifth week, the parathyroids, spleen, genital ridges and external genitalia begin to develop. The stomach begins to rotate and the midgut forms a loop.

The embryo becomes markedly curved. The appendages have formed from the limb buds that now show segments; paddle-shaped hand plates develop digital ridges called finger, or digital, rays. The head enlarges, and the developing eyes, ears, and nasal pit become obvious. The branchial arches undergo profound changes and partly disappear.

There is no definite neck region; it will later develop in the region of the fifth through twelfth somites. A slight depression between the cardiac prominence and the prominence of the developing liver indicates the position of the septum transversum, a component of the diaphragm.

The tiny, tadpole-like embryo is smaller than a grain of rice at the end of the first month.

Sixth Week (36 to 42 Days)

During the sixth week, the embryo is about 8–24 millimeters long. A flexure in the cervical region causes the body axis to bend nearly 90º, but the overall curvature of the embryo diminishes as the trunk and neck begin to straighten.

The trunk has straightened more and there is a suggestion of a lumbar curve. The developing liver causes the body wall to bulge superior to the umbilical cord. Together with the heart, the liver determines the shape of the ventral body until the eighth week when the gut dominates the belly cavity and the contour of the abdomen is more evenly rotund.

The head is much larger relative to the trunk, the brain has marked differentiation, and the branchial grooves disappear.

The limbs undergo substantial change during this week. The forelimbs lengthen and flex slightly, and notches appear between the rays in the hand and foot plates.

This is the most vulnerable period of development for many organs when teratogenic insults can cause considerable congenital damage.

Seventh and Eighth Weeks (43 to 56 Days)

The embryo now has distinctive human characteristics. The head is more round and erect but still disproportionately large, constituting almost half of the embryo's length. The eyes are well-developed, but the eyelids adhere to protect against probing fingers during muscular movement. The different parts of the auricle are distinguishable. The nostrils face forward but are plugged with mucus. Palatal development is incomplete. The upper lip is complete, and the nose is more prominent.

The head flexure gradually reduces, and although there are distinct cervical and lumbar curves, the trunk region continues to straighten. The neck establishes and the head partially extends. The abdomen becomes less protuberant. As the neck region establishes, the heart moves caudally to the thorax pulling the vagus and sympathetic nerves along with it.

Centers of ossification appear in the developing bones. The tail is still visible, but it is stubby.

Nipples begin to develop. The external genitalia are developing, but they are still undifferentiated.

A layer of periderm (epitrichium) covers the surface.

By the end of the embryonic period (end of the second month), the embryo measures from 27–31 millimeters in length from head to buttocks (one-third of it is the head), and weighs about 9.5 gm (about 1/3 oz).

The body systems are developed by the end of the embryonic period, and the nervous system begins coordinating body activity. The nervous and muscular systems have sufficient development so that spontaneous movements of the fetus are possible at this time. From this time on the developing human is a fetus.

Fetal Period

Second And Third Trimesters

This figure shows lateral views of the human fetus from the eleventh through the thirty-eighth week, depicting changes in external appearance. The fetal period does not have a formal system of staging. The following sections will consider the changes that occur in fetuses at periods of about every four weeks.

The fetal period extends from the ninth week (end of the second month) until birth, about ten lunar months after fertilization (usually about 38 weeks). The transition from embryo to fetus is gradual. The distinction is arbitrary but important because it emphasizes that the developing individual now has a recognizably human appearance.

During the fetal period the tissues and organs that became established by the primary germ layers during the embryonic period mature and very few new structures appear. This is primarily a period of tremendous body growth and specialization, integration, and final functional coordination of structure and function of body structures that results in a unified organism. A small amount of tissue differentiation and organ development still occurs during the fetal stage.

The fetus, encircled by the amnion, grows faster than the surrounding placenta throughout the fetal period. The mesodermal outer covering of the amnion soon fuses with the inner lining of the chorion.

The fetus is much less susceptible to the deforming effects of teratogens (viruses, drugs, and radiation) since most of the tissues and organs of the body appear during the embryonic period. Few, if any, malformations arise during the fetal period. Nevertheless, cytotoxic factors may injure or kill cells of the central nervous system resulting in postnatal behavioral disturbances and vision impairment.

During the third month, most body parts reach their final fetal positions. The rump and legs are relatively small and the tail completely disappears. The head, however, remains relatively large, about one half of the CR length at the beginning of the month. The head becomes comparatively smaller during the fetal period.

