This chapter should be cited as follows:
Fontanella F, Bardi F, et al, Glob. libr. women's med.,
ISSN: 1756-2228; DOI 10.3843/GLOWM.419353

The Continuous Textbook of Women’s Medicine Series – Obstetrics Module

Volume 18

Ultrasound in obstetrics

Volume Editors: Professor Caterina M (Katia) Bilardo, Amsterdam UMC, Amsterdam and University of Groningen, Groningen, The Netherlands
Dr Valentina Tsibizova, PREIS International School, Florence, Italy

Chapter

Evaluation of Fetal Anatomy in the First Trimester

First published: October 2024

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INTRODUCTION

The main applications of first-trimester ultrasound (US) are:

• Determination of location of pregnancy (intrauterine)
• Documentation of viability (heart activity)
• Dating of pregnancy based on the crown–rump length (CRL) measurement¹
• Diagnosis of multiple pregnancy
• Detection of obvious developmental disorders.

This chapter focuses on first-trimester US in screening for congenital anomalies. The rapid improvement in US imaging has shown that first-trimester US can be used to detect markers of chromosomal anomalies, such as increased nuchal translucency (NT) as part of the combined test (CT) and that certain severe structural anomalies can be detected in the first trimester.^2,3 Key to this development was the introduction of transvaginal US which enabled a more detailed visualization of the first-trimester fetus.^4,5

The focus was initially on high-risk pregnancies,⁶ but gradually shifted towards more unselected populations.⁷

The nuchal scan between 11 and 14 weeks has also become the first global risk profile assessment in pregnancy.^8,9,10

The Fetal Medical Foundation (FMF) has played a crucial role in setting standards and providing training and certification for the performance of first-trimester screening.

The two largest studies to date on euploid fetuses examined at the time of the nuchal scan, have shown that structural anomalies are observed in about 1% of cases.^7,11 Overall, 43% of the structural anomalies were detected at the first-trimester scan and the NT was enlarged in 30%. The authors state that about one-third of the structural anomalies are amenable to early diagnosis and another 40% can potentially be detected in the first-trimester.^7,11 The remaining 30% cannot be detected as these become evident or develop only at later stages in pregnancy.⁷ The other study confirmed that 45% of the structural anomalies, and 100% of the severe ones, are amenable to early diagnosis. The NT was enlarged in 50% of cases.¹¹ A meta-analysis of 19 studies (115,731 fetuses) on first-trimester US investigation showed an overall detection rate (DR) for structural anomalies of 46%, with 32% of anomalies detected in low-risk pregnancies and 60% in high-risk groups and when a screening protocol was used.¹²

In 2023, the International Society of Ultrasound in Obstetrics and Gynecology (ISUOG) published an updated guideline addressing the various goals of ultrasound investigation in the first trimester of pregnancy aimed at promoting standardization and uniformity.¹³

Worldwide, there is a variable policy regarding the offer of a first-trimester ultrasound scan as a first and early step in screening for structural anomalies. There are countries in which this is routinely offered, either as part of the CT or as early screening for anomalies or in the context of research, however, in most countries a national policy is still lacking.

Overall, in an unselected population and in a routine setting, about 40–50% of structural anomalies can potentially be detected in the first trimester, although considerable variations exist among studies, reflecting operator and population characteristics.^7,11,14 Severe and often lethal anomalies should be detected in 100% of cases.^7,11

Experts recommend that, when possible, first-trimester US should be offered as screening for both chromosomal and structural anomalies and should be carried out according to a structured protocol.^12,13 This scan should be regarded as the first global risk profile assessment in pregnancy capable of providing information that cannot be replaced by non-invasive screening for aneuploidies.¹⁵

ANATOMICAL SURVEY AT 11+0 TO 13+6 WEEKS

The first-trimester anatomical assessment can present some challenges: although the small fetal size enables quick visualization of different anatomical planes, its mobility can be an obstacle to a thorough examination (Video 1). The use of the cineloop function, if available, can be of great help for this purpose as it can expedite first-trimester US examination. According to the recently published ISUOG guidelines, a distinction can be made between basic first-trimester US investigation and advanced examination.¹³

BASIC ULTRASOUND EXAMINATION

Table 1 shows items that should be part of any scan performed in the first trimester. A combination of longitudinal and axial planes should be used.

