CHAPTER 14 • The Fetal Skeletal System. First Trimester Ultr

 CHAPTER 14 • The Fetal Skeletal System

INTRODUCTION

Ultrasound in the first trimester provides a distinct advantage over ultrasound in the

second and third trimester of pregnancy for the evaluation of the fetal skeletal system,

especially the upper and lower extremities. With advancing gestation, fetal crowding

makes evaluation of the extremities and spine more challenging. Sonographic evaluation

of the skeletal system in the first trimester includes imaging of the cranium, the ribs, the

spine, and the four extremities. An understanding of the gestational progression of bone

ossification is important in order to differentiate normal from abnormal findings. In this

chapter, we present a brief description of embryology of the skeletal system, its normal

sonographic examination, along with common skeletal system abnormalities that can be

diagnosed in the first trimester of pregnancy.

EMBRYOLOGY

The skeletal system includes the axial and appendicular skeleton. The axial skeleton

comprises the skull, spine, and rib cage, and the appendicular skeleton is made of the

upper and lower extremities along with the shoulder and pelvic girdles. The skeletal

system is primarily derived from the mesoderm, which appears during the third week of

embryogenesis. The mesoderm gives rise to mesenchymal cells, which differentiate into

fibroblasts, chondroblasts, and osteoblasts to form the tissue of the musculoskeletal

system. The embryonic mesoderm is divided into three distinct regions: paraxial

mesoderm (medially), intermediate mesoderm (middle part), and lateral plate

mesoderm (laterally). The skeletal system is formed from the paraxial and lateral plate

mesoderm, along with neural crest cells, derived from ectoderm. The paraxial

mesoderm forms the axial skeleton and lateral plate mesoderm forms the appendicular

skeleton.

The paraxial mesoderm segments into somites along the neural tube by the third

week of embryogenesis. The somites differentiate into the sclerotome (ventromedial

part) and the dermomyotome (dermatome and myotome) (dorsolateral part) (Fig. 14.1).During the fifth week of embryogenesis, the upper and lower limb buds are seen as

outpocketings from the ventrolateral body wall at the spinal levels of C5–C8 and L3–

L5, respectively (Fig. 14.2A). The terminal portions of limb buds flatten out in the fifth

week to form hand and foot plates (Fig. 14.2B). Circular constrictions are noted

between the proximal portions and the plates, representing the future wrist and ankle

creases (Fig. 14.2B). During the fifth week, the upper limbs rotate 90 degrees laterally,

whereas the lower limbs rotate 90 degrees medially. Growth of the limb buds continues

between the fifth and the eighth week until the extremities take their definitive form (Fig.

14.2C).

Bone ossification occurs in two types: membranous and intracartilaginous. The

membranous type is the process of bone formation directly from mesenchyme and is

typically seen in flat bone such as the skull, whereas intracartilaginous ossification is

the process of ossification from cartilaginous cells and is seen in the spine and long

bones. By the end of the fourth week, the cartilaginous centers appear in the long bones,

and bone ossification starts by the end of the sixth week. Bone ossification continues

postnatally into the second decade of life. The muscles of developing limbs and the

axial skeleton are formed from myotomes, derived from the somatic mesoderm. Retinoic

acid appears to be important for the initiation of limb bud outgrowth, and appropriate

differentiation of the skeletal system has been demonstrated to require sequential Hox

gene expression.1,2

Abnormal development of the skeletal system results in numerous congenital

anomalies such as reduction or duplication defects and skeletal dysplasia. Normal

anatomy of the skeletal system on ultrasound along with skeletal anomalies that can be

seen in the first trimester will be discussed in the following sections.

NORMAL SONOGRAPHIC ANATOMY

The first evidence of development of extremities includes the limb buds, which are first

seen on ultrasound at around the eighth week of gestation, with the upper limb buds seen

before the lower limb buds3 (Figs. 14.3 and 14.4). Three-dimensional (3D) ultrasound

in surface mode is very helpful in the identification of limb buds and four extremities in

the first trimester (Figs. 14.5 and 14.6). Visualization of the normal fetal extremities in

the first trimester ultrasound includes the demonstration of four limbs, each with three

segments along with normal orientations of hands and feet. This is easily accomplished

by obtaining a ventral view of the fetus (Fig. 14.6A and C) (see also Chapter 5).

Evaluation of a single extremity is commonly demonstrated in a longitudinal view (Figs.

14.7 and 14.8). Digits of the hands and feet are reported to be seen from the 11th week

of gestation onward3; with the new high-resolution transducers however, they can be

visualized from 9 weeks onward (Fig. 14.3). Imaging of the fingers may help in the

identification of abnormal conditions (polydactyly) and is accomplished by using a

high-resolution transducer, either transabdominally or transvaginally (Fig. 14.9). Aventral view of the feet also helps in the demonstration of terminal phalanges (Fig.

14.8D and E). By around the 10th week of gestation, ossification centers within all long

bones can be demonstrated. Note that when the lower legs are extended at the knees, the

whole lower extremities are seen on ultrasound obtained from the ventral aspect of the

fetus (Fig. 14.10A and B). When the legs are flexed at the knees, only the upper

segments (thighs) are seen (Fig. 14.10C). 3D ultrasound at 12 weeks or beyond,

obtained from the ventral or lateral approach, can clearly demonstrate upper and lower

extremities including both hands and feet (Fig. 14.11).