By the end of the second trimester, the fetus will weigh about 0.64 kg (1.4 lb). All of the organ systems become functional during the third trimester. The rate of growth begins to decrease, but the largest weight gain occurs during this trimester. In 3 months the fetus gains about 2.6 kg (5.7 lb), reaching a full-term weight of approximately 3.2 kg (7 lb).

Chronological Changes of the Embryo

Nine to Twelve Weeks

At the beginning of the ninth week, the fetus definitely resembles a human being, but the head is still disproportionately large, as large as the rest of the body (almost half the crown-rump length of the fetus). Head growth slows during the next three weeks, but growth in body length accelerates. The forehead is high and the face is broad. The eyes are widely spaced, and the ears are set low. The neck lengthens.

Ossification centers appear in most of the bones during the ninth week. Differentiation of the external genitalia becomes apparent at the end of the ninth week, but the genitalia are insufficiently developed to permit sex determination until the twelfth week.

By the end of 12 weeks, growth of the body has accelerated so rapidly that fetal length has more than doubled. The crown-rump length is about the same as the width of the adult palm (about 87 millimeters; 3.5 in). By the end of the twelfth week, the fetus weighs about 45 grams (1.6 oz).

The head is still relatively large and there is a well-defined neck. The eyes face forward, but the eyelids are fused (the eyes do not reopen until the seventh month). The external ears are on the side of the head at eye level. The nose gains a bridge.

The trunk region is slimmer. More organs are operating now. The liver produces bile, but the liver region is less protuberant.

The fetus can swallow, digest the fluid that passes through its alimentary tract, and defecate and urinate into the amniotic fluid. The fetus begins inhaling through its nose but can only take in amniotic fluid.

The fetus begins to move during the 9 to 12 week period. The nervous system and muscle coordination are developed sufficiently so that the fetus will withdraw its leg if tickled. Most muscular activity, however, is too slight to be felt by the mother.

Fetal ultrasound studies can detect major structural abnormalities that are not predictable from genetic analysis. Sound wave vibrations reflected from the interface of tissues with different densities (e.g., the interface between the fetus and amniotic fluid) produce an image. Fetal ultrasound is so sensitive that it can detect a fetal heartbeat several weeks before it can be heard through a stethoscope.

Thirteen to Sixteen Weeks

From thirteen through sixteen weeks, the facial features are well formed, and epidermal structures, such as eyelashes, eyebrows, hair on the head, fingernails, and nipples begin to develop. The extremities lengthen. The fetal heartbeat can be heard during the sixteenth week by applying a stethoscope to the mother’s abdomen. By the end of the sixteenth week, the fetus is about 140 mm in length (5.5 in) and weighs about 200 g (7 oz).

By the sixteenth week, the skeleton is sufficiently developed that it shows distinctly on a roentgenogram. Thus, after the sixteenth week, fetal length can be determined using X-ray film. The length of a fetus is generally reported as a straight-line measurement from the crown of the head to the developing ischium (crown-rump length). Measurements made on an embryo before the fetal stage, however, are reported as total length, not as crown-rump measurements.

Seventeen to Twenty Weeks

During the period from seventeen to twenty weeks, the legs achieve their final relative proportions. The mother can usually detect fetal movements, known as quickening. A white, cheese-like material called vernix caseosa and consisting of fatty secretions from the sebaceous glands and dead epidermal cells covers the skin. The vernix caseosa protects the fetus while it is bathed in amniotic fluid. The skin of twenty-week-old fetuses is usually covered by fine, silk-like fetal hair called lanugo that may hold the vernix caseosa on the skin and produce a ciliary-like motion that moves amniotic fluid. A twenty-week-old fetus is about 190 mm (7.5 in) in length and weighs 460 gm (16 oz). The fetus is cramped within the confines of the uterus and develops a marked spinal flexure commonly called the "fetal posture" with the head bent down in contact with the flexed knees.

Twenty-one to Twenty-five Weeks

During the period from twenty-one to twenty-five weeks, the fetus increases its weight to about 900 gm (32 oz), but body length increases only moderately (240 mm), so the weight is evenly proportioned. The skin is quite wrinkled and translucent pinkish in color because the blood flowing in the capillaries is visible.

Twenty-six to Twenty-nine Weeks

At the end of the seventh month, the crown rump length is about 270 mm (vertex to heels length is from 35–36 cm). The weight is about 1300 g (46 oz). The eyes open during this period. The body is well covered with lanugo. The testes should have begun descent into the scrotum.

As birth approaches, the fetus rotates to a vertex, or upside-down position, owing chiefly to the shape of the uterus and partly because the head is the heaviest part of the body.

