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Fetal Development and the Fetus as a Patient
Summary
The gestation period of humans from fertilization to birth is usually 266 days, or 38 weeks. As covered in the Introduction, the embryonic period , during which most of the major organ systems are formed, ends at the end of the eighth week of gestation. The remainder of gestation constitutes the fetal period , which is devoted mainly to the maturation of organ systems and to growth. For convenience, the 9-month gestation period is divided into three 3-month trimesters . It is not currently possible to keep alive fetuses born before about 22 weeks of gestation. Fetuses born between 22 and 28 weeks have progressively increasing survival rates (from about 15% at 22 weeks to about 90% at 28 weeks), but up to one-third of these have significant morbidity that affects their long-term survival.
Both the embryo, during weeks 3 to 8, and the fetus receive nutrients and eliminate their metabolic wastes via the placenta , an organ that has both maternal and fetal components. The mature placenta consists of a mass of feathery fetal villi that project into an intervillous space lined with fetal syncytiotrophoblast and filled with maternal blood. The fetal blood in the villous vessels exchanges materials with the maternal blood across the villus wall. However, exchange of nutrients is not the only function of the placenta; the organ also secretes a plethora of hormones, including the sex steroids that maintain pregnancy. Maternal antibodies cross the placenta to enter the fetus, where they provide protection against fetal and neonatal infections. Cell-free fetal DNA also crosses the placenta and can be detected in maternal blood plasma. Unfortunately, teratogenic compounds and some microorganisms also cross the placenta. The placenta grows along with the fetus; at birth it weighs about one-sixth as much as the fetus.
Development of the placenta begins when the implanting blastocyst induces the decidual reaction in the maternal endometrium, causing the endometrium to become a nutrient-packed, highly vascular tissue called the decidua . By the second month, the growing embryo begins to bulge into the uterine lumen. The protruding side of the embryo is covered with a thin capsule of decidua called the decidua capsularis , which later disintegrates as the fetus fills the womb. The decidua underlying the embedded embryonic pole of the embryo—the pole at which the embryonic disc and the connecting stalk are attached—is called the decidua basalis , which forms the maternal face of the developing placenta. The remainder of the maternal decidua is called the decidua parietalis .
The umbilical cord forms as a result of body folding. During this process, the amnion, which initially arises from the dorsal margin of the embryonic disc ectoderm, is carried ventrally to enclose the entire embryo, taking origin from the umbilical ring surrounding the roots of the vitelline duct and connecting stalk. The amnion also expands until it fills the chorionic space and fuses with the chorion. As the amnion expands, it encloses the connecting stalk and yolk sac neck in a sheath of amniotic membrane. This composite structure becomes the umbilical cord.
As covered in Chapter 2 , the intervillous space of the placenta originates as lacunae within the syncytiotrophoblast, which anastomose with maternal capillaries and become filled with maternal blood at about 10 weeks of gestation. Stem villi grow from the fetal chorion into these spaces. Each villus has a core of extraembryonic mesoderm containing blood vessels and a two-layered outer “skin” of cytotrophoblast and syncytiotrophoblast. Villi originally cover the entire chorion, but by the end of the third month, they are restricted to the area of the embryonic pole that becomes the site of the mature placenta. This part of the chorion is called the chorion frondosum ; the remaining, smooth chorion is the chorion laeve . The villi continue to grow and branch throughout gestation. The intervillous space is subdivided into 15 to 25 partially separated compartments, called cotyledons , by wedge-like walls of tissue called placental septae that grow inward from the maternal face of the placenta.
Twins formed by the splitting of a single early embryo (monozygotic twins) may share fetal membranes to varying degrees. In contrast, twins formed by the fertilization of two oocytes (dizygotic twins) always implant separately and develop independent sets of fetal membranes. Sharing of membranes can have negative consequences when vascular connections between the two placentas exist. Although rare, this can result in vascular compromise of one fetus and subsequent loss of that fetus, or even both fetuses.
Advances in analyzing fetal products in maternal serum, the safety and sophistication of techniques for sampling fetal tissues, the use of novel imaging techniques to examine the fetus, and the development of in utero fetal surgery are rapidly providing new approaches to the prenatal diagnosis and treatment of congenital disorders. Our improving ability to diagnose and treat diseases in utero and in very premature infants raises ethical and legal questions that require thoughtful debate. Questions of this nature have always arisen at the forefront of new medical techniques. What is somewhat unusual in this case is the extreme speed with which both our understanding of developmental biology and our clinical practice are advancing, along with the fact that decisions about, and solutions to, the resulting medical questions affect a new category of patient: the unborn fetus. The study and treatment of the fetus constitutes the field of prenatal pediatrics , or fetology .
