71 Fertilization and Development

In approximately nine months, a single cell—a fertilized egg—develops into a fully formed infant consisting of trillions of cells with myriad specialized functions. The dramatic changes of fertilization, embryonic development, and fetal development are followed by remarkable adaptations of the newborn to life outside the womb. An offspring’s normal development depends upon the appropriate synthesis of structural and functional proteins. This, in turn, is governed by the genetic material inherited from the parental egg and sperm, as well as environmental factors.

Females are considered the “fundamental” sex—that is, without much chemical prompting, all fertilized eggs would develop into females. To become a male, an individual must be exposed to the cascade of factors initiated by a single gene on the male Y chromosome. This is called the SRY (Sex-determining Region of the Y chromosome). Because females do not have a Y chromosome, they do not have the SRY gene. Without a functional SRY gene, an individual will be female.

Fertilization

Fertilization occurs when a sperm and an oocyte (egg) combine and their nuclei fuse. Because each of these reproductive cells is a haploid cell containing half of the genetic material needed to form a human being, their combination forms a diploid cell. This new single cell, called a zygote, contains all of the genetic material needed to form a human—half from the mother and half from the father.

Transit of Sperm

Fertilization is a numbers game. During ejaculation, hundreds of millions of sperm (spermatozoa) are released into the vagina. Almost immediately, millions of these sperm are overcome by the acidity of the vagina (approximately pH 3.8), and millions more may be blocked from entering the uterus by thick cervical mucus. Of those that do enter, thousands are destroyed by phagocytic uterine leukocytes. Thus, the race into the uterine tubes, which is the most typical site for sperm to encounter the oocyte, is reduced to a few thousand contenders. Their journey—thought to be facilitated by uterine contractions—usually takes from 30 minutes to 2 hours. If the sperm do not encounter an oocyte immediately, they can survive in the uterine tubes for another 3–5 days. Thus, fertilization can still occur if intercourse takes place a few days before ovulation. In comparison, an oocyte can survive independently for only approximately 24 hours following ovulation. Intercourse more than a day after ovulation will therefore usually not result in fertilization.

During the journey, fluids in the female reproductive tract prepare the sperm for fertilization through a process called capacitation, or priming. The fluids improve the motility of the spermatozoa. They also deplete cholesterol molecules embedded in the membrane of the head of the sperm, thinning the membrane in such a way that will help facilitate the release of the lysosomal (digestive) enzymes needed for the sperm to penetrate the oocyte’s exterior once contact is made. Sperm must undergo the process of capacitation in order to have the “capacity” to fertilize an oocyte. If they reach the oocyte before capacitation is complete, they will be unable to penetrate the oocyte’s thick outer layer of cells.

Contact Between Sperm and Oocyte

Upon ovulation, the oocyte released by the ovary is swept into—and along—the uterine tube. Fertilization must occur in the distal uterine tube because an unfertilized oocyte cannot survive the 72-hour journey to the uterus. As you will recall from your study of the oogenesis, this oocyte (specifically a secondary oocyte) is surrounded by two protective layers. The corona radiata is an outer layer of follicular (granulosa) cells that form around a developing oocyte in the ovary and remain with it upon ovulation. The underlying zona pellucida (pellucid = “transparent”) is a transparent, but thick, glycoprotein membrane that surrounds the cell’s plasma membrane.

As it is swept along the distal uterine tube, the oocyte encounters the surviving capacitated sperm, which stream toward it in response to chemical attractants released by the cells of the corona radiata. To reach the oocyte itself, the sperm must penetrate the two protective layers. The sperm first burrow through the cells of the corona radiata. Then, upon contact with the zona pellucida, the sperm bind to receptors in the zona pellucida. This initiates a process called the acrosomal reaction in which the enzyme-filled “cap” of the sperm, called the acrosome, releases its stored digestive enzymes. These enzymes clear a path through the zona pellucida that allows sperm to reach the oocyte. Finally, a single sperm makes contact with sperm-binding receptors on the oocyte’s plasma membrane. The plasma membrane of that sperm then fuses with the oocyte’s plasma membrane, and the head and mid-piece of the “winning” sperm enter the oocyte interior.

How do sperm penetrate the corona radiata? Some sperm undergo a spontaneous acrosomal reaction, which is an acrosomal reaction not triggered by contact with the zona pellucida. The digestive enzymes released by this reaction digest the extracellular matrix of the corona radiata. As you can see, the first sperm to reach the oocyte is never the one to fertilize it. Rather, hundreds of sperm cells must undergo the acrosomal reaction, each helping to degrade the corona radiata and zona pellucida until a path is created to allow one sperm to contact and fuse with the plasma membrane of the oocyte. If you consider the loss of millions of sperm between entry into the vagina and degradation of the zona pellucida, you can understand why a low sperm count can cause male infertility.

When the first sperm fuses with the oocyte, the oocyte deploys two mechanisms to prevent polyspermy, which is penetration by more than one sperm. This is critical because if more than one sperm were to fertilize the oocyte, the resulting zygote would be a triploid organism with three sets of chromosomes. This is incompatible with life.

The first mechanism is the fast block, which involves a near instantaneous change in sodium ion permeability upon binding of the first sperm, depolarizing the oocyte plasma membrane and preventing the fusion of additional sperm cells. The fast block sets in almost immediately and lasts for about a minute, during which time an influx of calcium ions following sperm penetration triggers the second mechanism, the slow block. In this process, referred to as the cortical reaction, cortical granules sitting immediately below the oocyte plasma membrane fuse with the membrane and release zonal inhibiting proteins and mucopolysaccharides into the space between the plasma membrane and the zona pellucida. Zonal inhibiting proteins cause the release of any other attached sperm and destroy the oocyte’s sperm receptors, thus preventing any more sperm from binding. The mucopolysaccharides then coat the nascent zygote in an impenetrable barrier that, together with hardened zona pellucida, is called a fertilization membrane.