The examination usually starts with visualization of the whole length of the fetus, in the attempt to measure the CRL (Video 2, Figure 1).

In a longitudinal plane, the fetal head and upper thorax can be displayed in the same plane as used for NT measurement. In this view, the nasal bone (NB) and brain structures including the diencephalon (DE), brainstem (BS) and fourth ventricle with its choroid plexus can also be appreciated (Figure 2).

The fourth ventricle appears as a rectangular structure delimited by two echogenic lines, which has been named intracranial translucency (IT).¹⁶ A midsagittal view including the whole fetal trunk, allows visualization of the diaphragm and of the entire abdominal wall and intra-abdominal content, including bladder filling and size. The fetal spine, although not yet completely ossified, can also be observed in its whole extent from the cervical origin to the sacrum (Figure 3). By tilting the probe on both sides of the fetal body the extremities can be visualized, including the three long bony segments of each extremity (Figures 4 and 5). The first-trimester fetus usually has open hands facilitating counting of fingers. The legs are often flexed and the feet can be seen close to each other in a single sweep.

Axial planes should be obtained starting from the head and moving in the caudal direction. The most cranial axial plane shows the intact skull and in the head the image of the falx (midline) and choroid plexuses. At this stage, these structures almost entirely fill the relatively large lateral ventricles. Of note is that the size of the lateral ventricles (usually 6–8 mm) will not change after 12–13 weeks. The typical appearance of the falx and of the two echogenic structures in the lateral ventricles has been called the ‘butterfly sign’ (Figure 6).¹⁷ One plane below this shows the thalami, the cerebral peduncles and the aqueduct (Figure 7), the latter very clearly visible at this stage of pregnancy. This is the plane in which biparietal diameter (BPD) and head circumference (HC) should be measured.

A cross-sectional view of the chest shows the four-chamber view of the heart, in which the size of the atria and ventricles can be appreciated (Figure 8a). The lung fields can also clearly be visualized (Figure 8a). In the same view, the heart axis can be measured (Figure 8b). This should measure between 25° and 65°. The four chambers can also be visualized with color or, even better, directional power Doppler (Figure 9a). Color Doppler is a crucial complement to 2D imaging for rapid visualization of cardiac structures. This includes filling of the chambers, and, if possible, visualization of the crossing of the outflow tracts and confluence of the aortic arch and ductal arches forming a V (V-sign) pointing towards the left shoulder of the fetus with (color) flow in the same direction (Figure 9b). More caudally, the fetal stomach is seen under the heart (Figure 10) just above the level of the umbilical cord insertion into the fetal abdomen (Figure 11). Finally, lower in the pelvis, the bladder is seen (Figures 12 and 13), flanked by the two umbilical arteries (Figure 14). The kidneys can occasionally be observed as two echogenic oval structures on both sides of the spine (Figure 15). This quick and gross anatomical survey enables exclusion of major and most lethal structural anomalies. Although, in favorable circumstances, a transabdominal (TA) scan performed with high resolution US systems gives excellent images, in obese women or when the uterus is retroverted, the TV approach is indicated to improve structure visualization.¹⁸ In obese women, a TV US can provide even better images than a TA mid-trimester scan.¹⁹

Anomalies unlikely to be missed at first-trimester ultrasound examination

According to Syngelaki et al., the fetal structural anomalies below are those that are likely to be recognized at first-trimester US investigation.⁷

