Trimesters of Pregnancy

Clinically, the gestational period is divided into three trimesters, each lasting 3 months. At the end of the first trimester, one third of the length of the pregnancy, all major systems are developed (Fig. 6-1B). In the second trimester, the fetus grows sufficiently in size so that good anatomic detail can be visualized during ultrasonography. During this period, most major birth defects can be detected using high-resolution real-time ultrasonography. By the beginning of the third trimester, the fetus may survive if born prematurely. The fetus reaches a major developmental landmark at 35 weeks of gestation and weighs approximately 2500 g, which is used to define the level of fetal maturity. At this stage, the fetus usually survives if born prematurely.

FIGURE 6–1 Ultrasound image of 9-week fetus (11 weeks gestational age). Note the amnion, amniotic cavity (A), and chorionic cavity (C). CRL 4.2 cm (calipers).

(Courtesy of Dr. E.A. Lyons, professor of radiology and obstetrics and gynecology and anatomy, Health Sciences Centre and University of Manitoba, Winnipeg, Manitoba, Canada.)

Measurements and Characteristics of Fetuses

Various measurements and external characteristics are useful for estimating fetal age (see Table 6-1). CRL is the method of choice for estimating fetal age until the end of the first trimester because there is very little variability in fetal size during this period. In the second and third trimesters, several structures can be identified and measured ultrasonographically, but the most common measurements are biparietal diameter (diameter of the head between the two parietal eminences), head circumference, abdominal circumference, femur length, and foot length. Weight is often a useful criterion for estimating age, but there may be a discrepancy between the age and the weight, particularly when the mother had metabolic disturbances such as diabetes mellitus during pregnancy. In these cases, weight often exceeds values considered normal for the corresponding CRL.

Fetal dimensions obtained from ultrasound measurements closely approximate CRL measurements obtained from spontaneously aborted fetuses. Determination of the size of a fetus, especially of its head, is helpful to the obstetrician for management of patients.

Nine to Twelve Weeks

At the beginning of the ninth week, the head constitutes approximately half the CRL of the fetus (Figs. 6-1 and 6-2A). Subsequently, growth in body length accelerates rapidly so that by the end of 12 weeks, the CRL has more than doubled (Fig. 6-1B; Table 6-1). Although growth of the head slows down considerably by this time, it is still disproportionately large compared with the rest of the body.

At 9 weeks, the face is broad, the eyes are widely separated, the ears are low set, and the eyelids are fused (Fig. 6-2B). By the end of 12 weeks, primary ossification centers appear in the skeleton, especially in the cranium (skull) and long bones. Early in the ninth week, the legs are short and the thighs are relatively small. By the end of 12 weeks, the upper limbs have almost reached their final relative lengths, but the lower limbs are still not so well developed and are slightly shorter than their final relative lengths.

FIGURE 6–2 A 9-week fetus in the amniotic sac exposed by removal from the chorionic sac. A, Actual size. The remnant of the umbilical vesicle is indicated by an arrow. B, Enlarged photograph of the fetus (x2). Note the following features: large head, fused eyelids, cartilaginous ribs, and intestines in umbilical cord (arrow).

(Courtesy of Professor Jean Hay [retired], Department of Human Anatomy and Cell Science, University of Manitoba, Winnipeg, Manitoba, Canada.)

The external genitalia of males and females appear similar until the end of the ninth week. Their mature fetal form is not established until the 12th week. Intestinal coils are clearly visible in the proximal end of the umbilical cord until the middle of the tenth week (see Fig. 6-2B). By the 11th week, the intestines have returned to the abdomen (Fig. 6-3).

FIGURE 6–3 An 11-week fetus (x1.5). Note its relatively large head and that the intestines are no longer in the umbilical cord.

(Courtesy of Professor Jean Hay [retired], Department of Human Anatomy and Cell Science, University of Manitoba, Winnipeg, Manitoba, Canada.)