The Zygote

Recall that at the point of fertilization, the oocyte has not yet completed meiosis; all secondary oocytes remain arrested in metaphase of meiosis II until fertilization. Only upon fertilization does the oocyte complete meiosis. The unneeded complement of genetic material that results is stored in a second polar body that is eventually ejected. At this moment, the oocyte has become an ovum, the female haploid gamete. The two haploid nuclei derived from the sperm and oocyte and contained within the egg are referred to as pronuclei. They decondense, expand, and replicate their DNA in preparation for mitosis. The pronuclei then migrate toward each other, their nuclear envelopes disintegrate, and the male- and female-derived genetic material intermingles. This step completes the process of fertilization and results in a single-celled diploid zygote with all the genetic instructions it needs to develop into a human.

Most of the time, a woman releases a single egg during an ovulation cycle. However, in approximately 1 percent of ovulation cycles, two eggs are released and both are fertilized. Two zygotes form, implant, and develop, resulting in the birth of dizygotic (or fraternal) twins. Because dizygotic twins develop from two eggs fertilized by two sperm, they are no more identical than siblings born at different times.

Much less commonly, a zygote can divide into two separate offspring during early development. This results in the birth of monozygotic (or identical) twins. Although the zygote can split as early as the two-cell stage, splitting occurs most commonly during the early blastocyst stage, with roughly 70–100 cells present. These two scenarios are distinct from each other, in that the twin embryos that separated at the two-cell stage will have individual placentas, whereas twin embryos that form from separation at the blastocyst stage will share a placenta and a chorionic cavity.

Embryonic Development

Throughout this chapter, we will express embryonic and fetal ages in terms of weeks from fertilization, commonly called conception. The period of time required for full development of a fetus in utero is referred to as gestation (gestare = “to carry” or “to bear”). It can be subdivided into distinct gestational periods. The first 2 weeks of prenatal development are referred to as the pre-embryonic stage. A developing human is referred to as an embryo during weeks 3–8, and a fetus from the ninth week of gestation until birth. In this section, we’ll cover the pre-embryonic and embryonic stages of development, which are characterized by cell division, migration, and differentiation. By the end of the embryonic period, all of the organ systems are structured in rudimentary form, although the organs themselves are either nonfunctional or only semi-functional.

Pre-implantation Embryonic Development

Following fertilization, the zygote and its associated membranes, together referred to as the conceptus, continue to be projected toward the uterus by peristalsis and beating cilia. During its journey to the uterus, the zygote undergoes five or six rapid mitotic cell divisions. Although each cleavage results in more cells, it does not increase the total volume of the conceptus. Each daughter cell produced by cleavage is called a blastomere (blastos = “germ,” in the sense of a seed or sprout).

Approximately 3 days after fertilization, a 16-cell conceptus reaches the uterus. The cells that had been loosely grouped are now compacted and look more like a solid mass. The name given to this structure is the morula (morula = “little mulberry”). Once inside the uterus, the conceptus floats freely for several more days. It continues to divide, creating a ball of approximately 100 cells, and consuming nutritive endometrial secretions called uterine milk while the uterine lining thickens. The ball of now tightly bound cells starts to secrete fluid and organize themselves around a fluid-filled cavity, the blastocoel. At this developmental stage, the conceptus is referred to as a blastocyst. Within this structure, a group of cells forms into an inner cell mass, which is fated to become the embryo. The cells that form the outer shell are called trophoblasts (trophe = “to feed” or “to nourish”). These cells will develop into the chorionic sac and the fetal portion of the placenta (the organ of nutrient, waste, and gas exchange between mother and the developing offspring).

The inner mass of embryonic cells is totipotent during this stage, meaning that each cell has the potential to differentiate into any cell type in the human body. Totipotency lasts for only a few days before the cells’ fates are set as being the precursors to a specific lineage of cells.

As the blastocyst forms, the trophoblast excretes enzymes that begin to degrade the zona pellucida. In a process called “hatching,” the conceptus breaks free of the zona pellucida in preparation for implantation.

Implantation

At the end of the first week, the blastocyst comes in contact with the uterine wall and adheres to it, embedding itself in the uterine lining via the trophoblast cells. Thus begins the process of implantation, which signals the end of the pre-embryonic stage of development. Implantation can be accompanied by minor bleeding. The blastocyst typically implants in the fundus of the uterus or on the posterior wall. However, if the endometrium is not fully developed and ready to receive the blastocyst, the blastocyst will detach and find a better spot. A significant percentage (50–75 percent) of blastocysts fail to implant; when this occurs, the blastocyst is shed with the endometrium during menses. The high rate of implantation failure is one reason why pregnancy typically requires several ovulation cycles to achieve.

When implantation succeeds and the blastocyst adheres to the endometrium, the superficial cells of the trophoblast fuse with each other, forming the syncytiotrophoblast, a multinucleated body that digests endometrial cells to firmly secure the blastocyst to the uterine wall. In response, the uterine mucosa rebuilds itself and envelops the blastocyst. The trophoblast secretes human chorionic gonadotropin (hCG), a hormone that directs the corpus luteum to survive, enlarge, and continue producing progesterone and estrogen to suppress menses. These functions of hCG are necessary for creating an environment suitable for the developing embryo. As a result of this increased production, hCG accumulates in the maternal bloodstream and is excreted in the urine. Implantation is complete by the middle of the second week. Just a few days after implantation, the trophoblast has secreted enough hCG for an at-home urine pregnancy test to give a positive result.