Increased nuchal translucency

Abundant nuchal fluid accumulations (large NT, cystic hygroma, generalized edema) (Video 3) are relatively obvious anomalies that can be associated with aneuploidy.⁸ When the karyotype is normal, a thickened NT (Figure 16) is a strong marker for structural and genetic disorders and poor pregnancy outcomes.^20,21 The chance of a poor outcome depends on the initial degree of enlargement.²⁰ The strongest association exists for cardiac defects,^20,21 with NT being enlarged in about 40% of cases with major cardiac defects.²²

Of all genetic syndromes, the most frequently associated with increased NT is Noonan syndrome, a relatively common syndrome.²³ To diagnose Noonan syndrome, a specific gene panel can be used with next generation sequencing (NGS).²⁴

An enlarged NT is common to many developmental disorders, appearing to be a non-specific US marker shared by different pathways.^25,26

The work-up after an enlarged NT with normal karyotype includes array comparative genomic hybridization (CGH) investigation and repeat scans.²⁷ Array CGH can reveal in these fetuses an additional 5–7% of pathological copy number variants.²⁷ Fetal exome sequencing is indicated only in cases in which the NT is >7 mm or with associated anomalies.²⁸ If the nuchal edema has completely disappeared in the second trimester and the 20-week scan is normal, the chance of an abnormal outcome is extremely low and not dissimilar to that of the normal population.²⁹

Acrania (anencephaly)

Acrania, which has a prevalence of about 3.7 : 10,000 pregnancies, is caused by failure of closure of the rostral part of the neural tube. In this condition the cranial bones and scalp skin have not yet developed, and the brain tissue is exposed to mechanical and chemical damage (Video 4). Eventually, brain tissue ‘dissolves’ in the amniotic fluid, producing a milky appearance on the scan. Later in pregnancy acrania evolves into exencephaly and, in the second trimester, into anencephaly, in which hardly any brain tissue is visible. Acrania can be seen in chromosomal or genetic conditions (Meckel-Gruber syndrome) or amniotic band syndrome and is associated with aneuploidy in up to 5% of cases.³⁰ Sonographic features of acrania are present from 9 weeks.³¹ Usual presentation of acrania at 11–13 weeks is an irregular contour of the head in the sagittal plane and absent or severe deficiency of cranial bones with distortion of the brain structures. In order not to miss this condition, an early scan should be performed after 11 weeks by trained sonographers.³² Other rare conditions that can be diagnosed early in gestation are iniencephaly and craniorachischisis, the latter morphologically similar to acrania. 

Encephalocele/cephalocele

Encephalocele/cephalocele (Video 5) (1 : 5000 live births) is a neural tube defect characterized by protrusion of intracranial structures through a defect in the skull. The first-trimester DR is 80%.¹¹ It is suggested that the anomaly is associated with an enlarged rhombencephalic cavity at earlier US investigation and that absence of one of the three posterior brain spaces can be helpful to identify fetuses with cephalocele.³³ By visualization of the fetal skull defect in the axial plane, a differentiation can be made between cranial meningocele (protrusion of only meninges; 37% of cases) and encephalocele (protrusion of brain tissue into the cephalocele; 63% of cases).³⁴ 

Holoprosencephaly 

Holoprosencephaly (Videos 6 and 7) (1 : 1300 pregnancies)  is characterized by failure of the prosencephalon to divide into two hemispheres, resulting in a single ventricle. The anomaly is often associated with severe skull and facial defects and more than two-thirds of cases are associated with chromosomal abnormalities, mainly trisomies 13 and 18.³⁵

Absence of the butterfly sign and presence of a single brain cavity anteriorly on the axial plane is specific for alobar holoprosencephaly with a high sensitivity.¹⁷

Lobar or semilobar holoprosencephaly, however, are more subtle to diagnose and will usually not be detected in the first trimester.

Abdominal wall defects

Abdominal wall defects can easily be diagnosed in the first trimester.¹¹ It is important that the diagnosis is made beyond the phase of physiological gut herniation within the umbilical cord. This is usually complete by about 12 weeks (CRL ≥45 mm).

