Fetal Period: Ninth Week to Birth

The transformation of an embryo to a fetus is gradual, but the name change is meaningful because it signifies that the primordia of all major systems have formed. Development during the fetal period is primarily concerned with rapid body growth and differentiation of tissues, organs, and systems. A notable change occurring during the fetal period is the relative slowdown in the growth of the head compared with the rest of the body. The rate of body growth during the fetal period is very rapid ( Table 6.1 ), and fetal weight gain is phenomenal during the terminal weeks. Periods of normal continuous growth alternate with prolonged intervals of absent growth.

Viability of Fetuses

Viability is defined as the ability of fetuses to survive in the extrauterine environment. Fetuses of less than 500 g at birth do not usually survive. In recent years, survival at gestational ages of 22 to 23 weeks has been increasingly reported, blurring the line at which the edge of viability is declared. If given expert postnatal care, many fetuses born at less than 1000 g may survive; such infants are referred to as extremely low-birth-weight infants. Many full-term, low-birth-weight infants result from intrauterine growth restriction (IUGR) . Consequently, if given expert postnatal care, some fetuses weighing less than 500 g may survive. Most fetuses weighing between 750 and 1500 g usually survive, but complications may occur.

Each year, approximately 500,000 preterm infants (<37 weeks) are born in the United States. Many of these infants suffer from severe medical complications or early mortality (death). The use of antenatal steroids and the postnatal administration of endotracheal surfactant have greatly lowered the rates of acute and long-term morbidity. Prematurity is one of the most common causes of morbidity and perinatal death .

Table 6.1

Criteria for Estimating Fertilization Age During the Fetal Period

Age (Weeks)	Crown–Rump Length (mm) *	Foot Length (mm) *	Fetal Weight (g) †	Main External Characteristics
Previable Fetuses
9	50	7	8	Eyelids closing or closed. Head large and more rounded. External genitalia are not distinguishable as male or female. Some of the small intestines are in the proximal part of umbilical cord. The ears are low set.
10	61	9	14	Intestines in abdomen. Early fingernail development.
12	87	14	45	Sex distinguishable externally. Well-defined neck.
14	120	20	110	Head erect. Eyes face anteriorly. Ears are close to their definitive position. Lower limbs well developed. Early toenail development.
16	140	27	200	External ears stand out from head.
18	160	33	320	Vernix caseosa covers skin. Quickening (first movements) felt by mother.
20	190	39	460	Head and body hair (lanugo) visible.
Viable Fetuses ^‡
22	210	45	630	Skin wrinkled, translucent, and pink to red.
24	230	50	820	Fingernails present. Lean body.
26	250	55	1000	Eyelids partially open. Eyelashes present.
28	270	59	1300	Eyes wide open. Considerable scalp hair sometimes present. Skin slightly wrinkled.
30	280	63	1700	Toenails present. Body filling out. Testes descending.
32	300	68	2100	Fingernails reach fingertips. Skin smooth.
36	340	79	2900	Body usually plump. Lanugo (hairs) almost absent. Toenails reach toe tips. Flexed limbs; firm grasp.
38	360	83	3400	Prominent chest; breasts protrude. Testes in scrotum or palpable in inguinal canals. Fingernails extend beyond fingertips.

* These measurements are averages and so may not apply to specific cases; dimensional variations increase with age.

† These weights refer to fetuses that have been fixed for approximately 2 weeks in 10% formalin. Fresh specimens usually weigh approximately 5% less.

‡ There is no sharp limit of development, age, or weight at which a fetus automatically becomes viable or beyond which survival is ensured, but experience has shown that it is rare for a baby to survive whose weight is less than 500 g or whose fertilization age is less than 22 weeks. Even fetuses born between 26 and 28 weeks have difficulty surviving, mainly because the respiratory system and the central nervous system are not completely differentiated.