Most of the time an embryo implants within the body of the uterus in a location that can support growth and development. However, in one to two percent of cases, the embryo implants either outside the uterus (an ectopic pregnancy) or in a region of uterus that can create complications for the pregnancy. If the embryo implants in the inferior portion of the uterus, the placenta can potentially grow over the opening of the cervix, a condition call placenta previa.

Disorders of Implantation

In the vast majority of ectopic pregnancies, the embryo does not complete its journey to the uterus and implants in the uterine tube, referred to as a tubal pregnancy. However, there are also ovarian ectopic pregnancies (in which the egg never left the ovary) and abdominal ectopic pregnancies (in which an egg was “lost” to the abdominal cavity during the transfer from ovary to uterine tube, or in which an embryo from a tubal pregnancy re-implanted in the abdomen). Once in the abdominal cavity, an embryo can implant into any well-vascularized structure—the rectouterine cavity (Douglas’ pouch), the mesentery of the intestines, and the greater omentum are some common sites.

Tubal pregnancies can be caused by scar tissue within the tube following a sexually transmitted bacterial infection. The scar tissue impedes the progress of the embryo into the uterus—in some cases “snagging” the embryo and, in other cases, blocking the tube completely. Approximately one half of tubal pregnancies resolve spontaneously. Implantation in a uterine tube causes bleeding, which appears to stimulate smooth muscle contractions and expulsion of the embryo. In the remaining cases, medical or surgical intervention is necessary. If an ectopic pregnancy is detected early, the embryo’s development can be arrested by the administration of the cytotoxic drug methotrexate, which inhibits the metabolism of folic acid. If diagnosis is late and the uterine tube is already ruptured, surgical repair is essential.

Even if the embryo has successfully found its way to the uterus, it does not always implant in an optimal location (the fundus or the posterior wall of the uterus). Placenta previa can result if an embryo implants close to the internal os of the uterus (the internal opening of the cervix). As the fetus grows, the placenta can partially or completely cover the opening of the cervix. Although it occurs in only 0.5 percent of pregnancies, placenta previa is the leading cause of antepartum hemorrhage (profuse vaginal bleeding after week 24 of pregnancy but prior to childbirth).

Embryonic Membranes

During the second week of development, with the embryo implanted in the uterus, cells within the blastocyst start to organize into layers. Some grow to form the extra-embryonic membranes needed to support and protect the growing embryo: the amnion, the yolk sac, the allantois, and the chorion.

At the beginning of the second week, the cells of the inner cell mass form into a two-layered disc of embryonic cells, and a space—the amniotic cavity—opens up between it and the trophoblast. Cells from the upper layer of the disc (the epiblast) extend around the amniotic cavity, creating a membranous sac that forms into the amnion by the end of the second week. The amnion fills with amniotic fluid and eventually grows to surround the embryo. Early in development, amniotic fluid consists almost entirely of a filtrate of maternal plasma, but as the kidneys of the fetus begin to function at approximately the eighth week, they add urine to the volume of amniotic fluid. Floating within the amniotic fluid, the embryo—and later, the fetus—is protected from trauma and rapid temperature changes. It can move freely within the fluid and can prepare for swallowing and breathing out of the uterus.

On the ventral side of the embryonic disc, opposite the amnion, cells in the lower layer of the embryonic disk (the hypoblast) extend into the blastocyst cavity and form a yolk sac. The yolk sac supplies some nutrients absorbed from the trophoblast and also provides primitive blood circulation to the developing embryo for the second and third week of development. When the placenta takes over nourishing the embryo at approximately week 4, the yolk sac has been greatly reduced in size and its main function is to serve as the source of blood cells and germ cells (cells that will give rise to gametes). During week 3, a finger-like outpocketing of the yolk sac develops into the allantois, a primitive excretory duct of the embryo that will become part of the urinary bladder. Together, the stalks of the yolk sac and allantois establish the outer structure of the umbilical cord.

The last of the extra-embryonic membranes is the chorion, which is the one membrane that surrounds all others. The development of the chorion will be discussed in more detail shortly, as it relates to the growth and development of the placenta.

Embryogenesis

As the third week of development begins, the two-layered disc of cells becomes a three-layered disc through the process of gastrulation, during which the cells transition from totipotency to multipotency. The embryo, which takes the shape of an oval-shaped disc, forms an indentation called the primitive streak along the dorsal surface of the epiblast. A node at the caudal or “tail” end of the primitive streak emits growth factors that direct cells to multiply and migrate. Cells migrate toward and through the primitive streak and then move laterally to create two new layers of cells. The first layer is the endoderm, a sheet of cells that displaces the hypoblast and lies adjacent to the yolk sac. The second layer of cells fills in as the middle layer, or mesoderm. The cells of the epiblast that remain (not having migrated through the primitive streak) become the ectoderm.

Each of these germ layers will develop into specific structures in the embryo. Whereas the ectoderm and endoderm form tightly connected epithelial sheets, the mesodermal cells are less organized and exist as a loosely connected cell community. The ectoderm gives rise to cell lineages that differentiate to become the central and peripheral nervous systems, sensory organs, epidermis, hair, and nails. Mesodermal cells ultimately become the skeleton, muscles, connective tissue, heart, blood vessels, and kidneys. The endoderm goes on to form the epithelial lining of the gastrointestinal tract, liver, and pancreas, as well as the lungs.