At 9 weeks, the liver is the major site of erythropoiesis (formation of red blood cells). By the end of 12 weeks, this activity has decreased in the liver and has begun in the spleen. Urine formation begins between the 9th and 12th weeks, and urine is discharged through the urethra into the amniotic fluid. The fetus reabsorbs some amniotic fluid after swallowing it. Fetal waste products are transferred to the maternal circulation by passing across the placental membrane (see Chapter 7).

Thirteen to Sixteen Weeks

Growth is rapid during this period (Figs. 6-4 and 6-5; see Table 6-1). By 16 weeks, the head is relatively small compared with that of the 12-week fetus and the lower limbs have lengthened. Limb movements, which first occur at the end of the embryonic period, become coordinated by the 14th week but are too slight to be felt by the mother. Limb movements are visible during ultrasound examinations.

FIGURE 6–4 Diagram, drawn to scale, illustrating the changes in the size of the human fetus.

FIGURE 6–5 Enlarged photograph of the head and superior part of the trunk of a 13-week fetus.

(Courtesy of Professor Jean Hay [retired], Department of Human Anatomy and Cell Science, University of Manitoba, Winnipeg, Manitoba, Canada.)

Ossification of the fetal skeleton is active during this period, and the bones are clearly visible on ultrasound images by the beginning of the 16th week. Slow eye movements occur at 14 weeks. Scalp hair patterning is also determined during this period. By 16 weeks, the ovaries are differentiated and contain primordial ovarian follicles that contain oogonia (see Chapter 12). The genitalia of the fetuses can be recognized by 12 to 14 weeks. By 16 weeks, the eyes face anteriorly rather than anterolaterally. In addition, the external ears are close to their definitive position on the sides of the head.

Seventeen to Twenty Weeks

Growth slows down during this period, but the fetus still increases its CRL by approximately 50 mm (Figs. 6-4 and 6-6; see Table 6-1). Fetal movements—quickening—are commonly felt by the mother. The skin is now covered with a greasy, cheese-like material—vernix caseosa. It consists of a mixture of dead epidermal cells and a fatty substance (secretion) from the fetal sebaceous glands. The vernix caseosa protects the delicate fetal skin from abrasions, chapping, and hardening that result from exposure to the amniotic fluid.

FIGURE 6–6 A, A 17-week fetus. Because there is little subcutaneous tissue and the skin is thin, the blood vessels of the scalp are visible. Fetuses at this age are unable to survive if born prematurely, mainly because their respiratory systems are immature. B, A frontal view of a 17-week fetus. Note that the eyes are closed at this stage.

(A, From Moore KL, Persaud TVN, Shiota K: Color Atlas of Clinical Embryology, 2nd ed. Philadelphia, WB Saunders, 2000; B, Courtesy of Dr. Robert Jordan, St. George’s University Medical School, Grenada.)

Eyebrows and head hair are visible at 20 weeks. The fetuses are usually completely covered with fine downy hair—lanugo—that helps to hold the vernix caseosa on the skin. Brown fat forms during this period and is the site of heat production, particularly in the newborn infant. This specialized adipose tissue, found chiefly at the root of the neck, posterior to the sternum, and in the perirenal area, produces heat by oxidizing fatty acids.

By 18 weeks, the fetal uterus is formed and canalization of the vagina has begun and many primordial ovarian follicles containing oogonia are visible. By 20 weeks, the testes have begun to descend, but they are still located on the posterior abdominal wall, as are the ovaries in female fetuses.

Twenty-One to Twenty-Five Weeks

There is a substantial weight gain during this period and the fetus is better proportioned (Fig. 6-7). The skin is usually wrinkled and more translucent, particularly during the early part of this period. The skin is pink to red because blood is visible in the capillaries. At 21 weeks, rapid eye movements begin and blink-startle responses have been reported at 22 to 23 weeks. The secretory epithelial cells (type II pneumocytes) in the interalveolar walls of the lung have begun to secrete surfactant, a surface-active lipid that maintains the patency of the developing alveoli of the lungs (see Chapter 10). Fingernails are present by 24 weeks. Although a 22- to 25-week fetus born prematurely may survive if given intensive care (Fig. 6-7), it may die because its respiratory system is still immature. The risk for neurodevelopmental disability is high in infants born before 26 weeks of gestation.