The fetus has a good chance of survival if born prematurely now, but the mortality rate is high. The respiratory system of the fetus is sufficiently mature by this time that she or he might survive if born premature. Its metabolism cannot yet maintain a constant body temperature, and the respiratory muscles have not matured enough to provide a regular respiratory rate. The premature infant may survive, however, if placed in an incubator with its breathing maintained by a respirator. Nevertheless, survival is difficult and full term fetuses have the best chances.

The fetus at this age may suck its thumb, hiccup, and cry. It can taste sweet or sour, and respond to stimuli, including pain, light, and sound.

Placental function begins to diminish, as does the volume of amniotic fluid as fetus fills the uterus.

Thirty to Thirty-eight Weeks

The fetus can see and hear. Most systems are well developed. The lungs may still be immature, but premature fetuses 32 weeks and older usually survive. Fetuses born at 36 weeks of gestation have excellent chances for survival.

Weight increases considerably during the second half of pregnancy, especially during the last 2 _ months, when the fetus gains half of the full term weight (approximately 3200 grams). At 32 weeks, the fetus is about 30 cm (12 in) long and weighs about 2.25 kg (5 lb). Growth, especially of the brain, is great in this period.

There is a slowing of growth as the time of birth approaches. At the end of the 9th month, the head has the largest circumference of all parts of the body, though this is nearly equal to that of the abdomen. After the ninth month, the circumference of the abdomen exceeds that of the head. The diameters of the body parts are important considerations with regard to passage through the birth canal. At birth the fetus weighs 3000–3500 grams, has a crown-rump length of about 36 centimeters, and a crown-heel length of about 50 centimeters.

Final preparations are being made for birth, which can safely take place any time after the eighth month because the lungs are mature. More confined, and possibly engaged in the pelvis, the fetus may seem less active. The fetus usually assumes an upside-down position as birth approaches; this position is partly the result of the shape of the uterus and partly because the head outweighs the feet.

By full term (38 weeks after fertilization or 40 weeks after LMP), fetuses are fully developed, or "full-term." About 5 cm (2 in) and 1 kg (2.5 lb) are added to the length and weight. Male fetuses generally grow faster than females, and they generally weigh more at birth, about 3400 gm (7.5 pounds; range about 6.5–8 pounds). The crown-rump length is about 360 millimeters or 14 in (total length from crown to heel is about 50 centimeters, or 20 inches). The chest is prominent and both sexes have protruding breasts. At birth the head is about one-fourth the crown-heel length and has the greatest circumference.

Most fetuses are plump and have smooth skin resulting from the accumulation of subcutaneous fat. The skin is pinkish-blue, even on fetuses of dark-skinned parents because melanocytes do not produce melanin until the skin is exposed to sunlight. Lanugo hair is sparse and generally occurs on the head and back.

The chest is prominent, and the mammary area protrudes in both males and females. The umbilicus is almost in the middle of the body. The external genitalia are somewhat swollen.

Pregnancy, Labor, and Delivery

Pregnancy

Pregnancy is a sequence of events that includes fertilization, implantation, embryonic growth, and fetal growth that terminates in birth. The period of gestation is the time of pregnancy, or the time the zygote, embryo, or fetus spends in prenatal development in the female reproductive tract. Obstetrics (obstetrix = midwife) is the specialized branch of medicine concerned with pregnancy, labor, and the period of time immediately following delivery. The total human gestational period is ordinarily 266 days or about 280 days from the beginning of the last menstrual period to birth, or parturition. Most fetuses are born within 10–15 days before or after this due date.

Gestation, and Trimesters

For convenience, the gestation period is usually regarded as three integrated trimesters, each of 3 months duration. The first trimester, the period of embryonic and early fetal development, is a critical period for development because during this time the rudiments of all the major organ systems develop. The process of organ formation is called organogenesis. Many important and complex developmental events occur during the first trimester, such as cleavage, implantation, placentation, and embryogenesis. By the end of the first trimester, the fetus is almost 75 m (3 in) long and weighs about 14 g (0.5 oz). Only about 40% of embryos survive the first trimester. For this reason, pregnant women should avoid drugs or other disruptive stresses during the first trimester, in the hope of preventing a developmental abnormality, or anomaly. During the second trimester, the organs and organ systems complete most of their development, the body proportions change, and the fetus begins to acquire distinctively human characteristics. The third trimester is a period of rapid fetal growth. Most of the major organ systems become fully functional early in the third trimester, and an infant born 1–2 months prematurely may survive.