Development of the Placenta

During the first several weeks of development, the cells of the endometrium—referred to as decidual cells—nourish the nascent embryo. During prenatal weeks 4–12, the developing placenta gradually takes over the role of feeding the embryo, and the decidual cells are no longer needed. The mature placenta is composed of tissues derived from the embryo, as well as maternal tissues of the endometrium. The placenta connects to the conceptus via the umbilical cord, which carries deoxygenated blood and wastes from the fetus through two umbilical arteries; nutrients and oxygen are carried from the mother to the fetus through the single umbilical vein. The umbilical cord is surrounded by the amnion, and the spaces within the cord around the blood vessels are filled with Wharton’s jelly, a mucous connective tissue.

The maternal portion of the placenta develops from the deepest layer of the endometrium, the decidua basalis. To form the embryonic portion of the placenta, the syncytiotrophoblast and the underlying cells of the trophoblast (cytotrophoblast cells) begin to proliferate along with a layer of extraembryonic mesoderm cells. These form the chorionic membrane, which envelops the entire conceptus as the chorion. The chorionic membrane forms finger-like structures called chorionic villi that burrow into the endometrium like tree roots, making up the fetal portion of the placenta. The cytotrophoblast cells perforate the chorionic villi, burrow farther into the endometrium, and remodel maternal blood vessels to augment maternal blood flow surrounding the villi. Meanwhile, fetal mesenchymal cells derived from the mesoderm fill the villi and differentiate into blood vessels, including the three umbilical blood vessels that connect the embryo to the developing placenta.

The placenta develops throughout the embryonic period and during the first several weeks of the fetal period; placentation is complete by weeks 14–16. As a fully developed organ, the placenta provides nutrition and excretion, respiration, and endocrine function. It receives blood from the fetus through the umbilical arteries. Capillaries in the chorionic villi filter fetal wastes out of the blood and return clean, oxygenated blood to the fetus through the umbilical vein. Nutrients and oxygen are transferred from maternal blood surrounding the villi through the capillaries and into the fetal bloodstream. Some substances move across the placenta by simple diffusion. Oxygen, carbon dioxide, and any other lipid-soluble substances take this route. Other substances move across by facilitated diffusion. This includes water-soluble glucose. The fetus has a high demand for amino acids and iron, and those substances are moved across the placenta by active transport.

Maternal and fetal blood does not commingle because blood cells cannot move across the placenta. This separation prevents the mother’s cytotoxic T cells from reaching and subsequently destroying the fetus, which bears “non-self” antigens. Further, it ensures the fetal red blood cells do not enter the mother’s circulation and trigger antibody development (if they carry “non-self” antigens)—at least until the final stages of pregnancy or birth. This is the reason that, even in the absence of preventive treatment, an Rh⁻ mother doesn’t develop antibodies that could cause hemolytic disease in her first Rh⁺ fetus.

Although blood cells are not exchanged, the chorionic villi provide ample surface area for the two-way exchange of substances between maternal and fetal blood. The rate of exchange increases throughout gestation as the villi become thinner and increasingly branched. The placenta is permeable to lipid-soluble fetotoxic substances: alcohol, nicotine, barbiturates, antibiotics, certain pathogens, and many other substances that can be dangerous or fatal to the developing embryo or fetus. For these reasons, pregnant women should avoid fetotoxic substances. Alcohol consumption by pregnant women, for example, can result in a range of abnormalities referred to as fetal alcohol spectrum disorders (FASD). These include organ and facial malformations, as well as cognitive and behavioral disorders.

Table 1: Functions of the Placenta

Nutrition and digestion	Respiration	Endocrine function
Mediates diffusion of maternal glucose, amino acids, fatty acids, vitamins, and minerals Stores nutrients during early pregnancy to accommodate increased fetal demand later in pregnancyExcretes and filters fetal nitrogenous wastes into maternal blood	Mediates maternal-to-fetal oxygen transport and fetal-to-maternal carbon dioxide transport	Secretes several hormones, including hCG, estrogens, and progesterone, to maintain the pregnancy and stimulate maternal and fetal development Mediates the transmission of maternal hormones into fetal blood and vice versa

 

Organogenesis

Following gastrulation, rudiments of the central nervous system develop from the ectoderm in the process of neurulation . Specialized neuroectodermal tissues along the length of the embryo thicken into the neural plate. During the fourth week, tissues on either side of the plate fold upward into a neural fold. The two folds converge to form the neural tube. The tube lies atop a rod-shaped, mesoderm-derived notochord, which eventually becomes the nucleus pulposus of intervertebral discs. Block-like structures called somites form on either side of the tube, eventually differentiating into the axial skeleton, skeletal muscle, and dermis. During the fourth and fifth weeks, the anterior neural tube dilates and subdivides to form vesicles that will become the brain structures.

Folate, one of the B vitamins, is important to the healthy development of the neural tube. A deficiency of maternal folate in the first weeks of pregnancy can result in neural tube defects, including spina bifida—a birth defect in which spinal tissue protrudes through the newborn’s vertebral column, which has failed to completely close. A more severe neural tube defect is anencephaly, a partial or complete absence of brain tissue.

The embryo, which begins as a flat sheet of cells, begins to acquire a cylindrical shape through the process of embryonic folding. The embryo folds laterally and again at either end, forming a C-shape with distinct head and tail ends. The embryo envelops a portion of the yolk sac, which protrudes with the umbilical cord from what will become the abdomen. The folding essentially creates a tube, called the primitive gut, that is lined by the endoderm. The amniotic sac, which was sitting on top of the flat embryo, envelops the embryo as it folds.