FIGURE 6–7 A 25-week-old normal female newborn weighing 725 g.

(Courtesy of Dean Barringer and Marnie Danzinger.)

Twenty-Six to Twenty-Nine Weeks

During this period, fetuses usually survive if born prematurely and given intensive care (Fig. 6-8). The lungs and pulmonary vasculature have developed sufficiently to provide adequate gas exchange. In addition, the central nervous system has matured to the stage where it can direct rhythmic breathing movements and control body temperature. The highest neonatal mortality occurs in infants classified as low (≤2500 g) and very low (≤1500 g) birth weight.

FIGURE 6–8 Magnetic resonance images (MRIs) of normal fetuses. A, At 18 weeks (20-week gestational age). B, At 26 weeks. C, At 28 weeks.

(Courtesy of Dr. Deborah Levine, Director of Obstetric and Gynecologic Ultrasound, Beth Israel Deaconess Medical Center, Boston, MA.)

The eyelids are open at 26 weeks, and lanugo and head hair are well developed. Toenails become visible and considerable subcutaneous fat is now present under the skin, smoothing out many of the wrinkles. During this period, the quantity of white fat increases to approximately 3.5% of body weight. The fetal spleen has been an important site of erythropoiesis (formation of red blood cells). This ends by 28 weeks, by which time bone marrow has become the major site of this process.

Thirty to Thirty-Four Weeks

The pupillary reflex (change in diameter of pupil in response to stimulus caused by light) can be elicited at 30 weeks. Usually by the end of this period, the skin is pink and smooth and the upper and lower limbs have a chubby appearance. At this age, the quantity of white fat is approximately 8% of body weight. Fetuses 32 weeks and older usually survive if born prematurely.

Thirty-Five to Thirty-Eight Weeks

Fetuses born at 35 weeks have a firm grasp and exhibit a spontaneous orientation to light. As term approaches, the nervous system is sufficiently mature to carry out some integrative functions. Most fetuses during this “finishing period” are plump (Fig. 6-9). By 36 weeks, the circumferences of the head and abdomen are approximately equal. After this, the circumference of the abdomen may be greater than that of the head. The fetal foot length is usually slightly larger than femoral length at 37 weeks, and is an alternative parameter for confirmation of fetal age (Fig. 6-10). There is a slowing of growth as the time of birth approaches (Fig. 6-11).

FIGURE 6–9 Healthy newborns. A, At 34 weeks (36-week gestational age). B, At 38 weeks (40-week gestational age).

(A, Courtesy of Michael and Michele Rice; B, Courtesy of Dr. Jon and Mrs. Margaret Jackson.)

FIGURE 6–10 Ultrasound scan of the foot of a fetus at 19 weeks.

(Courtesy of Dr. E.A. Lyons, Professor of Radiology, Obstetrics and Gynecology, and Anatomy, Health Sciences Centre and University of Manitoba, Winnipeg, Manitoba, Canada.)

FIGURE 6–11 Graph showing the rate of fetal growth during the last trimester (3 months). Average refers to babies born in the United States. After 36 weeks, the growth rate deviates from the straight line. The decline, particularly after full term (38 weeks), probably reflects inadequate fetal nutrition caused by placental changes.

(Adapted from Gruenwald P: Growth of the human fetus. I. Normal growth and its variation. Am J Obstet Gynecol 94:1112, 1966.)

By full term, most fetuses usually reach a CRL of 360 mm and weigh approximately 3400 g. The amount of white fat is approximately 16% of body weight. A fetus adds approximately 14 g of fat per day during these last weeks. The thorax (chest) is prominent and the breasts often protrude slightly in both sexes. The testes are usually in the scrotum in full-term male infants; premature male infants commonly have undescended testes. Although the head is smaller at full term in relation to the rest of the body than it was earlier in fetal life, it still is one of the largest regions of the fetus. In general, male fetuses are longer and weigh more at birth than females.