Clinical Taster
A young couple is seen for a routine midgestational (week 20) ultrasound during their first pregnancy. The ultrasonographer is showing the couple their child, a boy, when she pauses. After a couple of minutes, she says that there may be “abnormalities,” so she will ask the doctor to take a look. After reviewing the scans, the perinatologist (an obstetric subspecialist who provides care for mother and fetus in higher-risk pregnancies) comes in and explains that the fetus has oligohydramnios (too little amniotic fluid), hydronephrosis (dilated ureters and kidneys), and megacystis (dilated bladder). She states her suspicion that the boy has bladder outlet obstruction due to a condition called posterior urethral valves . She tells them this is an abnormality of the urethra that prevents normal urine excretion and causes the urine to back up into bladder, ureters, and kidneys. She says that this backup can damage the kidneys, and the lack of amniotic fluid can prevent the lungs from developing normally. She says that if left untreated, the child will develop a condition called Potter sequence . The parents are warned that if nothing is done, the child will die at the time of birth as the result of respiratory failure .
An amniocentesis is performed for subsequent chromosome analysis, which shows a normal 46,XY karyotype, and in a second ultrasound, no other structural abnormalities are found. The couple is referred to a center with expertise in fetal surgery for correcting posterior urethral valves. After weighing the risks of surgery against the likelihood of postnatal death from pulmonary hypoplasia , the couple elects to undergo placement of a vesicoamniotic catheter (which shunts urine from the bladder to the amniotic cavity) at 22 weeks of gestation. The procedure goes well, and a follow-up ultrasound shows decompression of the bladder and urinary collecting system. The pregnancy is followed closely for signs of shunt malfunction, infection, amniotic fluid leakage, and preterm labor. The boy is delivered at 36 weeks of gestation, and surgery is done to create a vesicostomy (opening from the bladder to the abdominal wall), with urinary reconstructive surgery planned in the future.
Potter sequence can have multiple causes. Other clinical scenarios that result in this sequence are given in the “Embryology in Practice” and “Clinical Taster” for Chapter 15 .
During Fetal Period, Embryonic Organ Systems Mature and Fetus Grows
The preceding chapters have focused on the embryonic period , the period during which the organs and systems of the body are formed ( Fig. 6.1A ). The succeeding fetal period , from 8 weeks to birth at about 38 weeks, is devoted to the maturation of these organ systems and to growth (see Fig. 6.1B ; Table 6.1 ). The fetus grows from 14 g at the beginning of the fetal period (end of the second month) to about 3500 g at birth—a 250-fold increase. Most of this weight is added in the third trimester (7 to 9 months), although the fetus grows in length mainly in the second trimester (4 to 6 months). The growth of the fetus is accompanied by drastic changes in proportion: at 9 weeks, the head of the fetus represents about half its crown-rump length (the “sitting height” of the fetus), whereas at birth, it represents about one-fourth of the crown-rump length (see Timeline for this chapter).
Table 6.1
Fetal Growth.
See Figure Credits.
| Gestational Age (Completed Months of Development) | Approximate CR a Length (cm/in) | Approximate Weight/Mass (g/oz) |
|---|---|---|
| 2 | 5.5/2 | 14/0.5 |
| 3 | 12/4.5 | 100/3.5 |
| 4 | 16.5/6.5 | 300/10.5 |
| Approximate CH b length (cm/in) | Approximate Weight/Mass (g/lb) | |
| 5 | 30/12 | 600/1.3 |
| 6 | 37.5/15 | 1000/2.2 |
| 7 | 42.5/16.5 | 1700/3.8 |
| 8 | 47/18.5 | 2600/5.8 |
| 9 | 51/20 | 3500/7.5 |
Although all organ systems are present by 8 weeks, few of them are functional. The most prominent exceptions are the heart and blood vessels, which begin to circulate blood during the fourth week. Even so, the reconfiguration of the fetal circulatory system, covered in Chapter 13 , is not complete until 3 months. The sensory systems also lag. For example, the auditory ossicles are not free to vibrate until just before birth, and although the neural retina of the eye differentiates during the third and fourth months, the eyelids remain closed until the fifth to seventh month, and the eyes cannot focus properly until several weeks after birth.