Exomphalos

The prevalence of exomphalos (omphalocele) (Video 8) at the first-trimester scan is 1 : 419, however, there is a tendency for the prevalence to decrease with advancing gestation and according to the content of the defect.³⁶ Herniation of the liver is rare (1 : 3360) and does not resolve, whereas for herniation of the bowel only (Video 9), the prevalence changes from 1 : 98 at a CRL of 45.0–54.9 mm, to 1 : 798 at a CRL of 55–64.9 mm and 1 : 2073 at a CRL of 65.0–84.0 mm.^37,38 The fetal karyotype is frequently abnormal (40.8%) in exomphalos in both liver- (52%) or bowel-only (55%) cases.³⁵ However, if the karyotype is normal, a bowel-only exomphalos has a 92% chance of spontaneous resolution by 20 weeks’ gestation and of an uneventful pregnancy and neonatal outcome. This suggests that in the large majority of bowel-only exomphalos cases diagnosed in the first trimester, this can be regarded as a delayed resolution of the physiological gut herniation within the umbilical cord. Therefore, in cases of low-risk assessment at first-trimester screening or non-invasive prenatal testing (NIPT), no karyotyping is necessary and the diagnosis of exomphalos should be reserved only for cases persisting in the second trimester.³⁵

In a recent study of 98 cases of exomphalos diagnosed before 14 weeks’ gestation, 46% were associated with other major structural anomalies: 21.4% had increased NT and 51% of the karyotyped fetuses had chromosomal anomalies, mainly trisomy 18.³⁹ In cases of exomphalos associated with other major structural abnormalities, or with increased NT, the incidence of aneuploidy was 78.9% and 72.2%, respectively. To improve the prognostic value of first-trimester examination, Tassin et al. investigated whether a standardized ratio (mean exomphalos diameter/transverse abdominal diameter) and exomphalos contents were predictive of neonatal morbidity.⁴⁰ Neonatal morbidity was increased when the ratio was greater than 0.8 or when liver was herniated in the first trimester. The authors concluded that the outcome of exomphalos (92.6% of live born infants survived the neonatal period, 96% without long-term sequelae) is relatively good, but only when isolated and when the ratio is below 0.8. Nine per cent of the fetuses diagnosed with isolated exomphalos before 14 weeks of gestation had severe malformations diagnosed later in pregnancy.³⁹

In conclusion, exomphalos diagnosed in the first trimester, regardless of its size or contents, requires additional investigations to establish the prenatal and postnatal prognosis. When exomphalos is not associated with aneuploidy or other abnormality, its size could be predictive of prenatal and postnatal outcome.

Gastroschisis 

Gastroschisis (Video 10) is observed less frequently than exomphalos at the first-trimester scan, but its prevalence is increasing (from 2.3 to 4.4 : 10,000).^11,41 This abdominal wall defect differs from exomphalos in embryological development, associated anomalies, risk factors and outcome. It is characterized by a full-thickness defect of the anterior abdominal wall, typically on the right side of a normally inserted umbilical cord, associated with evisceration of the abdominal contents.⁴² A recent accredited theory is that gastroschisis may be due to an abnormality of the rudimentary umbilical ring, resulting in a separation of the fetal ectoderm from the amnion’s epithelium on the right side.⁴³ Chronic stress and exposure to domestic violence are risk factors for gastroschisis, moreover mothers of fetuses with gastroschisis are more likely to be younger, smokers and more often users of recreational drugs than are controls.⁴⁴

Early diagnosis should be made with caution as the physiological gut herniation may mimic the defect or, alternatively, the defects may be missed as the presence of a few bowel loops herniating through a defect located on the right side of a normally inserted umbilical cord may not be seen in the midsagittal plane. The use of transverse planes is therefore indicated.