Cigarette Smoking

Smoking is a well-established cause of IUGR. The growth rate for fetuses of mothers who smoke cigarettes is less than normal during the last 6 to 8 weeks of pregnancy (Fig. 6-11). On average, the birth weight of infants whose mothers smoke heavily during pregnancy is 200 g less than normal, and perinatal morbidity (medical complications) is increased when adequate medical care is unavailable. The effect of maternal smoking is greater on fetuses whose mothers also receive inadequate nutrition.

Multiple Pregnancy

Individuals of multiple births usually weigh considerably less than infants resulting from a single pregnancy (Fig. 6-11). It is evident that the total metabolic requirements of two or more fetuses exceed the nutritional supply available from the placenta during the third trimester.

Alcohol and Illicit Drugs

Infants born to alcoholic mothers often exhibit IUGR as part of the fetal alcohol syndrome (see Chapter 20). Similarly, the use of marijuana and other illicit drugs (e.g., cocaine) can cause IUGR and other obstetric complications.

Impaired Uteroplacental and Fetoplacental Blood Flow

Maternal placental circulation may be reduced by conditions that decrease uterine blood flow (e.g., small chorionic vessels, severe maternal hypotension, and renal disease). Chronic reduction of uterine blood flow can cause fetal starvation resulting in IUGR. Placental dysfunction or defects (e.g., infarction; see Chapter 7) can also cause IUGR. The net effect of these placental abnormalities is a reduction of the total area for exchange of nutrients between the fetal and maternal blood streams. It is very difficult to separate the effect of these placental changes from the effect of reduced maternal blood flow to the placenta. In some instances of chronic maternal disease, the maternal vascular changes in the uterus are primary and the placental defects are secondary.

Genetic Factors and Growth Retardation

It is well established that genetic factors can cause IUGR. Repeated cases of this condition in one family indicate that recessive genes may be the cause of the abnormal growth. Structural and numerical chromosomal aberrations have also been shown to be associated with cases of retarded fetal growth. IUGR is pronounced in infants with Down syndrome and is very characteristic of fetuses with trisomy 18 syndrome (see Chapter 20).

Ultrasonography

Ultrasonography is the primary imaging modality in the evaluation of the fetus because of its wide availability, low cost, and lack of known adverse effects. The chorionic sac and its contents may be visualized by ultrasonography during the embryonic and fetal periods. Placental and fetal size, multiple births, abnormalities of placental shape, and abnormal presentations can also be determined. Ultrasound scans give accurate measurements of the biparietal diameter of the fetal cranium (skull), from which close estimates of fetal age and length can be made. Figures 6-10 and 6-12 illustrate how details of the fetus can be observed in ultrasound scans. Ultrasound examinations are also helpful for diagnosing abnormal pregnancies at a very early stage. Rapid advances in ultrasonography have made this technique a major tool for prenatal diagnosis of fetal abnormalities. Biopsy of fetal tissues, such as skin, liver, kidney, and muscle, can be performed with ultrasound guidance.

FIGURE 6–12 A, Three-dimensional ultrasound (sonogram) of a 28-week fetus showing the face. The surface features are clearly recognizable. B, Photograph of the newborn infant (from A) 3 hours after birth.

(Courtesy of Dr. E.A. Lyons, Professor of Radiology, Obstetrics and Gynecology, and Anatomy, Health Sciences Centre and University of Manitoba, Winnipeg, Manitoba, Canada.)

Diagnostic Amniocentesis

This is a common invasive prenatal diagnostic procedure, usually performed between 15 and 18 weeks gestation. Amniotic fluid is sampled by inserting a 22-gauge needle through the mother’s anterior abdominal and uterine walls into the amniotic cavity by piercing the chorion and amnion (Fig. 6-13A). Because there is relatively little amniotic fluid before the 14th week, amniocentesis is difficult to perform before this time. The amniotic fluid volume is approximately 200 ml, and 15 to 20 ml can be safely withdrawn. Amniocentesis is relatively devoid of risk, especially when the procedure is performed by an experienced physician using real-time ultrasonography guidance for outlining the position of the fetus and placenta.

