Development of the Fetus
The period from the beginning of the ninth week to birth is known as the fetal period. It is characterized by maturation of tissues and organs and rapid growth of the body. The length of the fetus is usually indicated as the crown-rump length (CRL) (sitting height) or as the crown-heel length (CHL), the measurement from the vertex of the skull to the heel (standing height). These measurements, expressed in centimeters, are correlated with the age of the fetus in weeks or months (Table 8.1). Growth in length is particularly striking during the third, fourth, and fifth months, while an increase in weight is most striking during the last 2 months of gestation. In general, the length of pregnancy is considered to be 280 days, or 40 weeks after the onset of the last normal menstrual period (LNMP) or, more accurately, 266 days or 38 weeks after fertilization. For the purposes of the following discussion, age is calculated from the time of fertilization and is expressed in weeks or calendar months.
Table 8.1.Growth in Length and Weight During the Fetal Period
|Age (Wk)||CRL (cm)||Weight (g)|
One of the most striking changes taking place during fetal life is the relative slowdown in growth of the head compared with the rest of the body. At the beginning of the third month, the head constitutes approximately half of the CRL (Figs. 8.1 and 8.2). By the beginning of the fifth month, the size of the head is about one third of the CHL, and at birth, it is approximately one quarter of the CHL (Fig. 8.2). Hence, over time, growth of the body accelerates but that of the head slows down.
Figure 8.1.A 9-week fetus.
Note the large head size compared with that of the rest of the body. The yolk sac and long vitelline duct are visible in the chorionic cavity. Note the umbilical cord and herniation of intestinal loops. One side of the chorion has many villi (chorion frondosum), while the other side is almost smooth (chorion laeve).
Figure 8.2.Size of the head in relation to the rest of the body at various stages of development.
During the third month, the face becomes more human looking (Figs. 8.3 and 8.4). The eyes, initially directed laterally, move to the ventral aspect of the face, and the ears come to lie close to their definitive position at the side of the head (Fig. 8.3). The limbs reach their relative length in comparison with the rest of the body, although the lower limbs are still a little shorter and less well developed than the upper extremities. Primary ossification centers are present in the long bones and skull by the 12th week. Also by the 12th week, external genitalia develop to such a degree that the sex of the fetus can be determined by external examination (ultrasound). During the sixth week, intestinal loops cause a large swelling (herniation) in the umbilical cord, but by the 12th week, the loops have withdrawn into the abdominal cavity. At the end of the third month, reflex activity can be evoked in aborted fetuses, indicating muscular activity.
Figure 8.3.An 11-week fetus.
The umbilical cord still shows a swelling at its base, caused by herniated intestinal loops. The skull of this fetus lacks the normal smooth contours. Fingers and toes are well developed.
Figure 8.4.A 12-week fetus in utero.
Note the extremely thin skin and underlying blood vessels. The face has all of the human characteristics, but the ears are still primitive. Movements begin at this time but are usually not felt by the mother.
During the fourth and fifth months, the fetus lengthens rapidly (Fig. 8.5 and Table 8.1), and at the end of the first half of intrauterine life, its CRL is approximately 15 cm, about half the total length of the newborn. The weight of the fetus increases little during this period and by the end of the fifth month is still <500 g. The fetus is covered with fine hair, called lanugo hair; eyebrows and head hair are also visible. During the fifth month, movements of the fetus can be felt by the mother.
Figure 8.5.An 18-week fetus connected to the placenta by its umbilical cord.
The skin of the fetus is thin because of lack of subcutaneous fat. Note the placenta with its cotyledons and the amnion.
During the second half of intrauterine life, weight increases considerably, particularly during the last 2.5 months, when 50% of the full-term weight (approximately 3,200 g) is added. During the sixth month, the skin of the fetus is reddish and has a wrinkled appearance because of the lack of underlying connective tissue. A fetus born early in the sixth month has great difficulty surviving. Although several organ systems are able to function, the respiratory system and the central nervous system have not differentiated sufficiently, and coordination between the two systems is not yet well established. By 6.5 to 7 months, the fetus has a CRL of about 25 cm and weighs approximately 1,100 g. If born at this time, the infant has a 90% chance of surviving. Some developmental events occurring during the first 7 months are indicated in Table 8.2.
Table 8.2.Developmental Horizons During Fetal Life Event
|Taste buds appear||7|
|Some sounds can be heard||24–26|
|Eyes sensitive to light||28|
During the last 2 months, the fetus obtains well-rounded contours as the result of deposition of subcutaneous fat (Fig. 8.6). By the end of intrauterine life, the skin is covered by a whitish, fatty substance (vernix caseosa) composed of secretory products from sebaceous glands.