Figure 14.1: Embryogenesis of the skeletal system. Note that during the third

week of embryogenesis, the paraxial mesoderm segments into somites along

the neural tube. The somites differentiate into the sclerotome (ventromedially)

and the dermomyotome (dorsolaterally). The dermomyotome includes the

dermatome and myotome as shown in this figure. Refer to the embryology

section in the chapter for more details on this subject.Figure 14.2: Development of limb buds in the embryo between the fifth and

eighth week of embryogenesis. During the early fifth week of embryogenesis

(A), the upper and lower limb buds are seen as outpocketings from the

ventrolateral body wall. Circular constrictions are noted at the sixth week (B)

between the proximal portions and the plates, representing the future wrist and

ankle creases. Growth of the limb buds continues between the fifth and the

eighth week (C) until the extremities take their definitive form. Refer to the

embryology section in the chapter for more details on this subject.Figure 14.3: Development of arms and hands between 9 and 10 weeks (A–D)

of gestation visualized on two-dimensional ultrasound. Note the position of the

arms at 9 weeks gestation (A and B) in close proximity to the anterior chest

wall. More upper extremity movements are seen by the 10th week of gestation,

and the upper arms’ segments are then clearly identified (C and D). Note that

at 10 weeks of gestation, the hands maintain their proximity to the anterior

chest wall and are best imaged in a superior–inferior view.Figure 14.4: Development of legs and feet between 7 and 10 weeks (A–D) of

gestation visualized on two-dimensional gray-scale ultrasound. Note that

between the 7th and the 8th week (A and B), the legs are straight and short,

and by the 9th and 10th week, the feet are in close proximity and touch each

other. Before 10 weeks of gestation, the most optimum approach to image the

lower extremities is a view inferior to the pelvis (looking from below). Threedimensional ultrasound is also very helpful in early gestation to assess upper

and lower extremities. See Figures 14.5 and 14.6 for more detail.Figure 14.5: Three-dimensional ultrasound in surface mode of the

embryo/fetus at 7 to 12 weeks of gestation (A–F) imaged from the lateral view,

demonstrating the development of the arms and legs. See text for details.

The fetal spine is difficult to image before the 11th week of gestation because of lack

of bone ossification (Fig. 14.12). At 12 weeks of gestation and beyond, the spine is

imaged on ultrasound with such details to allow for diagnosis of major spinal

deformities (Fig. 14.13). In the first trimester, the fetal spine can be evaluated in the

sagittal (Figs. 14.13 and 5.22) and coronal views (Fig. 5.23), but also where possible

in axial views at the cervical, thoracic, and lumbosacral regions (Fig. 14.14). This

approach is important when spinal abnormalities are suspected such as spina bifida.

When technically feasible, 3D ultrasound in surface mode allows for an excellent

evaluation of the integrity of the fetal back and spine for open spina bifida in the first

trimester (Figs. 14.15, 8.45, and 8.47). Furthermore, 3D ultrasound in skeletal mode of

a coronal view of the fetus allows for the evaluation of the spine and thoracic cavity(Fig. 14.16A). 3D ultrasound in skeletal mode also allows for an evaluation of facial

and cranial bones in the first trimester (Fig. 14.16B and C). Imaging of the fetal cranium

has been discussed in Chapter 8.

Figure 14.6: Three-dimensional ultrasound in surface mode of an embryo at 10

weeks of gestation imaged from the frontal (A), right lateral (B), and inferior

(C) approach. Note in A and C the close proximity of the hands and feet at this

gestation. See text for details.Figure 14.7: Schematic drawing (A) and corresponding two-dimensional

ultrasound images of the upper extremity visualized near a cross-section of the

chest in two fetuses at 13 weeks of gestation (B and C). Note the upper arm,

lower arm, and hand (all labeled).Figure 14.8: Schematic drawing (A) and corresponding two-dimensional

ultrasound images (B and C) of the lower extremity visualized in a parasagittal

plane in two fetuses at 13 weeks of gestation. Note the upper leg, lower leg,

and foot (all labeled). Planes D and E show a ventral view of the foot. Note that

the toes can be visualized at this early gestation (asterisk).Figure 14.9: Two-dimensional ultrasound of the upper extremity at 13 weeks of

gestation imaged from different angles (A–C). Note the visualization of arms

and hands. Note that at this early gestation all five fingers can be well seen

(arrows) because the hand is always open.Figure 14.10: Axial views (A–C) of the fetal pelvis demonstrating the lower

extremities. Note that when the lower legs are extended at the knees (A and

B), the whole lower extremities are seen. When the legs are flexed at the knee

(C), only the upper segments (thighs) are seen.Figure 14.11: Three-dimensional ultrasound in surface mode of the entire fetus

in three fetuses (A–C) at 12 weeks of gestation. Note that the upper and lower

extremities can be clearly seen. With high-resolution transducers, the fingers

and toes can also be seen. Note the common position of the hands and feet in

front of the fetus at this early gestation, which makes visualization easier than

later on in pregnancy.Figure 14.12: Visualization of the fetal spine between 8 and 10 weeks of

gestation (A–D) on two-dimensional transvaginal ultrasound with high resolution.