A number of organs do not finish maturing until after birth. The most obvious example is the reproductive system and associated sexual characteristics, which, as in most animals, do not finish developing until the individual is old enough to be likely to reproduce successfully. In humans, a relatively large number of other organs are also immature at birth. This accounts for the prolonged helpless infancy of humans as compared with many mammals. The most slowly maturing organ of humans—the one that largely sets the pace of infancy and childhood—is the brain. Both the cerebrum and the cerebellum are quite immature at birth.
In the Research Lab
How Are Organ Growth and Body Growth Controlled During Embryogenesis?
What stops the continued growth of an organ, or of the fetus itself, once it reaches a particular size is a largely unanswered question. Circulating hormones and the availability of nutrients in utero clearly play an important role in growth, but how is growth regulated so that optimal size is obtained to allow the various organ systems to function in a coordinated fashion? Three factors are known to play integral roles in limiting organ growth. Two of these factors, the TOR pathway, which senses the availability of nutrients and regulates growth, and the growth factor insulin-like growth factor 1 (Igf-like1), were covered in the Introduction chapter in the context of aging. In addition to having a role in aging, it is now known that mutations in an allele of Igf-like1, which presumably regulate the functioning of the growth factor, are linked to the size of different breeds of domestic dogs. For example, little dogs, like Chihuahuas, have one gene variant that makes them small, and big dogs, like Great Danes, have another that makes them large. This correlation between type of variant and body size held when 3000 dogs from almost 150 breeds were genetically evaluated.
The third factor known to limit growth is a recently discovered pathway called the hippo pathway. Hippo signaling involves a kinase cascade (kinase signaling is covered in Chapter 5 ) with multiple other members with whimsical names such as warts, yorkie, salvador, and mats. When various members of this pathway are mutated, in organisms as diverse as Drosophila and mouse, overgrowth of organs or tissues occurs.
Development of Placenta
As the blastocyst implants, it stimulates a response in the uterine endometrium called the decidual reaction . The cells of the endometrial stroma (the fleshy layer of endometrial tissue that underlies the endometrial epithelium lining the uterine cavity) accumulate lipid and glycogen and are then called decidual cells . The stroma thickens and becomes more highly vascularized, and the endometrium as a whole is then called the decidua .
Late in the embryonic period, the abembryonic side of the growing embryo (the side opposite to the embryonic pole, where the embryonic disc and the connecting stalk attach) begins to bulge into the uterine cavity ( Fig. 6.2 ). This protruding portion of the embryo is covered by a thin capsule of endometrium called the decidua capsularis . The embedded embryonic pole of the embryo is underlain by a zone of decidua called the decidua basalis , which will participate in forming the mature placenta. The remaining areas of decidua are called the decidua parietalis . In the third month, as the growing fetus begins to fill the womb, the decidua capsularis is pressed against the decidua parietalis, and in the fifth and sixth months, the decidua capsularis disintegrates. By this time, the placenta is fully formed and has distinct fetal and maternal surfaces ( Fig. 6.3 ).
As covered in Chapter 2 , development of the uteroplacental circulatory system begins late in the second week, as cavities called trophoblastic lacunae form in the syncytiotrophoblast of the chorion and anastomose with maternal capillaries. At the end of the third week, fetal blood vessels begin to form in the connecting stalk and extraembryonic mesoderm. Meanwhile, the extraembryonic mesoderm lining the chorionic cavity proliferates to form tertiary stem villi that project into the trophoblastic lacunae, which become blood-filled after 10 weeks. By the end of the fourth week, tertiary stem villi cover the entire chorion. Hypoxia, or lower tissue oxygen content in the decidua, is critical for normal trophoblast invasion.
As the embryo begins to bulge into the uterine lumen during the second month, the villi on the protruding abembryonic side of the chorion disappear (see Fig. 6.2 ). This region of the chorion is now called the smooth chorion , or the chorion laeve , whereas the portion of the chorion associated with the decidua basalis retains its villi and is called the chorion frondosum (from Latin frondosus , leafy).