Within the first 8 weeks of gestation, a developing embryo establishes the rudimentary structures of all of its organs and tissues from the ectoderm, mesoderm, and endoderm. This process is called organogenesis.

Like the central nervous system, the heart also begins its development in the embryo as a tube-like structure, connected via capillaries to the chorionic villi. Cells of the primitive tube-shaped heart are capable of electrical conduction and contraction. The heart begins beating in the beginning of the fourth week, although it does not actually pump embryonic blood until a week later, when the oversized liver has begun producing red blood cells. (This is a temporary responsibility of the embryonic liver that the bone marrow will assume during fetal development.) During weeks 4–5, the eye pits form, limb buds become apparent, and the rudiments of the pulmonary system are formed.

During the sixth week, uncontrolled fetal limb movements begin to occur. The gastrointestinal system develops too rapidly for the embryonic abdomen to accommodate it, and the intestines temporarily loop into the umbilical cord. Paddle-shaped hands and feet develop fingers and toes by the process of apoptosis (programmed cell death), which causes the tissues between the fingers to disintegrate. By week 7, the facial structure is more complex and includes nostrils, outer ears, and lenses. By the eighth week, the head is nearly as large as the rest of the embryo’s body, and all major brain structures are in place. The external genitalia are apparent, but at this point, male and female embryos are indistinguishable. Bone begins to replace cartilage in the embryonic skeleton through the process of ossification. By the end of the embryonic period, the embryo is approximately 3 cm (1.2 in) from crown to rump and weighs approximately 8 g (0.25 oz).

Fetal Development

As you will recall, a developing human is called a fetus from the ninth week of gestation until birth. This 30-week period of development is marked by continued cell growth and differentiation, which fully develop the structures and functions of the immature organ systems formed during the embryonic period. The completion of fetal development results in a newborn who, although still immature in many ways, is capable of survival outside the womb.

Sexual Differentiation

Sexual differentiation does not begin until the fetal period, during weeks 9–12. Embryonic males and females, though genetically distinguishable, are morphologically identical. Bipotential gonads, or gonads that can develop into male or female sexual organs, are connected to a central cavity called the cloaca via Müllerian ducts and Wolffian ducts. (The cloaca is an extension of the primitive gut.) Several events lead to sexual differentiation during this period.

During male fetal development, the bipotential gonads become the testes and associated epididymis. The Müllerian ducts degenerate. The Wolffian ducts become the vas deferens, and the cloaca becomes the urethra and rectum.

During female fetal development, the bipotential gonads develop into ovaries. The Wolffian ducts degenerate. The Müllerian ducts become the uterine tubes and uterus, and the cloaca divides and develops into a vagina, a urethra, and a rectum.

The Fetal Circulatory System

During prenatal development, the fetal circulatory system is integrated with the placenta via the umbilical cord so that the fetus receives both oxygen and nutrients from the placenta. However, after childbirth, the umbilical cord is severed, and the newborn’s circulatory system must be reconfigured. When the heart first forms in the embryo, it exists as two parallel tubes derived from mesoderm and lined with endothelium, which then fuse together. As the embryo develops into a fetus, the tube-shaped heart folds and further differentiates into the four chambers present in a mature heart. Unlike a mature cardiovascular system, however, the fetal cardiovascular system also includes circulatory shortcuts, or shunts. A shunt is an anatomical (or sometimes surgical) diversion that allows blood flow to bypass immature organs such as the lungs and liver until childbirth.

The placenta provides the fetus with necessary oxygen and nutrients via the umbilical vein. (Remember that veins carry blood toward the heart. In this case, the blood flowing to the fetal heart is oxygenated because it comes from the placenta. The respiratory system is immature and cannot yet oxygenate blood on its own.) From the umbilical vein, the oxygenated blood flows toward the inferior vena cava, all but bypassing the immature liver, via the ductus venosus shunt. The liver receives just a trickle of blood, which is all that it needs in its immature, semifunctional state. Blood flows from the inferior vena cava to the right atrium, mixing with fetal venous blood along the way.

Although the fetal liver is semifunctional, the fetal lungs are nonfunctional. The fetal circulation therefore bypasses the lungs by shifting some of the blood through the foramen ovale, a shunt that directly connects the right and left atria and avoids the pulmonary trunk altogether. Most of the rest of the blood is pumped to the right ventricle, and from there, into the pulmonary trunk, which splits into pulmonary arteries. However, a shunt within the pulmonary artery, the ductus arteriosus, diverts a portion of this blood into the aorta. This ensures that only a small volume of oxygenated blood passes through the immature pulmonary circuit, which has only minor metabolic requirements. Blood vessels of uninflated lungs have high resistance to flow, a condition that encourages blood to flow to the aorta, which presents much lower resistance. The oxygenated blood moves through the foramen ovale into the left atrium, where it mixes with the now deoxygenated blood returning from the pulmonary circuit. This blood then moves into the left ventricle, where it is pumped into the aorta. Some of this blood moves through the coronary arteries into the myocardium, and some moves through the carotid arteries to the brain.

The descending aorta carries partially oxygenated and partially deoxygenated blood into the lower regions of the body. It eventually passes into the umbilical arteries through branches of the internal iliac arteries. The deoxygenated blood collects waste as it circulates through the fetal body and returns to the umbilical cord. Thus, the two umbilical arteries carry blood low in oxygen and high in carbon dioxide and fetal wastes. This blood is filtered through the placenta, where wastes diffuse into the maternal circulation. Oxygen and nutrients from the mother diffuse into the placenta and from there into the fetal blood, and the process repeats.