Estimation of Fetal Age

Ultrasound measurements of the crown−rump length (CRL) of the fetus are taken to determine its size and probable age and to provide a prediction of the expected date of delivery . Fetal head measurements and femur length are also used to evaluate age. In clinical practice, gestational age is usually timed from the onset of the last normal menstrual period (LNMP) .

In embryology, gestational age based on the LNMP is superfluous because gestation (time of fertilization) does not begin until the oocyte is fertilized, which occurs around the middle of the menstrual cycle. This difference in the use of the term gestational age may be confusing; therefore, it is important that the person ordering the ultrasound examination and the ultrasonographer use the embryologic terminology (see Chapter 1 , Fig. 1.1 ).

The intrauterine period may be divided into days, weeks, or months ( Table 6.2 ), but confusion arises if it is not stated whether the age is calculated from the onset of the LNMP or from the estimated day of fertilization of the oocyte. Uncertainty about age arises when months are used, particularly when it is not stated whether calendar months (28 to 31 days) or lunar months (28 days) are meant. Unless otherwise stated, embryologic or fetal age in this book is calculated from the estimated time of fertilization .

Table 6.2

Comparison of Gestational Time Units and Date of Birth *

Reference Point	Days	Weeks	Calendar Months	Lunar Months
Fertilization	266	38	8.75	9.5
Last normal menstrual period	280	40	9.25	10

* The common delivery date rule (Nägele's rule) for estimating the expected date of delivery is to count back 3 months from the first day of the last normal menstrual period and add a year and 7 days.

Trimesters of Pregnancy

Clinically, the gestational period is divided into three trimesters, each lasting 3 months. By the end of the first trimester, one third of the length of the pregnancy, major systems have been developed (see Table 6.1 ). In the second trimester, the fetus grows sufficiently in size so that good anatomical 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 and weighs approximately 2500 g and usually survives if born prematurely.

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 weight, particularly when the mother has had metabolic disturbances such as diabetes mellitus during pregnancy. In these cases, the 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 its head circumference, is helpful to the obstetrician for management of patients.

Highlights of Fetal Period

There is no formal staging system for the fetal period; however, it is helpful to describe the changes that occur in periods of 4 to 5 weeks.

Nine to Twelve Weeks

At the beginning of the fetal period (ninth week), the head constitutes approximately half of the CRL of the fetus ( Figs. 6.1 and 6.2 A ). Subsequently, growth in body length accelerates rapidly, so that by the end of 12 weeks, the CRL has almost doubled ( Fig. 6.2 B , and see Table 6.1 ). Although growth of the head slows down considerably by this time, the head is still disproportionately large compared with the rest of the body ( Fig. 6.3 ).

Fig. 6.1, Ultrasound image of 9-week fetus (11 weeks’ gestational age). Note the amnion, amniotic cavity (AC), and chorionic cavity (CC). Crown–rump length, 4.2 cm (calipers) .

Fig. 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 , A transabdominal 3D ultrasound of a fetus at 10 weeks + 2 days. The umbilical cord insertion can be observed on the abdomen. The amniotic membrane is seen surrounding the fetus. The small umbilical vesicle (yolk sac) remnant can be seen in the upper portion of the image close to the amniotic membrane.

Fig. 6.3, A transvaginal 3D ultrasound (with superficial rendering) of an 11-week fetus. Note its relatively large head. The limbs are fully developed. An auricle can also be observed on the left lateral aspect of the head.

At 9 weeks, the face is broad, the eyes are widely separated, the ears are low set, and the eyelids are fused (see Fig. 6.2 B ). 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 (see Fig. 6.2 ). 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 they are slightly shorter than their final relative lengths.

The external genitalia of males and females appear similar until the end of the ninth week. Their mature 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 10th week (see Fig. 6.2 B ). By the 11th week, the intestines have returned to the abdomen (see Fig. 6.3 ).