FIGURE 6–13 A, Illustration of amniocentesis. A needle is inserted through the lower abdominal and uterine walls into the amniotic cavity. A syringe is attached and amniotic fluid is withdrawn for diagnostic purposes. B, Drawing illustrating chorionic villus sampling. Two sampling approaches are illustrated: through the maternal anterior abdominal wall with a needle and through the vagina and cervical canal using a malleable catheter. A speculum is an instrument for exposing the vagina.

Alpha-Fetoprotein Assay

Alpha-fetoprotein (AFP) is a glycoprotein that is synthesized in the fetal liver, umbilical vesicle, and gut. AFP is found in high concentration in fetal serum, peaking 14 weeks after the LNMP. Small amounts of AFP normally enter the amniotic fluid.

Spectrophotometric Studies

Examination of amniotic fluid by this method may be used for assessing the degree of erythroblastosis fetalis, also called hemolytic disease of newborn. This disease results from destruction of fetal red blood cells by maternal antibodies (see Chapter 7).

Chorionic Villus Sampling

Biopsies of trophoblastic tissue (5–20 mg) may be obtained by inserting a needle, guided by ultrasonography, through the mother’s abdominal and uterine walls (transabdominal) into the uterine cavity (see Fig. 6-13B). Chorionic villus sampling (CVS) can also be performed transcervically by passing a polyethylene catheter through the cervix and guided by real-time ultrasonography. For assessing the condition of a fetus at risk, the fetal karyotype (chromosome characteristics) can be obtained and a diagnosis made weeks earlier when CVS is performed, compared with amniocentesis. The risk of miscarriage with CVS is approximately 1%, more than with amniocentesis.

Sex Chromatin Patterns

Fetal sex can be determined by noting the presence or absence of sex chromatin in the nuclei of cells recovered from amniotic fluid. These tests were developed after it was discovered that sex chromatin was visible in nuclei of normal female cells but not in normal male cells (Fig. 6-14A and B). Females with three X chromosomes (46, XXX) have two masses of sex chromatin (Fig. 6-14C). By use of a special staining technique, the Y chromosome can also be identified in cells recovered from the amniotic fluid surrounding male fetuses (Fig. 6-14D). Knowledge of fetal sex can be useful in diagnosing the presence of severe sex-linked hereditary diseases, such as hemophilia and muscular dystrophy.

FIGURE 6–14 Oral epithelial nuclei stained with cresyl echt violet (A, B, and C) and quinacrine mustard (D) (x2000). A, From normal male. No sex chromatin is visible (chromatin negative). B, From normal female. The arrow indicates a typical mass of sex chromatin (chromatin positive). C, From female with 47, XXX trisomy. The arrows indicate two masses of sex chromatin. D, From normal male. The arrow indicates a mass of Y chromatin as an intensely fluorescent body.

(A and B, From Moore KL, Barr ML: Smears from the oral mucosa in the detection of chromosomal sex. Lancet 2:57, 1955.)

Cell Cultures and Chromosomal Analysis

The prevalence of chromosomal disorders is approximately one in 120 live-born infants. Fetal sex and chromosomal aberrations can be determined by studying the sex chromosomes in cultured fetal cells obtained during amniocentesis. These cultures are commonly done when an autosomal abnormality, such as occurs in Down syndrome, is suspected. Moreover, microdeletions and microduplications, as well as subtelomeric rearrangements, can now be detected with fluorescence in situ hybridization technology. Inborn errors of metabolism in fetuses can also be detected by studying cell cultures. Enzyme deficiencies can be determined by incubating cells recovered from amniotic fluid and then detecting the specific enzyme deficiency in the cells (see Chapter 20).