Other Organ Systems

During weeks 9–12 of fetal development, the brain continues to expand, the body elongates, and ossification continues. Fetal movements are frequent during this period, but are jerky and not well-controlled. The bone marrow begins to take over the process of erythrocyte production—a task that the liver performed during the embryonic period. The liver now secretes bile. The fetus circulates amniotic fluid by swallowing it and producing urine. The eyes are well-developed by this stage, but the eyelids are fused shut. The fingers and toes begin to develop nails. By the end of week 12, the fetus measures approximately 9 cm (3.5 in) from crown to rump.

Weeks 13–16 are marked by sensory organ development. The eyes move closer together; blinking motions begin, although the eyes remain sealed shut. The lips exhibit sucking motions. The ears move upward and lie flatter against the head. The scalp begins to grow hair. The excretory system is also developing: the kidneys are well-formed, and meconium, or fetal feces, begins to accumulate in the intestines. Meconium consists of ingested amniotic fluid, cellular debris, mucus, and bile.

During approximately weeks 16–20, as the fetus grows and limb movements become more powerful, the mother may begin to feel quickening, or fetal movements. However, space restrictions limit these movements and typically force the growing fetus into the “fetal position,” with the arms crossed and the legs bent at the knees. Sebaceous glands coat the skin with a waxy, protective substance called vernix caseosa that protects and moisturizes the skin and may provide lubrication during childbirth. A silky hair called lanugo also covers the skin during weeks 17–20, but it is shed as the fetus continues to grow. Extremely premature infants sometimes exhibit residual lanugo.

Developmental weeks 21–30 are characterized by rapid weight gain, which is important for maintaining a stable body temperature after birth. The bone marrow completely takes over erythrocyte synthesis, and the axons of the spinal cord begin to be myelinated, or coated in the electrically insulating glial cell sheaths that are necessary for efficient nervous system functioning. (The process of myelination is not completed until adolescence.) During this period, the fetus grows eyelashes. The eyelids are no longer fused and can be opened and closed. The lungs begin producing surfactant, a substance that reduces surface tension in the lungs and assists proper lung expansion after birth. Inadequate surfactant production in premature newborns may result in respiratory distress syndrome, and as a result, the newborn may require surfactant replacement therapy, supplemental oxygen, or maintenance in a continuous positive airway pressure (CPAP) chamber during their first days or weeks of life. In male fetuses, the testes descend into the scrotum near the end of this period. The fetus at 30 weeks measures 28 cm (11 in) from crown to rump and exhibits the approximate body proportions of a full-term newborn, but still is much leaner.

The fetus continues to lay down subcutaneous fat from week 31 until birth. The added fat fills out the hypodermis, and the skin transitions from red and wrinkled to soft and pink. Lanugo is shed, and the nails grow to the tips of the fingers and toes. Immediately before birth, the average crown-to-rump length is 35.5–40.5 cm (14–16 in), and the fetus weighs approximately 2.5–4 kg (5.5–8.8 lbs). Once born, the newborn is no longer confined to the fetal position, so subsequent measurements are made from head-to-toe instead of from crown-to-rump. At birth, the average length is approximately 51 cm (20 in).

Disorders of the Developing Fetus

Throughout the second half of gestation, the fetal intestines accumulate a tarry, greenish black meconium. The newborn’s first stools consist almost entirely of meconium; they later transition to seedy yellow stools or slightly formed tan stools as meconium is cleared and replaced with digested breast milk or formula, respectively. Unlike these later stools, meconium is sterile; it is devoid of bacteria because the fetus is in a sterile environment and has not consumed any breast milk or formula. Typically, an infant does not pass meconium until after birth. However, in 5–20 percent of births, the fetus has a bowel movement in utero, which can cause major complications in the newborn.

The passage of meconium in the uterus signals fetal distress, particularly fetal hypoxia (i.e., oxygen deprivation). This may be caused by maternal drug abuse (especially tobacco or cocaine), maternal hypertension, depletion of amniotic fluid, long labor or difficult birth, or a defect in the placenta that prevents it from delivering adequate oxygen to the fetus. Meconium passage is typically a complication of full-term or post-term newborns because it is rarely passed before 34 weeks of gestation, when the gastrointestinal system has matured and is appropriately controlled by nervous system stimuli. Fetal distress can stimulate the vagus nerve to trigger gastrointestinal peristalsis and relaxation of the anal sphincter. Notably, fetal hypoxic stress also induces a gasping reflex, increasing the likelihood that meconium will be inhaled into the fetal lungs.

Although meconium is a sterile substance, it interferes with the antibiotic properties of the amniotic fluid and makes the newborn and mother more vulnerable to bacterial infections at birth and during the perinatal period. Specifically, inflammation of the fetal membranes, inflammation of the uterine lining, or neonatal sepsis (infection in the newborn) may occur. Meconium also irritates delicate fetal skin and can cause a rash.

The first sign that a fetus has passed meconium usually does not come until childbirth, when the amniotic sac ruptures. Normal amniotic fluid is clear and watery, but amniotic fluid in which meconium has been passed is stained greenish or yellowish. Antibiotics given to the mother may reduce the incidence of maternal bacterial infections, but it is critical that meconium is aspirated from the newborn before the first breath. Under these conditions, an obstetrician will extensively aspirate the infant’s airways as soon as the head is delivered, while the rest of the infant’s body is still inside the birth canal.