The uterus occupies most of the pelvic cavity by about the end of the third month of gestation. The uterus extends ever higher into the abdominal cavity as the fetus continues to grow. Toward the end of a full-term pregnancy, the uterus occupies nearly the entire abdominal cavity, rising above the costal margin almost to the xiphoid process of the sternum. The uterus will expand from 7.5 cm (3 in) to 30 cm (12 in) long and will contain approximately 5 liters of fluid. The uterus and its contents weigh approximately 10 kg (22 lb). This remarkable expansion occurs through enlargement and elongation of existing smooth muscle fibers. The expansion causes displacement of the maternal intestines, liver, and stomach upward, elevation of the diaphragm, widening of the thoracic cavity, and compression of the ureters and urinary bladder. Furthermore, the breasts enlarge in anticipation of lactation, and the areolae around the nipples become darkly pigmented.

Besides the anatomical changes associated with pregnancy, there are also physiological changes induced by pregnancy. Cardiac output rises by 30–40% by the twenty-seventh week attributable to increased maternal blood flow to the placenta and increased metabolism. Pulse rate increases by about 15 beats per minute. Blood volume increases up to 30–50%, mostly during the latter half of pregnancy. In the supine position, the enlarged uterus may compress the aorta, causing diminished blood flow to the uterus. Hormonal changes associated with pregnancy and compression of the inferior vena cava can cause varicose veins. Pulmonary function changes during pregnancy in that functional residual capacity decreases and tidal volume increases; the latter is attributable to hypocapnia and compensated respiratory alkalosis. There is a general decrease in gastrointestinal motility that can produce constipation and a delay in gastric emptying time. Pressure on the urinary bladder by the enlarging uterus can cause urinary symptoms, such as frequency, urgency, and stress incontinence.

 

Labor and Delivery

The delivery or expulsion of the fetus, a process known as parturition, or birth, is accompanied by a sequence of physiological and physical events called labor.

The onset of labor apparently relates to a complex interaction of many factors. Just before birth, the myometrium layer of the uterus contracts rhythmically and forcefully. Placental and ovarian hormones seem to play a role in these contractions. Labor cannot occur until the inhibitory effects of progesterone on uterine contractions are diminished. At the end of gestation, there is a sufficient level of estrogens in the mother’s blood to overcome the inhibiting effects of progesterone and labor commences. Perhaps some factor released by the placenta, fetus, or mother rather suddenly overcomes the inhibiting effects of progesterone so that estrogens can exert their effect. The contractions in the myometrium during labor are stimulated by (1) oxytocin, a polypeptide hormone produced in the hypothalamus and secreted by the posterior pituitary, and (2) prostaglandins , a class of fatty acids produced within the uterus itself. Labor can indeed be induced artificially by injections of oxytocin or by the insertion of prostaglandins into the vagina as a suppository. The hormone relaxin, produced by the corpus luteum, may also assist in labor and parturition. Relaxin softens the symphysis pubis in preparation for parturition and probably also softens the cervix in preparation for dilation. Relaxin, however, may not affect the uterus, but rather progesterone and estradiol may be responsible for this effect. Further research is necessary to understand the physiological effects of these hormones.

Uterine contractions, like peristaltic contractions, occur in waves; they begin at the fundus of the uterus and sweeps downward toward the cervix to expel the fetus. True labor begins when the pains corresponding to uterine contractions occur at regular intervals and intensify as the interval between contractions shortens. Another sign of true labor in some women is localization of pain in the back that is intensified by walking. A reliable indication of true labor is dilation of the cervix and a "show," or discharge of blood-containing mucus that accumulates in the cervical canal and vagina during labor. As parturition approaches, the force and frequency of the contractions increase, changing the position of the fetus and moving it toward the cervical canal. In false labor, abdominal pain is felt at irregular intervals, the pain does not intensify and is not changed significantly by walking, and there is a lack of cervical dilations and cervical "show."

Three to five percent of newborns are born breech. In a breech birth, the fetus has not rotated and the buttocks or legs are the presenting part; that is, these parts enter the vaginal canal before the fetal head. The main concern of a breech birth is the increased time and difficulty of the expulsion stage of parturition. Risks to the infant are relatively higher in breech births because the umbilical cord may become constricted, thus ending placental circulation. The cervix may dilate sufficiently to pass the legs and body but not the head, normally the widest part of the fetus. Entrapment of the fetal head compresses the umbilical cord, prolongs delivery, and subjects the fetus to severe distress and potential harm. Attempts to rotate the fetus by using forceps may injure the infant. If the fetus cannot be repositioned manually or delivered breech, a cesarean section must be performed. A cesarean section is delivery of the fetus through an incision into the abdominal wall and the uterus.