Figure 8.6.A 7-month fetus.
This fetus would be able to survive. It has well-rounded contours as a result of deposition of subcutaneous fat. Note the twisting of the umbilical cord.
At the end of the ninth month, the skull has the largest circumference of all parts of the body, an important fact with regard to its passage through the birth canal. At the time of birth, the weight of a normal fetus is 3,000 to 3,400 g, its CRL is about 36 cm, and its CHL is about 50 cm. Sexual characteristics are pronounced, and the testes should be in the scrotum.
Time of Birth
The date of birth is most accurately indicated as 266 days, or 38 weeks, after fertilization. The oocyte is usually fertilized within 12 hours of ovulation; however, sperm deposited in the reproductive tract up to 6 days prior to ovulation can survive to fertilize oocytes. Thus, most pregnancies occur when sexual intercourse occurs within a 6-day period that ends on the day of ovulation. A pregnant woman usually will see her obstetrician when she has missed two successive menstrual bleeds. By that time, her recollection about coitus is usually vague, and it is readily understandable that the day of fertilization is difficult to determine.
The obstetrician calculates the date of birth as 280 days or 40 weeks from the first day of the LNMP. In women with regular 28-day menstrual periods, the method is fairly accurate, but when cycles are irregular, substantial miscalculations may be made. An additional complication occurs when the woman has some bleeding about 14 days after fertilization as a result of erosive activity by the implanting blastocyst (see Chapter 4, Day 13). Hence, the day of delivery is not always easy to determine. Most fetuses are born within 10 to 14 days of the calculated delivery date. If they are born much earlier, they are categorized as premature; if born later, they are considered postmature.
Occasionally, the age of an embryo or small fetus must be determined. By combining data on the onset of the last menstrual period with fetal length, weight, and other morphological characteristics typical for a given month of development, a reasonable estimate of the age of the fetus can be formulated. A valuable tool for assisting in this determination is ultrasound, which can provide an accurate (1 to 2 days) measurement of CRL during the 7th to 14th weeks. Measurements commonly used in the 16th to 30th weeks are biparietal diameter (BPD), head and abdominal circumference, and femur length. An accurate determination of fetal size and age is important for managing pregnancy, especially if the mother has a small pelvis or if the baby has a birth defect.
Low Birth Weight
There is considerable variation in fetal length and weight, and sometimes these values do not correspond with the calculated age of the fetus in months or weeks. Most factors influencing length and weight are genetically determined, but environmental factors also play an important role.
The average size of a newborn is 2,500 to 4,000 g (6 to 9 lb) with a length of 51 cm (20 in). The term low birth weight (LBW) refers to a weight <2,500 g, regardless of gestational age. Many infants weigh <2,500 g because they are preterm (born before 37 weeks of gestation). In contrast, the terms intrauterine growth restriction (IUGR) and small for gestational age (SGA) take into account gestational age.
IUGR is a term applied to infants who do not attain their optimal intrauterine growth. These infants are pathologically small and at risk for poor outcomes. Infants who are SGA have a birth weight that is below the 10th percentile for their gestational age. These babies may be pathologically small (they may have IUGR) or they may be constitutionally small (healthy, but smaller in size). The challenge is to differentiate the two conditions so that healthy, but small babies are not subjected to high-risk protocols used for babies with IUGR.
Approximately 1 in 10 babies have IUGR and therefore have an increased risk of neurological problems, congenital malformations, meconium aspiration, hypoglycemia, hypocalcemia, and respiratory distress syndrome (RDS). There are also long-term effects on these infants. For example, babies with IUGR have been shown to have a greater chance as adults to develop a metabolic disorder later in life, such as obesity, hypertension, hypercholesterolemia, cardiovascular disease, and type 2 diabetes (called Barker’s hypothesis).
The incidence of IUGR is higher in blacks than in whites. Causative factors include chromosomal abnormalities; teratogens; congenital infections (rubella, cytomegalovirus, toxoplasmosis, and syphilis); poor maternal health (hypertension and renal and cardiac disease); the mother’s nutritional status and socioeconomic level; her use of cigarettes, alcohol, and other drugs; placental insufficiency; and multiple births (e.g., twins, triplets).
The major growth-promoting factor during development before and after birth is insulin-like growth factor-I (IGF-I), which has mitogenic and anabolic effects. Fetal tissues express IGF-I, and serum levels are correlated with fetal growth. Mutations in the IGF-I gene result in IUGR, and this growth retardation is continued after birth. In contrast to the prenatal period, postnatal growth depends on growth hormone (GH). This hormone binds to its receptor (GHR), activating a signal transduction pathway and resulting in synthesis and secretion of IGF-I. Mutations in the GHR result in Laron’s dwarfism, which is characterized by marked short stature, and sometimes blue sclera. These individuals show little or no IUGR, because IGF-I production does not depend on GH during fetal development.