Aspiration of meconium with the first breath can result in labored breathing, a barrel-shaped chest, or a low Apgar score. An obstetrician can identify meconium aspiration by listening to the lungs with a stethoscope for a coarse rattling sound. Blood gas tests and chest X-rays of the infant can confirm meconium aspiration. Inhaled meconium after birth could obstruct a newborn’s airways leading to alveolar collapse, interfere with surfactant function by stripping it from the lungs, or cause pulmonary inflammation or hypertension. Any of these complications will make the newborn much more vulnerable to pulmonary infection, including pneumonia.

Maternal Changes During Pregnancy, Labor, and Birth

A full-term pregnancy lasts approximately 270 days (approximately 38.5 weeks) from conception to birth. Because it is easier to remember the first day of the last menstrual period (LMP) than to estimate the date of conception, obstetricians set the due date as 284 days (approximately 40.5 weeks) from the LMP. This assumes that conception occurred on day 14 of the woman’s cycle, which is usually a good approximation. The 40 weeks of an average pregnancy are usually discussed in terms of three trimesters, each approximately 13 weeks. During the second and third trimesters, the pre-pregnancy uterus—about the size of a fist—grows dramatically to contain the fetus, causing a number of anatomical changes in the mother.

Effects of Hormones

Virtually all of the effects of pregnancy can be attributed in some way to the influence of hormones—particularly estrogens, progesterone, and hCG. During weeks 7–12 from the LMP, the pregnancy hormones are primarily generated by the corpus luteum. Progesterone secreted by the corpus luteum stimulates the production of decidual cells of the endometrium that nourish the blastocyst before placentation. As the placenta develops and the corpus luteum degenerates during weeks 12–17, the placenta gradually takes over as the endocrine organ of pregnancy.

The placenta converts weak androgens secreted by the maternal and fetal adrenal glands to estrogens, which are necessary for pregnancy to progress. Estrogen levels climb throughout the pregnancy, increasing 30-fold by childbirth. Estrogens have the following actions:

• They suppress FSH and LH production, effectively preventing ovulation. (This function is the biological basis of hormonal birth control pills.)
• They induce the growth of fetal tissues and are necessary for the maturation of the fetal lungs and liver.
• They promote fetal viability by regulating progesterone production and triggering fetal synthesis of cortisol, which helps with the maturation of the lungs, liver, and endocrine organs such as the thyroid gland and adrenal gland.
• They stimulate maternal tissue growth, leading to uterine enlargement and mammary duct expansion and branching.

Relaxin, another hormone secreted by the corpus luteum and then by the placenta, helps prepare the mother’s body for childbirth. It increases the elasticity of the symphysis pubis joint and pelvic ligaments, making room for the growing fetus and allowing expansion of the pelvic outlet for childbirth. Relaxin also helps dilate the cervix during labor.

The placenta takes over the synthesis and secretion of progesterone throughout pregnancy as the corpus luteum degenerates. Like estrogen, progesterone suppresses FSH and LH. It also inhibits uterine contractions, protecting the fetus from preterm birth. This hormone decreases in late gestation, allowing uterine contractions to intensify and eventually progress to true labor. The placenta also produces hCG. In addition to promoting survival of the corpus luteum, hCG stimulates the male fetal gonads to secrete testosterone, which is essential for the development of the male reproductive system.

The anterior pituitary enlarges and ramps up its hormone production during pregnancy, raising the levels of thyrotropin, prolactin, and adrenocorticotropic hormone (ACTH). Thyrotropin, in conjunction with placental hormones, increases the production of thyroid hormone, which raises the maternal metabolic rate. This can markedly augment a pregnant woman’s appetite and cause hot flashes. Prolactin stimulates enlargement of the mammary glands in preparation for milk production. ACTH stimulates maternal cortisol secretion, which contributes to fetal protein synthesis. In addition to the pituitary hormones, increased parathyroid levels mobilize calcium from maternal bones for fetal use.

Changes in Organ Systems During Pregnancy

As the woman’s body adapts to pregnancy, characteristic physiologic changes occur. These changes can sometimes prompt symptoms often referred to collectively as the common discomforts of pregnancy.

Digestive and Urinary System Changes

Nausea and vomiting, sometimes triggered by an increased sensitivity to odors, are common during the first few weeks to months of pregnancy. This phenomenon is often referred to as “morning sickness,” although the nausea may persist all day. The source of pregnancy nausea is thought to be the increased circulation of pregnancy-related hormones, specifically circulating estrogen, progesterone, and hCG. Decreased intestinal peristalsis may also contribute to nausea. By about week 12 of pregnancy, nausea typically subsides.

A common gastrointestinal complaint during the later stages of pregnancy is gastric reflux, or heartburn, which results from the upward, constrictive pressure of the growing uterus on the stomach. The same decreased peristalsis that may contribute to nausea in early pregnancy is also thought to be responsible for pregnancy-related constipation as pregnancy progresses.

The downward pressure of the uterus also compresses the urinary bladder, leading to frequent urination. The problem is exacerbated by increased urine production. In addition, the maternal urinary system processes both maternal and fetal wastes, further increasing the total volume of urine.

Circulatory System Changes

Blood volume increases substantially during pregnancy, so that by childbirth, it exceeds its preconception volume by 30 percent, or approximately 1–2 liters. The greater blood volume helps to manage the demands of fetal nourishment and fetal waste removal. In conjunction with increased blood volume, the pulse and blood pressure also rise moderately during pregnancy. As the fetus grows, the uterus compresses underlying pelvic blood vessels, hampering venous return from the legs and pelvic region. As a result, many pregnant women develop varicose veins or hemorrhoids.