Fetal Transfusion

Fetuses with hemolytic disease of the newborn (HDN) can be treated by intrauterine blood transfusions. The blood is injected through a needle inserted into the fetal peritoneal cavity. With recent advances in percutaneous umbilical cord blood sampling (PUBS), blood and packed red blood cells are transfused directly into the umbilical vein for the treatment of fetal anemia due to isoimmunization. The need for fetal blood transfusions is reduced nowadays owing to the treatment of Rh-negative mothers of Rh-positive fetuses with anti-Rh immunoglobulin, which in many cases prevents development of this disease of the Rh system. Fetal transfusion of platelets directly into the umbilical cord vein is carried out for the treatment of alloimmune thrombocytopenia. Also, fetal infusion of drugs in a similar manner for the treatment of a few medical conditions in the fetus has been reported.

Fetoscopy

Using fiberoptic instruments, parts of the fetal body may be directly observed. It is possible to visualize the entire fetus looking for birth defects, such as cleft lip and limb defects. The fetoscope is usually introduced through the abdominal and uterine walls into the amniotic cavity, similarly to the way in which the needle is inserted during amniocentesis. Fetoscopy is usually carried out at 17 to 20 weeks of gestation, but with new approaches such as transabdominal thin-gauge embryo fetoscopy, it is possible to detect certain defects in the embryo or fetus during the first trimester. Because of the risk to the fetus compared with other prenatal diagnostic procedures, fetoscopy now has few indications for routine prenatal diagnosis or treatment of the fetus. Fetoscopy combined with laser coagulation has been used to treat fetal conditions such as twin–twin transfusion syndrome (TTTS). Fetoscopy has also been used for the release of amniotic bands (see Fig. 7-21).

Percutaneous Umbilical Cord Blood Sampling

Fetal blood samples may be obtained directly from the umbilical vein by percutaneous umbilical cord blood sampling (PUBS) or cordocentesis for the diagnosis of many fetal abnormal conditions, including aneuploidy, fetal growth restriction, fetal infection, and fetal anemia. PUBS is usually performed after 18 weeks of gestation under continuous direct ultrasound guidance, which is used to locate the umbilical cord and its vessels. Moreover, the procedure permits treating the fetus directly, including the transfusion of packed red blood cells for the management of fetal anemia resulting from isoimmunization.

Magnetic Resonance Imaging

When planning fetal treatment, magnetic resonance imaging (MRI) may be used to provide more information about an abnormality that has been detected in ultrasonic images. Important advantages of magnetic resonance imaging are that it does not use ionizing radiation and that it has high soft-tissue contrast and resolution (Fig. 6-15).

FIGURE 6–15 Sagittal magnetic resonance image of the pelvis of a pregnant woman. The fetus is in the breech presentation. Note the brain, eyes, and liver.

(Courtesy of Dr. Deborah Levine, Director of Obstetric and Gynecologic Ultrasound, Beth Israel Deaconess Medical Center, Boston, MA.)

Fetal Monitoring

Continuous fetal heart rate monitoring in high-risk pregnancies is routine and provides information about the oxygenation of the fetus. There are various causes of prenatal fetal distress, such as maternal diseases that reduce oxygen transport to the fetus (e.g., cyanotic heart disease). Fetal distress (e.g., indicated by an abnormal heart rate or rhythm) suggests that the fetus is in jeopardy. A noninvasive method of monitoring uses transducers placed on the mother’s abdomen.

Case 6–1

A woman in the 20th week of a high-risk pregnancy was scheduled for a repeat cesarean section. Her physician wanted to establish an expected date of delivery.

Case 6–2

A 44-year-old pregnant woman was worried that she might be carrying a fetus with major birth defects.

Case 6–3

A 19-year-old woman in the second trimester of pregnancy asked a physician whether her fetus was vulnerable to over-the-counter drugs and street drugs. She also wondered about the effect of her heavy drinking and cigarette smoking on her fetus.

Case 6–4

An ultrasound examination of a pregnant woman revealed IUGR of the fetus.

Case 6–5

A woman in the first trimester of pregnancy who was to undergo amniocentesis expressed concerns about a miscarriage and the possibility of injury to her fetus.

Case 6–6

A pregnant woman is told that she is going to have an AFP test to determine whether there are any fetal anomalies.