Management of gastroschisis diagnosed in the first trimester differs from management of exomphalos as, if the defect is isolated, karyotyping is not indicated.⁴³

Fetal megacystis

Fetal megacystis is defined as a longitudinal bladder diameter ≥7 mm and is detected in 0.06% of first-trimester scans (Video 11).⁴⁵ The underlying cause of this rather rare condition ranges from lower urinary tract obstruction (LUTO), to chromosomal abnormalities and congenital syndromes, to transient enlargement with spontaneous resolution and normal urinary system after birth.^46,47 In a study of 142 cases of first-trimester megacystis, the outcome was mainly determined by the degree of bladder enlargement: moderate enlargement with a longitudinal diameter <12 mm was associated with spontaneous resolution in euploid fetuses and an increased NT with complex megacystis (chromosomal anomalies or syndromal associations). Severe distension with a longitudinal diameter >15 mm mainly progressed to obstructive uropathy and, when this was associated with an umbilical cord cyst, there was a high likelihood of urethral atresia, a severe condition especially present in female fetuses.⁴⁷ Therefore, when the bladder diameter is between 7 and 12–15 mm, karyotyping and repeat ultrasound 2 weeks later is recommended.

Major developmental disorders

Body stalk anomaly

Body stalk anomaly (Video 12) is characterized by the presence of a major abdominal wall defect and severe kyphoscoliosis, probably the result of a short umbilical cord, in which half of the fetal body lies in the amniotic cavity and the other half is in the celomic cavity. Owing to its severity, the anomaly is usually detected at the first-trimester scan from as early as 11 weeks.⁴⁸

Bladder exstrophy, cloacal exstrophy and omphalocele, bladder/cloacal exstrophy, imperforate anus, spina bifida complex (OEIS)

This is a group of rare defects (1 : 30,000–1 : 100,000) of closure of the lower abdominal wall, characterized by protrusion and eversion of the bladder outside the peritoneal cavity and by other major associated defects with derangement of the lower body anatomy. All these defects are characterized by non-visualization of the fetal bladder that, by 12–13 weeks’ gestation, should always be visible. In cases of persistent failure to visualize it, bilateral renal pathology or bladder exstrophy should be suspected.⁴⁹ When, besides non-visualization of the fetal bladder, other anomalies of the lower part of the body are present (omphalocele, lower abdominal mass, abnormal genitals, lumbosacral spinal defect or a thin-walled intra-abdominal cyst), one of these more complex rare anomalies should be suspected.⁵⁰

Pentalogy of Cantrell/ectopia cordis

Pentalogy of Cantrell (Video 13) and ectopia cordis are rare but, owing to their distinctive presentation of an extracorporeal heart and common association with increased NT and other anomalies, the defects are amenable to first-trimester diagnosis.⁵¹

Conjoined twins

Conjoined twinning (Figure 17) is a rare complication of multiple pregnancy, occurring in 50,000–200,000 pregnancies, with ethnic variations. There are different sorts and degrees of fusion of anatomical structures and the prognosis and therapeutic options very much depend on this.⁵²

Molar pregnancy 

In a molar pregnancy, first-trimester ultrasound examination reveals that, in spite of high beta human chorionic gonadotropin (hCG) levels, the fetus has not developed, and the uterus is filled by a mass of cystic structures of variable size. This is defined as complete mole. A partial mole is when the fetus is visible with a normal placenta, but next to it a mass with a typical molar appearance can be seen.⁵³

ADVANCED FIRST-TRIMESTER ULTRASOUND INVESTIGATION

The updated ISUOG guidelines' advice is to follow the basic examination with a more detailed examination of the fetal anatomy, which includes more views.¹³ Ideally, this should be the case in any first-trimester scan, although the situation is not homogeneous, and local circumstances should be taken into account. The ISUOG protocol for an advanced anatomical assessment in the first trimester is presented in Table 2.

We describe in more detail examination of the brain, neural tube and heart.