Note that the spine is not yet ossified before 11 weeks of gestation, which

makes its assessment somewhat difficult in a midline sagittal plane. The

combination of a coronal plane (A and B) along with a midline sagittal plane (C

and D) is occasionally needed to evaluate the spine in early gestation. When

technically feasible, three-dimensional ultrasound in surface mode allows for an

excellent evaluation of the fetal back and spine.Figure 14.13: Midline sagittal planes of the fetal spine in two-dimensional

ultrasound in three fetuses at 11 (A), 12 (B), and 13 (C) weeks of gestation.

Note the progressive ossification of the spine between 11 (A) and 13 (C)

weeks of gestation. Compare the spine ossification with Figure 14.12.Figure 14.14: Cervical (A), thoracic (B), and lumbosacral (C) axial planes of

the spine in a fetus at 12 weeks of gestation. Note the normal spine and the

overlying skin (arrow). Along with a sagittal and coronal view of the spine,

these planes allow for a comprehensive evaluation of the fetal spine in the first

trimester.

Figure 14.15: Three-dimensional (3D) ultrasound in surface mode

demonstrating the back in three fetuses at 10 (A), 11 (B), and 13 (C) weeks of

gestation. Note the absence of a defect in the back, confirming the lack of an

open spina bifida. When technically feasible, 3D ultrasound in surface modeallows for an excellent evaluation of the fetal back and spine for open spina

bifida.

Figure 14.16: Three-dimensional (3D) ultrasound in maximum mode in a fetus

at 13 weeks of gestation demonstrating the ossified spine, ribs, and scapulae

(A), the facial (B) and skull (C) bones.

SKELETAL SYSTEM ABNORMALITIES

When compared to the second and third trimester of pregnancy, fewer abnormalities of

the skeletal system can be diagnosed in the first trimester primarily because of delayedossification of bone. In general, the more severe the skeletal abnormality, the more

evident it is on ultrasound in the first trimester. Furthermore, confirming the exact type

of skeletal abnormality can be challenging in the first trimester. There are two major

types of skeletal abnormalities: generalized and localized. Generalized skeletal

abnormalities refer to skeletal dysplasia(s), and localized abnormalities refer to more

focal malformations of spine and limbs.

Skeletal Dysplasias

Definition

Skeletal dysplasias are a large mixed group of bone and cartilage abnormalities

resulting in abnormal growth, shape, and/or density of the skeleton. The birth

prevalence of skeletal dysplasias ranges from 2 to 7 per 10,000 births.4 The first

trimester diagnosis of a case of skeletal dysplasia (thanatophoric dwarfism) was

originally performed in 1988,5 and since then, several cases have been diagnosed by

ultrasound in the first trimester6–14 (Table 14.1). When technically feasible, the first

trimester diagnosis of skeletal dysplasia is helpful because it allows for fetal

karyotyping and for molecular genetic testing. Molecular genetic testing takes time, and

thus, its performance in the first trimester allows for the results to be available in the

second trimester for appropriate patient counseling. Mutation in the FGFR3 gene is

responsible for a spectrum of skeletal dysplasias to include thanatophoric dysplasia on

one end and achondroplasia and hypochondroplasia on the other end.15 When a lethal

skeletal dysplasia is suspected in the first trimester, a follow-up ultrasound examination

is recommended at around 15 to 17 weeks of gestation, because detailed sonographic

features of the malformation are commonly present by then. It is important to note,

however, that the typical sonographic features of many significant skeletal dysplasias

are present by about the 14th week of gestation, and thus, suspecting its presence is

possible in most cases. Suspicion for and/or detection of skeletal dysplasia in the first

trimester has been reported in up to 80% in some series,16 with lethal abnormalities

having the highest detection rates. Accurate diagnosis of the specific subtype of skeletal

dysplasia is often difficult in the absence of a relevant family history.14 Enlarged nuchal

translucency (NT) and/or hydrops is commonly seen in fetuses with skeletal dysplasias

in the first trimester.14,16,17 There is considerable phenotypic overlap between various

types of skeletal dysplasia, and the specific diagnosis may be difficult to make in the

first trimester.

Table 14.1 • Skeletal Dysplasias That Can Be Diagnosed by 14 Weeks of

Gestation

Achondrogenesis I and II

Ellis–van Creveld syndromeOsteogenesis imperfecta II

Thanatophoric dysplasia

Campomelic dysplasia

Diastrophic dysplasia

Congenital hypophosphatasia

Jeune asphyxing thorax dysplasia

Short-rib polydactyly syndromes

Roberts syndrome

Cleidocranial dysplasia

Adapted from Khalil A, Pajkrt E, Chitty LS. Early prenatal diagnosis of

skeletal anomalies. Prenat Diagn. 2011;31:115–124; copyright John Wiley

& Sons, Ltd., with permission.