Fetal Membranes and Placenta
The placenta is the organ that facilitates nutrient and gas exchange between the maternal and fetal compartments. As the fetus begins the ninth week of development, its demands for nutritional and other factors increase, causing major changes in the placenta. Foremost among these is an increase in surface area between maternal and fetal components to facilitate exchange. The disposition of fetal membranes is also altered as production of amniotic fluid increases.
Changes in the Trophoblast
The fetal component of the placenta is derived from the trophoblast and extraembryonic mesoderm (the chorionic plate); the maternal component is derived from the uterine endometrium. By the beginning of the second month, the trophoblast is characterized by a great number of secondary and tertiary villi, which give it a radial appearance (Fig. 8.7). Stem (anchoring) villi extend from the mesoderm of the chorionic plate to the cytotrophoblast shell. The surface of the villi is formed by the syncytium, resting on a layer of cytotrophoblastic cells that in turn cover a core of vascular mesoderm (Fig. 8.8A,C). The capillary system developing in the core of the villous stems soon comes in contact with capillaries of the chorionic plate and connecting stalk, thus giving rise to the extraembryonic vascular system.
Figure 8.7.Human embryo at the beginning of the second month of development.
At the embryonic pole, villi are numerous and well formed; at the abembryonic pole, they are few in number and poorly developed.
Figure 8.8.Structure of villi at various stages of development.
A. During the fourth week. The extraembryonic mesoderm penetrates the stem villi in the direction of the decidual plate. B. During the fourth month. In many small villi, the wall of the capillaries is in direct contact with the syncytium. C,D. Enlargement of the villus as shown in Figures 8.8A,B.
Maternal blood is delivered to the placenta by spiral arteries in the uterus. Erosion of these maternal vessels to release blood into intervillous spaces (Figs. 8.7 and 8.8) is accomplished by endovascular invasion by cytotrophoblast cells. These cells, released from the ends of anchoring villi (Figs. 8.7 and 8.8), invade the terminal ends of spiral arteries, where they replace maternal endothelial cells in the vessels’ walls, creating hybrid vessels containing both fetal and maternal cells. To accomplish this process, cytotrophoblast cells undergo an epithelial-to-endothelial transition. Invasion of the spiral arteries by cytotrophoblast cells transforms these vessels from small-diameter, high-resistance vessels to larger-diameter, low-resistance vessels that can provide increased quantities of maternal blood to intervillous spaces (Figs. 8.7 and 8.8).
During the following months, numerous small extensions grow out from existing stem villi and extend as free villi into the surrounding lacunar or intervillous spaces. Initially, these newly formed free villi are primitive (Fig. 8.8C), but by the beginning of the fourth month, cytotrophoblastic cells and some connective tissue cells disappear. The syncytium and endothelial wall of the blood vessels are then the only layers that separate the maternal and fetal circulations (Fig. 8.8B,D). Frequently, the syncytium becomes very thin, and large pieces containing several nuclei may break off and drop into the intervillous blood lakes. These pieces, known as syncytial knots, enter the maternal circulation and usually degenerate without causing any symptoms. Disappearance of cytotrophoblastic cells progresses from the smaller to larger villi, and although some always persist in large villi, they do not participate in the exchange between the two circulations.
Preeclampsia is a condition characterized by maternal hypertension and proteinuria due to reduced organ perfusion and occurs in approximately 5% of pregnancies. The condition may progress to eclampsia, which is characterized by seizures. Preeclampsia begins suddenly anytime from approximately 20 weeks’ gestation to term and may result in fetal growth retardation, fetal death, or death of the mother. In fact, preeclampsia is a leading cause of maternal mortality in the United States and is completely reversible by delivery of the baby. However, delivery too early puts the infant at risk for complications related to preterm birth. Despite many years of research, the cause of preeclampsia is unknown. The condition appears to be a trophoblastic disorder related to failed or incomplete differentiation of cytotrophoblast cells, many of which do not undergo their normal epithelial-to-endothelial transformation. As a result, invasion of maternal blood vessels by these cells is rudimentary. How these cellular abnormalities lead to hypertension and other problems is not clear. Risk factors for preeclampsia include, preeclampsia in a previous pregnancy, nulliparity (first pregnancy), obesity, family history of preeclampsia, multiple gestation (twins or more), and medical conditions, such as hypertension and diabetes. Preeclampsia also commonly occurs in women with hydatidiform moles (see Chapter 4) in which case it occurs early in pregnancy.