First-trimester fetal brain and spine investigation

The importance of early diagnosis of central nervous system (CNS) anomalies lies in the fact that they are common, and often lethal or associated with severe mental disability and/or motor dysfunction. Early detection offers parents the option to terminate the pregnancy at a stage when termination may be less traumatic.⁵⁴

Neurodevelopment starts from the neurulation phase, from around 19 days of embryonic life to around day 26. The neural plate becomes the neural tube, and this further develops into prosencephalon (forebrain), mesencephalon (midbrain), rhombencephalon (hindbrain) and the spinal cord. Cranial bone ossification should be completed by 11 weeks. At the time of the first-trimester scan (11–13 weeks), rudimentary brain structures are present and can be assessed by ultrasound.⁵⁵

It is helpful to look specifically for bone ossification in the axial and coronal planes. No bony defects (distortion or disruption) of the skull should be present. Lateral ventricles are relatively large and filled by the echogenic choroid plexuses in their posterior two-thirds. The hemispheres appear symmetrical and separated by a clearly visible interhemispheric fissure and falx (Figures 6 and 7). The thin brain mantle is best appreciated anteriorly, lining the large fluid-filled ventricles, an appearance which should not be mistaken for hydrocephalus. At this early stage, some cerebral structures (e.g. corpus callosum, cerebellum) are not yet sufficiently developed to allow accurate assessment.

The midsagittal view of the fetal head, routinely used for the assessment of NT thickness and NB at 11–13 weeks, can also be used to assess early fetal brain anatomy (Figures 18 and 19). The configuration of the midbrain, brainstem and fourth ventricle changes in cases of open spina bifida (OSB). The intracranial translucency (IT), corresponding to the fourth ventricle, has been proposed as a marker for normal brain development and intact spine.^56,57 In fetuses with OSB, the biparietal diameter is affected from as early as the first trimester and is relatively smaller than the head circumference.^58,59 Cystic abnormalities of the posterior fossa, suggestive of Dandy–Walker complex can also occasionally be detected.⁶⁰

There has been some debate as to which view, midsagittal or axial, is the most informative for early investigation of fetal brain abnormalities.⁶¹ When anomalies are suspected, the use of transabdominal or transvaginal parallel axial planes and 3D neurosonography, performed by experts, is recommended to reach a final diagnosis.⁶²

Most common brain and neural tube anomalies amenable to first-trimester diagnosis (sometimes detectable)

Open spina bifida (OSB) 

OSB (Video 15) (prevalence in Europe about 1 : 2000 pregnancies) is caused by failure of closure of the neural tube 24–27 days after conception. Typical associated brain changes are due to leakage of cerebrospinal fluid. The developing spinal cord and exposed nerves are damaged by direct trauma and by the neurotoxicity of the amniotic fluid.⁶³ In the first trimester, these secondary changes have just started and are therefore subtle, moreover, the spinal defect and the myelomeningocele (Figure 20) may be challenging to visualize.

The IT is the most well-known first-trimester marker for OSB, which can be measured in the same plane as that for NT.¹⁶ It can be identified in 98% of normal fetuses by trained sonographers, and a meta-analysis of nine studies has indicated that non-visualization of the IT has a sensitivity of 53.5% and specificity of 99.7% for diagnosing OSB.⁶⁴

To increase sensitivity, numerous approaches have been proposed including measurements of the cisterna magna (CM)^65,66,67 the brainstem (BS) and the brainstem occipital bone distance (BSOB)^68,69 (Figure 19), or evaluation of the posterior fossa fluid area, and the four-line view⁶⁹ (Figure 18). Non-visualization of the CM or a CM width below the 5th percentile are both suggested to have a sensitivity for OSB of 50–73%.^66,67 In the same image it can be appreciated if one of the three posterior brain spaces is absent and the BSOB distance can be measured. In a retrospective study, a BS diameter above the 95th percentile, a BSOB distance below the 5th percentile, and a BS to BSOB ratio above the 95th percentile had a sensitivity for diagnosing OSB of 96.7%, 86.7%, and 100%, respectively.⁶⁸ In the only prospective study, the Berlin IT Multicenter Berlin study on 15 526 consecutive patients, experts were able to diagnose all 11 OSB cases based on suspicious findings at the 11–13-week scan, but only by combining all posterior fossa parameters.⁷⁰ Other markers proposed on the sagittal view include the maxillary occipital line (MO), defined as a straight line drawn along the superior border of the maxilla until it reaches the inner border of the occiput in the midsagittal plane of the fetal face. In cases with OSB, the junction between the midbrain and BS is below the MO line.^71,72 Another sign described more recently is the inferior displacement of the torcular Herophili and the larger brainstem–tentorium angle in cases of OSB (Figure 21).⁷³