Dystocia, or difficult labor, may result from various deformities of the female pelvis that may be congenital or acquired from disease, fractures, or poor posture. Malposition of the fetus, malpresentation of the fetus, and premature rupture of the fetal membranes are among the conditions associated with difficult labor.

If the vaginal canal is too small to allow passage of the fetus and there is acute danger of perineal tearing, the passageway may be temporarily enlarged by performing an incision, or episiotomy, through the perineal musculature. After delivery the episiotomy can be repaired with sutures, a much simpler procedure than trying to control bleeding and repairing tissue damage associated with a potentially extensive perineal tear. If either dystocia or prolonged labor are present or if unexpected complications arise during the dilation or expulsion stages, it may be necessary to deliver the baby by a cesarean section. In a c-section, a low, horizontal incision is made through the abdominal wall and uterus, through which the baby and placenta are removed. Cesarean sections are performed during 15–25% of the deliveries in the United States. Efforts are being undertaken to reduce the frequency of episiotomies and cesarean sections.

Premature labor is true labor that begins before the fetus has completed normal development. The chances of newborn survival directly relate to body weight at delivery. Newborns that weigh less than 400 g (14 oz) will not survive even with massive supportive efforts, primarily because the respiratory, cardiovascular, and urinary systems cannot support life without the aid of maternal systems. Consequently, the separation between spontaneous abortion and immature delivery is usually 500 g (17.6 oz), the normal weight near the end of the second trimester.

Infants delivered before completing 7 months of gestation (weight less than 1 kg) have less than a 50% chance of survival. Most survivors suffer severe developmental abnormalities. A premature delivery produces a newborn that weighs more than 1 kg (35.2 oz); its chances of survival are fair to excellent, depending on individual circumstances.

Stages of Labor

Labor is usually divided into three stages—dilation, expulsion, and placental.

Dilation Stage

The stage of dilation is the time from the onset of true labor to complete dilation of the cervix. During this stage there are regular contractions of the uterus, usually a rupturing of the amniotic sac ("bag of waters"), and complete dilation of the cervix to a diameter of approximately 10 cm; the fetus begins to slide down the cervical canal. The amniotic sac is ruptured artificially if it does not rupture spontaneously. The dilation stage may last eight to twenty-four hours, depending on whether it is occurring in the first or a subsequent pregnancy. During this period the labor contractions occur at intervals of once every 10–30 minutes.

Expulsion Stage

The stage of expulsion is the time from complete cervical dilation to birth, or delivery (parturition). This period may require thirty minutes to 2 hours in a first pregnancy, but only a few minutes in subsequent pregnancies. The expulsion stage begins as the cervix dilates completely, pushed open by the descending fetus. Forceful uterine contractions and abdominal compressions expel the fetus from the uterus and through the vagina.

A pudendal nerve block may be administered during the early part of the expulsion stage to ease the trauma of delivery for the mother and for procedures such as episiotomy. The pudendal nerve provides the primary innervation to the skin and muscles of the perineum. In the transvaginal approach, the needle is inserted through the lateral vaginal wall to a point medial to the ischial spine. The anesthesia produces loss of the anal reflex, relaxation of the muscles of the floor of the pelvis, and loss of sensation to the vulva and lower third of the vagina.

Placental Stage

The placental stage is the period between delivery and expulsion of the placenta, or "afterbirth." Expulsion of the placenta usually occurs within an hour after delivery, and generally within ten to fifteen minutes after parturition. Powerful uterine contractions tear the connections between the endometrium and the placenta and constrict uterine blood vessels that were torn during delivery to reduce the possibility of hemorrhage. Blood loss accompanying disruption of the placenta in a normal delivery does not exceed 350 ml but may be as much as 500-600 ml, but the loss can be tolerated without difficulty because the maternal blood volume increased during pregnancy.

Figures for Second Submission

The table is arranged so that graphics (identified in column III) can be associated with the appropriate text topic (identified in column II).

descriptions for histology photomicrographs

Fertilization

Cleavage

Blastocyst Formation (Blastulation)

Second Week Implantation

Gastrulation (Formation of Germ Layers)

Folding

Extraembryonic Membranes, Umbilical Cord, Multiple Pregnancy
Umbilical cord histology
Prenatal Development
 
Chronological Changes of the Embryo
Embryonic development in lateral views

Fetal Period

Labor and Delivery



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