The placental villi continue to grow during most of the remainder of gestation. Starting in the ninth week, the tertiary stem villi lengthen by the formation of terminal mesenchymal villi , which originate as sprouts of syncytiotrophoblast ( trophoblastic sprouts ) similar in cross section to primary stem villi ( Fig. 6.4 ). These terminal extensions of the tertiary stem villi, called immature intermediate villi , reach their maximum length in the 16th week. The cells of the cytotrophoblastic layer become more dispersed in these villi, leaving gaps in that layer of the villus wall.
Starting near the end of the second trimester, the tertiary stem villi also form numerous slender side branches called mature intermediate villi . The first-formed mature intermediate villi finish forming by week 32 and then begin to produce small, nodule-like secondary branches called terminal villi . These terminal villi complete the structure of the placental villous tree . It has been suggested that the terminal villi are formed not by active outgrowth of the syncytiotrophoblast but rather by coiled and folded villous capillaries that bulge against the villus wall.
Because the intervillous space into which the villi project is formed from trophoblastic lacunae that grow and coalesce, it is lined on both sides with syncytiotrophoblast (see Fig. 6.4 ). The maternal face of the placenta, called the basal plate , consists of this syncytiotrophoblast lining plus a supporting layer of decidua basalis. On the fetal side, the layers of the chorion form the chorionic plate of the placenta.
During the fourth and fifth months, wedge-like walls of decidual tissue called placental (decidual) septa grow into the intervillous space from the maternal side of the placenta, separating the villi into 15 to 25 groups called cotyledons (see Figs. 6.3B, 6.4 ). Because the placental septa do not fuse with the chorionic plate, maternal blood can flow freely from one cotyledon to another.
Development of Umbilical Cord
As covered in Chapter 4 , body folding separates the forming embryo from its extraembryonic membranes . As this process occurs and the embryo grows, the amnion keeps pace, expanding until it encloses the entire embryo except for the umbilical area, where the connecting stalk and the yolk sac emerge ( Fig. 6.5 ). Between the fourth and eighth weeks, an increase in the production of amniotic fluid causes the amnion to swell until it completely takes over the chorionic space ( Fig. 6.6 ). When the amnion contacts the soft chorion, the layers of extraembryonic mesoderm covering the two membranes fuse loosely. Thus, the chorionic cavity disappears except for a few rudimentary vesicles.
After embryonic folding is complete, the amnion takes origin from the umbilical ring surrounding the roots of the vitelline duct and connecting stalk. Therefore, the progressive expansion of the amnion creates a tube of amniotic membrane that encloses the connecting stalk and the vitelline duct. This composite structure is now called the umbilical cord (see Figs. 6.1A, 6.3A ). As the umbilical cord lengthens, the vitelline duct narrows and the pear-shaped body of the yolk sac remains within the umbilical sheath. Normally, both the yolk sac and the vitelline duct disappear by birth.
The main function of the umbilical cord is to circulate blood between the embryo and the placenta. Umbilical arteries and veins develop in the connecting stalk to perform this function (covered in Chapter 13 ). The expanded amnion creates a roomy, weightless chamber in which the fetus can grow and develop freely. If the supply of amniotic fluid is inadequate (the condition known as oligohydramnios ), the abnormally small amniotic cavity may restrict fetal growth, which may result in severe malformations and pulmonary hypoplasia (covered in the “Clinical Taster” for this chapter).
Exchange of Substances Between Maternal and Fetal Blood in Placenta
Maternal blood enters the intervillous spaces of the placenta through about 100 spiral arteries , bathes the villi, and leaves again via endometrial veins . The placenta contains approximately 150 mL of maternal blood, and this volume is replaced about three or four times per minute. Nutrients and oxygen pass from the maternal blood across the cell layers of the villus into the fetal blood, and waste products such as carbon dioxide, urea, uric acid, and bilirubin (a breakdown product of hemoglobin) reciprocally pass from the fetal blood to the maternal blood.
Maternal proteins are endocytosed and degraded by the trophoblast unless bound to receptors (e.g., immunoglobulin [Ig]G, transcobalamin II). Antibodies cross the placenta to enter the fetal circulation; in this way, the mother gives the fetus limited passive immunity against a variety of infections, such as diphtheria and measles. These antibodies persist in the infant’s blood for several months after birth, guarding the infant against infectious diseases until its own immune system matures.