Ultrasound Findings

Common ultrasound features of skeletal dysplasia in the first trimester include short

femur, abnormal skull shape and mineralization, and abnormal fetal profile or chest.14 In

our experience, the presence on the first trimester ultrasound of shortened, misshapen,

or fractured long bones is typically the first clue for the presence of skeletal dysplasia

in the fetus (Fig. 14.17). A small thorax with shortened ribs, when seen at 14 weeks of

gestation, should also raise the suspicion for skeletal dysplasia (Fig. 14.18). Fetal

biometric measurements, especially when performed at 14 to 15 weeks, may give a clue

to the presence of skeletal dysplasia. For instance, the combination of long bone

measurements at less than the 5th percentile along with a head circumference greater

than the 75th percentile is highly suspicious for the presence of skeletal dysplasia.18

When bone abnormalities are suspected in the first trimester, detailed evaluation by

high-resolution ultrasound transducers (transvaginal when feasible) is helpful in order

to assess the fetal skeletal system in its entirety. Evaluation of the cranium, spine, ribs,

long bones, and digits should be performed. Along with genetic and molecular testing, a

follow-up ultrasound at 15 to 16 weeks of gestation is recommended in order to assess

the severity of the skeletal abnormality and to ascertain the specific subtype of skeletal

dysplasia. Figures 14.19 to 14.23 show typical sonographic features of some major

skeletal dysplasias in the first trimester. Table 14.2 lists ultrasound findings that are

helpful in the evaluation of suspected skeletal dysplasia in early gestation.Figure 14.17: Longitudinal view of the fetal femur on two-dimensional

ultrasound in four fetuses (A–D) between 11 and 13 weeks of gestation. A: A

normal femur at 12 weeks of gestation. Note that the shape and ossification of

the femur at 12 weeks of gestation is similar to that seen later on in pregnancy.

B: A fractured and short femur at 13 weeks of gestation in a fetus with

osteogenesis imperfecta (see also Fig.14.19). C: A short femur at 13 weeks of

gestation in a fetus with diastrophic dysplasia (see also Fig.14.20). D: A short

femur in a malformed leg at 12 weeks of gestation in a fetus with sacral

agenesis.Figure 14.18: Axial plane of the fetal chest in two-dimensional ultrasound at 13

weeks of gestation in two fetuses (A) and (B) with skeletal dysplasia and

abnormal ribs. Note in A, the presence of broken ribs (arrow) in a fetus with

osteogenesis imperfecta and in B, short ribs (arrows) in a fetus with short-rib

polydactyly syndrome. Compare with Figure 14.22 and note that short ribs may

not appear at less than 14 weeks of gestation.Figure 14.19: Two-dimensional ultrasound images of the extremities and head

in a fetus with osteogenesis imperfecta type 2, diagnosed at 13 weeks of

gestation and confirmed by molecular genetic testing. Note in A–C the

presence of abnormally shortened and bowed long bones with discrepant

length and shape between the left and right side. The fetal ribs also appeared

abnormal and broken and are shown in Figure 14.18A. Note the presence of a

hypomineralized skull in D and E, which also suggested the diagnosis. Compare

with the fetus in Figure 14.21 with thanatophoric dysplasia, with shortened long

bones but with increased mineralization of skull.Figure 14.20: Two-dimensional and three-dimensional ultrasound images of the

upper and lower extremities in a fetus with diastrophic dysplasia, diagnosed at

13 weeks of gestation and confirmed by molecular genetic testing. Note the

presence of short long bones (A) along with abnormal long bone shape and

overall short extremities (B and C). The presence of an abducted thumb,

known as “hitchhiker” thumb, in D and E, suggested the diagnosis of diastrophic

dysplasia.Figure 14.21: Two-dimensional ultrasound images of a fetus with suspected

thanatophoric dysplasia (type 1) at 13 weeks of gestation. Note the presence

of bowed and shortened long bones in A and B. The axial view of the fetal head

in C shows increased ossification of the skull and an abnormally shaped

cranium. Midsagittal view of the fetal head in D shows a large head and the

beginning of frontal bossing. Hypoplasia of the thorax is not yet evident at this

early gestation (D).Figure 14.22: A–D: Two-dimensional and three-dimensional ultrasound images

of fetal extremities and chest in a monochorionic twin pregnancy at 13 weeks of

gestation. Note the presence of short femurs in A and B, normal-appearing ribs

in C, and polydactyly in D. Follow-up ultrasound examination at 15 weeks (E)

shows a new finding of short ribs, thus suspecting the diagnosis of short-rib

polydactyly syndrome. Molecular genetic diagnosis confirmed the presence of

Ellis–van Creveld syndrome, belonging to the group of short-rib polydactyly

syndromes.