At 9 weeks, the beginning of the fetal period, 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 in the amnionic cavity. The fetus reabsorbs some amniotic fluid after swallowing it. Fetal waste products are transferred to the maternal circulation by passage across the placental membrane (see Chapter 7 , Fig. 7.7 ).

Thirteen to Sixteen Weeks

Growth is very rapid during this period ( Figs. 6.4 and 6.5 , and see Table 6.1 ). By 16 weeks, the head is relatively smaller than the head of a 12-week fetus, and the lower limbs have lengthened ( Fig. 6.6 A ). Limb movements , which first occur at the end of the embryonic period, become coordinated by the 14th week, but they are too slight to be felt by the mother. However, these movements are visible during ultrasonographic examinations.

Fig. 6.4, Diagram, drawn to scale, illustrating the changes in the size of a human fetus.

Fig. 6.5, Enlarged photograph of the head and superior part of the trunk of a 13-week fetus.

Fig. 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.

Ossification of the fetal skeleton is active during this period, and the developing 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 , which contain oogonia , or primordial germ cells (see Chapter 12 , Fig. 12.31 ).

The genitalia of male and female 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 positions 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 (see Fig. 6.4 , Fig. 6.6 , and Table 6.1 ). Fetal movements (quickening) are commonly felt by the mother. The skin is now covered with a greasy, cheese-like material, the vernix caseosa . It consists of a mixture of dead epidermal cells and a fatty substance from the fetal sebaceous glands. The vernix protects the delicate fetal skin from abrasions, chapping, and hardening that result from exposure to the amniotic fluid. Fetuses are covered with fine, downy hair, lanugo , which helps the vernix to adhere to the skin.

Eyebrows and head hair are visible at 20 weeks. Brown fat forms during this period and is the site of heat production. This specialized adipose tissue is connective tissue that consists chiefly of fat cells; it is found mostly at the root of the neck, posterior to the sternum, and in the perirenal area. The brown fat produces heat by oxidizing fatty acids.

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

Twenty-One to Twenty-Five Weeks

Substantial weight gain occurs 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 in the capillaries is visible. 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 ).

Fig. 6.7, A 25-week-old normal female neonate weighing 725 g.

Fingernails are present by 24 weeks. Although a 22- to 25-week fetus born prematurely may survive if given intensive care (see Fig. 6.7 ), there is also a chance that it may die because its respiratory system is still immature. The risk for neurodevelopmental disability (e.g., mental deficiency) is high in fetuses born before 26 weeks.

Twenty-Six to Twenty-Nine Weeks

During this period, fetuses usually survive if they are born prematurely and given intensive care ( Fig. 6.8 B and C ). 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 rate of neonatal mortality occurs in infants classified as low birth weight (≤2500 g) and very low birth weight (≤1500 g).

Fig. 6.8, Magnetic resonance images of normal fetuses. A , At 18 weeks. B , At 26 weeks. C , At 28 weeks.

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

Thirty to Thirty-Four Weeks

The pupillary reflex (change in diameter of the pupil in response to a 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 the 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. 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 foot length of fetuses is usually slightly larger than the femoral length (long bone of the thigh) at 37 weeks and is an alternative parameter for confirmation of fetal age ( Fig. 6.9 ). There is a slowing of growth as the time of birth approaches ( Fig. 6.10 ).

Fig. 6.9, Ultrasound scan of the foot of a fetus at 19 weeks.

Fig. 6.10, Graph showing the rate of fetal growth during the last trimester (3 months). Average refers to neonates in the United States. After 36 weeks, the growth rate deviates from the straight line. The decline, particularly after full term (38 weeks) has been reached, probably reflects inadequate fetal nutrition caused by placental changes.

At full term (38 weeks) ( Fig. 6.11 B ), most fetuses usually reach a CRL of 360 mm and weigh approximately 3400 g. The amount of white fat is approximately 16% of the 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 neonates; premature male neonates 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 is still one of the largest regions of the fetus. In general, male fetuses are longer and weigh more at birth than females.