Erythroblastosis Fetalis
The transfer of antibodies from mother to fetus is not beneficial in one fairly common instance: when antibodies are directed against an Rh factor on the fetal red blood cells, causing hemolysis (dissolution) of the fetal red blood cells. The Rh factors are a group of genetically determined surface molecules that are present on the plasma membrane of red blood cells in most, but not all, individuals. Individuals whose blood cells carry an Rh factor are Rh+ ; individuals whose blood cells lack one are Rh− . Rh factors provoke a strong immune response in Rh− individuals. If an Rh− mother carries an Rh+ fetus, and fetal blood leaks into the maternal circulation, the mother will manufacture antibodies against the fetal red blood cells. Significant leaks of fetal blood across the placenta into the maternal circulation normally occur only at birth, so the resulting antibodies do not form in time to harm the fetus that first induces them. However, if the same mother bears a second Rh+ fetus, her anti-Rh antibodies can cross the placenta and destroy fetal red blood cells, causing anemia in the fetus and newborn. This condition is called hemolytic disease of the newborn , or erythroblastosis fetalis . The latter name comes from the fact that the destruction of red blood cells stimulates a compensatory production of large numbers of immature nucleated fetal red blood cells called erythroblasts . Another, sometimes fatal, consequence of the disease is hydrops fetalis : the accumulation of water in the fetus. Moreover, the destruction of red blood cells releases large amounts of bilirubin (a breakdown product of hemoglobin) into the fetal circulation. This substance can be deposited in the developing brain, leading to cerebral damage and, in some cases, to death.
The effects of erythroblastosis fetalis can be prevented by giving transfusions of Rh− blood to the fetus in utero and to the newborn, so that maternal antibodies find fewer cells to destroy. A more economical preventive approach is to administer anti-Rh antibodies (RhoGam) to the Rh− mother immediately after the birth of each Rh+ baby. These antibodies destroy the fetal Rh+ red blood cells in her circulation before they stimulate her own immune system, preventing her from manufacturing anti-Rh antibodies.
Transfer of Cell-Free Fetal DNA to Maternal Plasma
Recall that the fetal side of the placenta, including the external covering of the placental villi and the entire intervillous space, is lined with a layer of syncytiotrophoblast derived from the outer layer of the blastocyst (see Fig. 6.4C ). Apoptosis (programmed cell death) normally occurs throughout the syncytiotrophoblast during gestation, releasing fetal DNA, which enters the maternal circulation. Approximately 10% of the free-floating DNA in maternal plasma is fetal. Thus, using the polymerase chain reaction (PCR), fetal DNA can be detected in maternal plasma, beginning at about week 7 of gestation and continuing to birth, after which it is rapidly cleared. PCR of fetal DNA in maternal plasma allows early and accurate prenatal genetic diagnosis of the fetus. Recently, it was shown that the entire genome sequence of a fetus could be obtained in this non-invasive manner using “a teaspoon’s worth of maternal blood.” Currently, fetal DNA in maternal plasma is being used to diagnose trisomies and other chromosomal abnormalities (see Chapter 1 ) in the fetus developing in utero.
This noninvasive prenatal screening (NIPS, covered later in this chapter) analysis of fetal DNA is also used to sex the fetus near the end of the second month of gestation by looking for the presence or absence of the SRY and other genes present on the Y chromosome (covered in Chapter 16 ). Using amniocentesis or chorionic villus sampling (covered later in the chapter), fetuses can be sexed near the end of the third to fourth month of gestation (i.e., 1 to 2 months later). However, both of these procedures are invasive and have a risk as high as about 1% of inducing miscarriage. Finally, fetuses can be sexed and routinely are sexed by non-invasive ultrasonography (covered later in the chapter). However, ultrasonography cannot be done until still later, that is, not until 18 to 20 weeks of gestation.
Under what conditions would it be relevant to ascertain the sex of the fetus as early as possible? Two examples are compelling. First, if a couple already has a child with a rare genetic disorder that typically affects only boys, such as muscular dystrophy or hemophilia, they will of course be worried about having a second child with a disorder. Early sexing of the fetus would alleviate this concern early if the fetus is a girl. Second, as covered later in this chapter, women at risk of carrying a child with congenital adrenal hyperplasia (CAH) undergo preventive treatment during pregnancy with the potent corticosteroid dexamethasone to reduce masculinization of the external genitalia in affected female fetuses. If the fetus is a boy, such treatment could be stopped without ill effect on the fetus.
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