Making a diagnosis in the first trimester of a specific type of skeletal dysplasia is

challenging. The presence of typical features of some skeletal dysplasias, however, can

be helpful in that regard (Tables 14.1 and 14.2). In general, the main leading sign for

the presence of a skeletal abnormality in the first trimester is short limbs or shortfemur(s) (Fig. 14.17). Absent, or significantly reduced, cranial ossification is typical

for osteogenesis imperfecta type 2 (Fig . 14.19), whereas an increased cranial

ossification is an important finding in thanatophoric dysplasia (Fig. 14.21). Careful

examination of the hands is crucial, because the presence of hitchhiker thumbs, in

addition to short and bowed femurs, suggests the diagnosis of diastrophic dysplasia

(Fig. 14.20). The presence of polydactyly with short femurs not only can be suggestive

for chromosomal aneuploidy but also is a very important early clue for the presence of

short rib polydactyly or Ellis–van Creveld syndrome (Fig. 14.22). The latter is typically

associated with cardiac defects, but their absence does not exclude this diagnosis. In

our experience, short ribs are first evident around 14 weeks of gestation (Fig. 14.18), as

shown in the case presented in Figure 14.22 with normal-appearing fetal ribs at 13

weeks and short ribs noted on follow-up ultrasound at 15 weeks. A short and bowed

femur with a clubfoot with a normal-appearing humerus suggests the diagnosis of

campomelic dysplasia (Fig. 14.23). When campomelic dysplasia is suspected, look for

the presence of sex reversal in males, where female genitalia are found, and hypoplastic

scapulae (Fig. 14.23). In a fetus with a significantly thickened NT with short femur and

micrognathia, the diagnosis of achondrogenesis should be suspected, especially when

the spine shows near-absent ossification. Despite all these anatomic markers, a detailed

ultrasound examination in the early second trimester along with fetal echocardiogram is

indicated when a skeletal dysplasia is suspected in the first trimester, because

additional anatomic findings can become more apparent with the growth of the fetus.Figure 14.23: Two-dimensional ultrasound images of a fetus with campomelic

dysplasia at 14 weeks of gestation. The diagnosis was suspected because of

the presence of a thickened nuchal translucency with short bowed femurs

(arrow) (A and B) and clubfeet. The upper limbs appear normal (C) with a

straight humerus. Visualization of hypoplastic scapulae (arrows) as shown in D

in addition to hemivertebra (yellow arrow ) confirmed the diagnosis of

campomelic dysplasia. This male fetus had male genitalia. Chorionic villous

sampling confirmed the diagnosis with the SOX-9 gene mutation. E: A scapula

in a normal fetus at 13 weeks of gestation for comparison sake.

Table 14.2 • First Trimester Ultrasound Findings in Skeletal Dysplasias

Thickened nuchal translucency

Abnormality of ductus venosus flow

Femur: short, bowed, broken, absentArms and legs: short, abnormal shape, asymmetric

Thorax: small, narrow, short ribs, broken ribs

Skull ossification: decreased or increased

Abnormal hands: polydactyly, oligodactyly, hitchhiker thumb, radius

aplasia, club hands, cleft hand, absent hand

Abnormal feet: clubfeet, polydactyly, oligodactyly, absent foot, cleft foot

Spine: reduced ossification, abnormal shape, convex angle

Associated Malformations

Enlarged NT and abnormal ductus venosus Doppler are common associated

findings.14,16,17 Associated fetal malformations are common and are typically related to

the specific type of skeletal dysplasia.

Abnormalities of Fetal Limbs

Definition

Congenital abnormalities of fetal limbs include limb reduction defects such as complete

absence of an extremity, absence of a hand or foot or radial ray abnormalities, limb

deformities such as clubfoot, abnormalities of digits such as polydactyly and syndactyly,

and fusion of lower extremities as in sirenomelia, among others. Limb abnormalities can

be isolated or more commonly seen in association with structural and chromosomal

malformations and syndromic conditions. The overall incidence of fetal limb

abnormalities was reported as 0.38% in a large retrospective cohort of pregnancies

undergoing fetal NT and detailed fetal anatomic survey in the first trimester.19 In this

study, a total of 36 fetal limb abnormalities were identified in the cohort, with 23

(63.9%) diagnosed in the first trimester by transabdominal ultrasound.19 Limb

abnormalities are more commonly detected in the first trimester when associated with

other fetal abnormalities.19,20 An enlarged NT is an uncommon finding when fetal limb

anomalies are isolated.19 A detailed classification of limb abnormalities is beyond the

scope of this chapter. Detailed discussion on forearm anomalies are presented in the

overview of Pajkrt et al.21Figure 14.24: Two- (left image) and three-dimensional (right image) ultrasound

in surface mode of a fetus with distal transverse limb reduction with an absent

hand (arrow) at 13 weeks of gestation. This fetus also had a thickened nuchal

translucency (not shown), and genetic testing revealed trisomy 21.