Low Birth Weight

Not all low-birth-weight babies are premature. Approximately one third of those with a birth weight of 2500 g or less are actually small for gestational age. These “small-for-date” infants may be underweight because of placental insufficiency (see Chapter 7 ). The placentas are often small or poorly attached and/or have undergone degenerative changes that progressively reduce the oxygen supply and nourishment to the fetus.

It is important to distinguish between full-term neonates who have a low birth weight because of IUGR and preterm neonates who are underweight because of a shortened gestation (i.e., premature by date). IUGR may be caused by preeclampsia (hypertension), smoking or some illicit drugs, multiple gestations (e.g., triplets), infectious diseases, cardiovascular defects, inadequate maternal nutrition, and maternal and fetal hormones. Teratogens and genetic factors are also known to cause IUGR (see Chapter 20 ). Infants with asymmetrical forms of IUGR who have a large head circumference relative to the infant's weight and length show a characteristic lack of subcutaneous fat, and their skin is wrinkled, suggesting that white fat has actually been lost.

Fig. 6.11, Healthy neonates. A , At 34 weeks. B , At 38 weeks.

Expected Date of Delivery

The expected date of delivery of a fetus is 266 days or 38 weeks after fertilization, that is, 280 days or 40 weeks after the LNMP (see Table 6.2 ). Approximately 12% of fetuses are born 1 to 2 weeks after the expected time of birth.

Postmaturity Syndrome

Prolongation of pregnancy for 3 or several weeks beyond the expected date of delivery occurs in 5% to 6% of women. Some infants in such pregnancies develop the postmaturity syndrome , which may be associated with fetal dysmaturity : absence of subcutaneous fat, wrinkling of the skin, or meconium (greenish-colored feces) staining of the skin , and, often, excessive weight. Fetuses with this syndrome have an increased risk of mortality. Labor is usually induced when the fetus is postmature.

Factors Influencing Fetal Growth

By accepting the shelter of the uterus, the fetus also takes the risk of maternal disease or malnutrition and of biochemical, immunological and hormonal adjustment. —GEORGE W. CORNER, RENOWNED AMERICAN EMBRYOLOGIST, 1888 TO 1981

Fetuses require substrates (nutrients) for growth and production of energy. Gases and nutrients pass freely to the fetus from the mother through the placental membrane (see Chapter 7 , Fig. 7.7 ). Glucose is a primary source of energy for fetal metabolism and growth; amino acids are also required. These substances pass from the mother's blood to the fetus through the placental membrane. Insulin required for the metabolism of glucose is secreted by the fetal pancreas; no significant quantities of maternal insulin reach the fetus because the placental membrane is relatively impermeable to this hormone. Insulin, insulin-like growth factors, human growth hormone, and some small polypeptides (such as somatomedin C) are believed to stimulate fetal growth.

Many factors may affect prenatal growth; they may be maternal, fetal, or environmental factors. Some factors operating throughout pregnancy, such as maternal vascular disease, intrauterine infection, cigarette smoking, and consumption of alcohol, tend to produce infants with IUGR or small-for-gestational-age (SGA) infants, whereas factors operating during the last trimester, such as maternal malnutrition, usually produce underweight infants with normal length and head size. The terms IUGR and SGA are related, but they are not synonymous.

IUGR refers to a process that causes a reduction in the expected pattern of fetal growth as well as fetal growth potential. Constitutionally small-for-gestational-age infants have a birth weight that is lower than a predetermined cutoff value for a particular gestational age (<2 standard deviations below the mean or less than the third percentile). Severe maternal malnutrition resulting from a poor-quality diet is known to cause restricted fetal growth (see Fig. 6.10 ).

Low birth weight has been shown to be a risk factor for many adult conditions, including hypertension, diabetes, and cardiovascular disease. High birth weight due to maternal gestational diabetes is associated with later obesity and diabetes in the offspring.

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