Respiratory System Changes

During the second half of pregnancy, the respiratory minute volume (volume of gas inhaled or exhaled by the lungs per minute) increases by 50 percent to compensate for the oxygen demands of the fetus and the increased maternal metabolic rate. The growing uterus exerts upward pressure on the diaphragm, decreasing the volume of each inspiration and potentially causing shortness of breath, or dyspnea. During the last several weeks of pregnancy, the pelvis becomes more elastic, and the fetus descends lower in a process called lightening. This typically ameliorates dyspnea.

The respiratory mucosa swell in response to increased blood flow during pregnancy, leading to nasal congestion and nose bleeds, particularly when the weather is cold and dry. Humidifier use and increased fluid intake are often recommended to counteract congestion.

Integumentary System Changes

The dermis stretches extensively to accommodate the growing uterus, breast tissue, and fat deposits on the thighs and hips. Torn connective tissue beneath the dermis can cause striae (stretch marks) on the abdomen, which appear as red or purple marks during pregnancy that fade to a silvery white color in the months after childbirth.

An increase in melanocyte-stimulating hormone, in conjunction with estrogens, darkens the areolae and creates a line of pigment from the umbilicus to the pubis called the linea nigra. Melanin production during pregnancy may also darken or discolor skin on the face to create a chloasma, or “mask of pregnancy.”

Summary of Fertilization and Development

Fertilization

• Hundreds of millions of sperm deposited in the vagina travel toward the oocyte, but only a few hundred actually reach it. The number of sperm that reach the oocyte is greatly reduced because of conditions within the female reproductive tract. Many sperm are overcome by the acidity of the vagina, others are blocked by mucus in the cervix, whereas others are attacked by phagocytic leukocytes in the uterus.
• The sperm that do survive undergo a change in response to those conditions. They go through the process of capacitation, which improves their motility and alters the membrane surrounding the acrosome, the cap-like structure in the head of a sperm that contains the digestive enzymes needed for it to attach to and penetrate the oocyte.
• The oocyte that is released by ovulation is protected by a thick outer layer of granulosa cells known as the corona radiata and by the zona pellucida, a thick glycoprotein membrane that lies just outside the oocyte’s plasma membrane.
• When capacitated sperm make contact with the oocyte, they release the digestive enzymes in the acrosome (the acrosomal reaction) and are thus able to attach to the oocyte and burrow through to the oocyte’s zona pellucida. One of the sperm will then break through to the oocyte’s plasma membrane and release its haploid nucleus into the oocyte. The oocyte’s membrane structure changes in response (cortical reaction), preventing any further penetration by another sperm and forming a fertilization membrane.
• Fertilization is complete upon unification of the haploid nuclei of the two gametes, producing a diploid zygote.

Embryonic Development

• As the zygote travels toward the uterus, it undergoes numerous cleavages in which the number of cells doubles (blastomeres). Upon reaching the uterus, the conceptus has become a tightly packed sphere of cells called the morula, which then forms into a blastocyst consisting of an inner cell mass within a fluid-filled cavity surrounded by trophoblasts.
• The blastocyst implants in the uterine wall, the trophoblasts fuse to form a syncytiotrophoblast, and the conceptus is enveloped by the endometrium. Four embryonic membranes form to support the growing embryo: the amnion, the yolk sac, the allantois, and the chorion. The chorionic villi of the chorion extend into the endometrium to form the fetal portion of the placenta. The placenta supplies the growing embryo with oxygen and nutrients; it also removes carbon dioxide and other metabolic wastes.
• Following implantation, embryonic cells undergo gastrulation, in which they differentiate and separate into an embryonic disc and establish three primary germ layers (the endoderm, mesoderm, and ectoderm). Through the process of embryonic folding, the fetus begins to take shape. Neurulation starts the process of the development of structures of the central nervous system and organogenesis establishes the basic plan for all organ systems.

Fetal Development

• The fetal period lasts from the ninth week of development until birth. During this period, male and female gonads differentiate. The fetal circulatory system becomes much more specialized and efficient than its embryonic counterpart. It includes three shunts—the ductus venosus, the foramen ovale, and the ductus arteriosus—that enable it to bypass the semifunctional liver and pulmonary circuit until after childbirth.
• The brain continues to grow and its structures differentiate. Facial features develop, the body elongates, and the skeleton ossifies. In the womb, the developing fetus moves, blinks, practices sucking, and circulates amniotic fluid. The fetus grows from an embryo measuring approximately 3.3 cm (1.3 in) and weighing 7 g (0.25 oz) to an infant measuring approximately 51 cm (20 in) and weighing an average of approximately 3.4 kg (7.5 lbs). Embryonic organ structures that were primitive and nonfunctional develop to the point that the newborn can survive in the outside world.

Maternal Changes

• Hormones (especially estrogens, progesterone, and hCG) secreted by the corpus luteum and later by the placenta are responsible for most of the changes experienced during pregnancy. Estrogen maintains the pregnancy, promotes fetal viability, and stimulates tissue growth in the mother and developing fetus. Progesterone prevents new ovarian follicles from developing and suppresses uterine contractility.
• Pregnancy weight gain primarily occurs in the breasts and abdominal region. Nausea, heartburn, and frequent urination are common during pregnancy. Maternal blood volume increases by 30 percent during pregnancy and respiratory minute volume increases by 50 percent. The skin may develop stretch marks and melanin production may increase.
• Toward the late stages of pregnancy, a drop in progesterone and stretching forces from the fetus lead to increasing uterine irritability and prompt labor. Contractions serve to dilate the cervix and expel the newborn. Delivery of the placenta and associated fetal membranes follows.