Ultrasound Findings

A combined transabdominal and transvaginal ultrasound examination increases

detection of limb abnormalities in the first trimester.22–24 The authors recommend the

use of high-frequency transducers and magnification of ultrasound images in order to

allow detailed evaluation of fetal extremities in early gestation. Limb reduction defects

appear to be the most common abnormalities detected in the first trimester19,20 and

include absence of a hand (Fig. 14.24) or foot (transverse limb reduction), unilateral ray

abnormalities (Figs. 14.25 and 14.26), bilateral radial ray abnormalities (Figs. 14.27 to

14.29), among others. Transverse limb reduction defect can be an isolated finding, a

sign of vascular disruption, or seen in combination with amniotic bands.Figure 14.25: Two-dimensional (2D) ultrasound (A and B) and threedimensional (3D) ultrasound in surface mode (C) in a fetus at 13 weeks of

gestation with femur-fibula-ulna complex and unilateral (left) forearm

abnormality shown in B on 2D and in C on 3D ultrasound (arrows). The right

upper extremity appears normal as shown in A and C (asterisk). It is important

to image both upper and lower extremities in order to detect such anomalies.Figure 14.26: Fetus with trisomy 18 at 13 weeks of gestation. Note the

presence in A of a normal nuchal translucency (asterisk) and hypoplastic nasal

bone (arrow). B: A normal left upper extremity, and C shows an abnormal right

upper extremity with radial aplasia (arrow). In addition to these findings, early

growth restriction and a cardiac defect were also present.

There is inconsistency in the literature with regard to the ability to make the

diagnosis of clubfoot in the first trimester, and this may be related to the nonossification

of the ankle in early gestation. In some studies,20,22,23 clubfoot was diagnosed in each

case in the first trimester, whereas in others, most if not all cases were missed.25 In our

experience, careful attention to the position of the foot is required in order to make the

diagnosis of clubfoot in the first trimester (Fig. 14.30). The addition of 3D ultrasound in

surface mode is helpful to confirm the diagnosis when suspected on the twodimensional ultrasound examination (Fig. 14.30). It is important to note, however, that a

normal anatomic position of the foot in the first trimester does not preclude the presence

of clubfoot later on in pregnancy.22 Other major abnormalities of the lower extremities,

such as sirenomelia (Fig. 14.31) and femur-fibula-ulna complex (Fig. 14.32), can also

be diagnosed in the first trimester. In the presence of a prior family history of a genetic

abnormality that involves limb deformities, careful evaluation of the extremities in the

first trimester can help in the early gestation diagnosis of a recurrence (Fig. 14.33).Figure 14.27: Three-dimensional ultrasound in surface mode of a fetus with

trisomy 18 at 13 weeks of gestation. Note the presence of bilateral radius ray

abnormalities (vertical arrow) in the upper extremities and an omphalocele

(horizontal arrow). Also note the abnormal facial profile and the thickened

region of the neck (asterisk).Figure 14.28: Two-dimensional (2D) (A and C) and three-dimensional (3D)

ultrasound (B and D) in a fetus at 13 weeks of gestation with bilateral radial

ray abnormalities. Note the correlation between the 2D images in A and B and

3D images in C and D.Figure 14.29: Two-dimensional and three-dimensional ultrasound in surface

mode of a fetus at 12 weeks of gestation with multiple malformations. Bilateral

radial ray abnormalities are noted with radial aplasia in one upper extremity

shown in A and C and radius dysplasia in the other upper extremity shown in B.

The fetus also had short stature because of spinal abnormalities (see Fig. 14-

41). The authors suspected Roberts syndrome, which could not be confirmed

on molecular genetics testing.Figure 14.30: Two-dimensional ultrasound of the lower extremity in two fetuses

(A and B) at 13 weeks of gestation with clubfoot (F). Close examination of the

lower extremities in the first trimester is needed in order to diagnose clubfoot.

Second trimester ultrasound follow-up examination is required to confirm this

finding. Three-dimensional ultrasound in surface mode of the back and lower

extremities of a fetus (C) at 13 weeks of gestation with bilateral clubfeet (F).

Abnormalities of the fingers and toes that have been diagnosed in the first trimester

include polydactyly (Fig. 14.34), syndactyly, overlapping digits, split hand as in

ectrodactyly (Fig. 14.35), adactyly, and thumb abnormalities (Fig. 14.20).22 Polydactyly

is one of the most common skeletal findings in the first trimester.25 Polydactyly can be

present in both hands and feet or only in hands or feet (Fig. 14.36), bilateral and

unilateral. The presence of a family history is a common clue for the diagnosis of

polydactyly in the first trimester. The combination of polydactyly with multiple

anomalies mainly of the heart, face, and kidneys can be typical for aneuploidy such as

trisomy 13 or 18 (Fig. 14.37).21 On the other hand, if polydactyly is found together with

other signs of skeletal dysplasia such as a short femur, short-rib polydactyly syndrome

should be considered (Fig. 14.22), even if the ribs appear normal in the first trimester.Polydactyly is commonly seen in the first trimester in association with other

malformations.22 Forearm anomalies are more common than anomalies of lower

extremities, and their differential diagnosis includes chromosomal anomalies and

genetic syndromes, especially if present bilaterally or in association with other

anomalies.21

Figure 14.31: Two-dimensional (A and B) and three-dimensional ultrasound (C

and D) in a fetus at 13 weeks of gestation with sirenomelia. Both legs are

fused into one lower limb (arrows), with no feet. One femur (F) bone is seen

along with fused bones in the lower segment (asterisk). Some fetuses with

sirenomelia have only one femur, whereas others may have two femurs. Renal

agenesis is part of the disease.Figure 14.32: Two-dimensional (2D) (A) and three-dimensional ultrasound in

surface mode (B and C) in a fetus at 12 weeks of gestation with femur-fibulaulna complex. Note that the left leg and foot is malformed as shown on 2D (A)

and 3D ultrasound (B and C) (arrows).

Figure 14.33: Two-dimensional (2D) (A) and three-dimensional (3D) ultrasound

in surface mode (B) in a fetus at 10 weeks of gestation with Grebe dysplasia.Grebe dysplasia has an autosomal recessive inheritance resulting from

mutation of the GDF-5 gene. This pregnancy was a recurrent case of Grebe

dysplasia with a previous child with severely malformed legs and feet. The

patient presented at 10 weeks of gestation for chorionic villous sampling and on

2D and 3D ultrasound, the images were clearly similar to the limbs of the

previous child. Note that after 10 weeks of gestation, the normal feet should be

touching each other as shown in Figure 14.4.

Figure 14.34: Two-dimensional ultrasound at 13 weeks (A) and threedimensional ultrasound in surface mode at 12 weeks (B) of the upper extremity

in two fetuses with postaxial polydactyly (arrows). Note that with high-resolution

ultrasound, polydactyly can be seen as early as 12 weeks of gestation.Figure 14.35: Ectrodactyly (split hand) in a fetus at 11 weeks of gestation

(arrow). Ectrodactyly can be diagnosed in the first trimester with high-resolution

ultrasound transducers and with the transvaginal approach when feasible.

Associated Malformations

It is important to note that most limb anomalies reported in the literature in the first

trimester were described in association with other fetal malformations. Common

associated abnormalities include hydrops, single umbilical artery, cardiac

abnormalities, and megacystis.19,20 As stated, the presence of an enlarged NT is a

common finding in limb anomalies, especially when associated with other findings.

Bilateral occurrence of limb anomalies is concerning for the presence of a genetic or

chromosomal etiology, and a detailed first trimester ultrasound along with follow-up in

the second trimester is recommended.21 A search for the presence of fetal limb

abnormalities should be performed when other fetal malformations are diagnosed in the

first trimester. Table 14.3 lists typical conditions associated with forearm anomalies.Figure 14.36: Two-dimensional (2D) ultrasound of fetal feet in two fetuses

(A,B) at 13 weeks of gestation with polydactyly. Note that high-resolution

transducers and magnification of the foot is required to image the toes in early

gestation.

Figure 14.37: Three-dimensional ultrasound in surface mode of a fetus with

trisomy 18 at 12 weeks of gestation. Note the presence of a flat facial profile

(arrows) and postaxial polydactyly (6 digits).Abnormalities of Spine

Definition

The most common spinal abnormality in the fetus is spina bifida, with a reported

incidence of 1/1,000 live births. Body stalk anomaly is also a malformation that is

associated with significant spinal deformity and is commonly diagnosed in the first

trimester. Spina bifida along with body stalk anomaly has been discussed in detail in

Chapters 8 and 12, respectively. Other spinal abnormalities include isolated or multiple

hemivertebrae, iniencephaly, an interrupted lower spine in segmental spinal dysplasia,

caudal regression, and severe sacral agenesis. Although sacrococcygeal teratoma is not

a spinal defect, we will include it in this section for completeness sake.

Table 14.3 • Selected Etiologies of Fetal Forearm Anomalies Listed

Alphabetically

Amniotic band

Cornelia de Lange syndrome

Femur-fibula-ulna (FFU) complex

Gallop syndrome

Holt–Oram

Isolated bilateral

Isolated unilateral

Roberts syndrome

Thrombocytopenia absent radius (TAR)

Trisomy 13

Trisomy 18

VACTERL (vertebral, anal, cardiac, tracheo-esophageal, renal, limbs)

Vascular incident

Adapted from Pajkrt E, Cicero S, Griffin DR. Fetal forearm anomalies:

prenatal diagnosis, associations and management strategy. Prenat Diagn.

2012;32:1084–1093; Copyright John Wiley & Sons, Ltd., with permission.

Ultrasound Findings

Evaluation of fetal spine biometry on ultrasound has been reported between 11 and 14

weeks of gestation.26 With the exception of large spina bifida, body stalk anomaly, or

severe spinal deformity, the prenatal diagnosis of other spinal abnormalities is rather

uncommon in the first trimester because of the lack of spinal ossification.27 In general,spinal abnormalities detected in the first trimester are likely to represent severe spinal

deformities associated with other fetal anatomic (Figs. 14.38 and 14.39) and

chromosomal abnormalities. Suboptimal visualization of the fetal spine in the first

trimester has been reported in about 15% of cases because of unfavorable fetal position,

decreased ossification, and maternal body habitus.28 Small and isolated spinal defects

typically escape first trimester detection unless there is a high index of suspicion and

optimal imaging conditions. In a review of the sonographic features of spinal anomalies

in first trimester fetuses presenting for screening for chromosomal abnormalities, a total

of 21 fetuses were diagnosed including 8 with body stalk anomaly, 7 with spina bifida,

2 with vertebral, anal, cardiac, tracheal, esophageal, renal, and limb (VACTERL)

association, and 1 case each of isolated kyphoscoliosis, tethered cord, iniencephaly,

and sacrococcygeal teratoma.29 Sacral agenesis in the first trimester is associated with

abnormal proportions of the head to body, short crown-rump length, interruption of

spine in the lumbar region, and multiple lower extremity abnormalities30 (Figs. 14.40 to

14.42). The presence of hemivertebrae is first suspected by the presence of spinal

deformities, such as kyphoscoliosis31 (Fig. 14.43). 3D ultrasound in maximum or

skeleton mode is helpful in the evaluation of the spine when hemivertebrae are

suspected (Fig. 14.43C and D). Iniencephaly is a very rare fetal anomaly that typically

belongs to the neural tube defects category. Typically, it is associated with an extreme

retroflexion of the head, in association with an occipital encephalocele (Fig. 14.44) or

rachischisis of the cervical or thoracic spine. Sacrococcygeal teratoma is diagnosed in

the first trimester when a mass is seen protruding below the spine on a sagittal view

(Fig. 14.45). Color Doppler can help assess the vascularity of the sacrococcygeal

teratoma and identify feeding vessel(s) (Fig. 14.45).Figure 14.38: Two-dimensional (2D) ultrasound in A and B and threedimensional (3D) ultrasound in maximum mode in C of a fetus with multiple

abnormalities at 12 weeks of gestation (same fetus as in Fig. 14.29). Note the

presence of abnormal proportions (double-headed arrows) of head to chest

and abdomen in the midsagittal view in A. Note also the presence of a severely

malformed spine with multiple hemivertebrae and scoliosis, shown in B and C

(arrows). This fetus also had significant abnormalities in the upper and lower

extremities as shown in Figure 14.29.Figure 14.39: Two-dimensional ultrasound of two fetuses (11 weeks in A and

12 weeks in B) with an interrupted spine (arrow), abdominal wall defect, and

absent bladder and kidneys representing an OEIS complex. OEIS complex

include an omphalocele, exstrophy of the bladder, imperforate anus, and spinal

defects.Figure 14.40: Two-dimensional ultrasound in A and B and three-dimensional

ultrasound in surface mode in C and D of a fetus at 12 weeks of gestation with

sacral agenesis. Note the abnormal proportions (double-headed arrows) of

head to chest and abdomen in the midsagittal views in A and B. This

disproportion along with a shortened crown-rump length should alert for the

presence of sacral agenesis. In sacral agenesis, the lower extremities are in a

typical position with the knees wide apart and the feet touching (C and D)

(open circle), a position referred to as the “Buddha position.”

Associated Malformations

Congenital vertebral defects can be a prominent feature of several syndromes including

the VACTERL and others such as an OEIS complex in association with an omphalocele,

exstrophy of the bladder, imperforate anus, and spine abnormalities (Fig. 14.39)

(Chapters 12 and 13). Increased NT was found in about a third of spinal abnormalities

diagnosed in the first trimester.29Figure 14.41: Two-dimensional ultrasound in A and three-dimensional (3D)

ultrasound in maximum mode in B and C in a fetus at 14 weeks of gestation

with sacral agenesis. This pregnancy was complicated by maternal diabetes.

Note that the spine is interrupted at the level of the lumbar region as shown in

A–C (arrows). A short crown-rump length for gestational age along with body

disproportion as shown in A suspected the presence of spinal abnormality. 3D

ultrasound in B and C clearly shows the level of spine interruption (arrows).Figure 14.42: Two-dimensional (2D) ultrasound in A and B and threedimensional (3D) ultrasound in surface mode in C of a fetus at 12 weeks of

gestation with sacral agenesis. Note in A that the spine is interrupted at the

lumbar region (arrow). In B and C, abnormal pelvic bones are noted along with

a severely malformed lower extremity (small arrows), which also appears to

arise from the lateral lower abdomen. Fetal death occurred 1 week later

following this ultrasound examination.Figure 14.43: Two-dimensional (2D) ultrasound in A and B and threedimensional (3D) ultrasound in maximum mode in C, and D of four fetuses at 12

to 14 weeks of gestation with spinal deformities because of hemivertebrae

(arrows). Note the presence of scoliosis in C, and D. 3D ultrasound in maximum

or skeleton mode is helpful in the evaluation of the spine in early gestation when

spinal abnormalities are suspected on 2D ultrasound.Figure 14.44: Two-dimensional (A) and corresponding three-dimensional

ultrasound of a fetus with iniencephaly and encephalocele at 13 weeks of

gestation. Note the presence of significant dorsal flexion of the head and spine

(arrow) and the presence of a large encephalocele (asterisks).1.

2.

3.

4.

5.

6.

Figure 14.45: Two-dimensional (2D) ultrasound in gray scale (A) and color

Doppler (B) of a sagittal view of a fetus at 13 weeks of gestation with

sacrococcygeal teratoma (small arrows). Note in A and B that the

sacrococcygeal teratoma is a mass that is posterior and inferior to the pelvis.

B: Color Doppler of the feeding artery (long arrow) arising from the iliac artery

(IA). UA, umbilical artery.