Of the markers for OSB evaluated on the axial plane, besides a smaller BPD,^58,59 also an altered BPD/transverse abdominal diameter ratio was proposed.⁷⁴ It was also observed that, due to the loss of cerebrospinal fluid the distance between aqueduct of Silvius (AoS) and occiput is shorter in cases of OSB.⁷⁵ Cerebrospinal fluid leakage leads to ‘dry brain’ impacting skull and brain morphology of fetuses with OSB.⁷⁶ Another consequence of this is the posterocaudal displacement of the mesencephalon, called ‘crash sign’ as the midbrain seems to ‘crash’ against the occipital bone.⁷⁷ Also, when the brain is ‘dry’, the choroid plexus fills the lateral ventricles and occupies a relatively larger area of the fetal head.⁷⁸

A recent analysis of the various head signs indicates that markers involving changes in the BS and posterior fossa configuration seem superior to others⁷² (Table 3).

However, large prospective studies are still mandatory to define the role of early US in the diagnosis of OSB. It is expected that by combining signs of both sagittal and axial views of the brain (Figures 18, 19 and 21) high DRs of OSB can be achieved.

Dandy–Walker malformation (DWM)

DWM (1 : 30,000 live births) may be suggested by a markedly enlarged intracranial translucency and BSOB, with absence of the septum separating the fourth ventricle and the cisterna magna.^60,62 DWM can be associated with chromosomal anomalies or other fetal abnormalities.^60,79 A recently described clue for the differential diagnosis of DWM or Blake’s pouch cyst, an innocent anatomical variant, is the position of the choroid plexus of the fourth ventricle.⁸⁰ Direct assessment of the cerebellar vermis is not possible as its development is completed only at around 18 weeks. Caution should therefore be used in first trimester diagnosis of vermian anomalies and repetition of the US scan until after 18 weeks’ gestation is recommended.

Ventriculomegaly (VM)

Lateral ventricles measuring more than 10 mm are mainly a second- and third-trimester diagnosis. Using again the relationship between choroid plexus size and ventricular size, it has been suggested that it may be possible to diagnose VM as early as in the first trimester, with a sensitivity of 60–70%.⁸¹ Lateral ventricles can appear enlarged in first-trimester fetuses with chromosomal anomalies,⁷³ especially trisomies 18 and 13, in some genetic syndromes and in aqueduct stenosis.⁸² An abducted thumb may suggest X-linked hydrocephalus.⁸³

To summarize, first-trimester diagnosis of conditions such as acrania, alobar holoprosencephaly and encephalocele is possible and these anomalies should actively be excluded at every early scan. Screening for spina bifida is feasible in expert hands with DRs of 50–100% and very low false-positive rates, however, large studies in low-risk populations should indicate which (combination of) markers should be used. All other brain anomalies (mild ventriculomegaly, agenesis of the corpus callosum, migration disorders, tumors, schizencephaly) cannot be diagnosed in early gestation.

Congenital heart defects (CHD)

CHD is the most common malformation (8–10 : 1000 live births). About 30% are severe and responsible for significant mortality and morbidity in the neonatal period and infancy.⁸⁴

Since the widespread use of NT screening and the recognition of other early markers, first-trimester diagnosis of CHD has been extensively investigated.⁸⁵ Early fetal echocardiography (EFEC) is commonly offered in high-risk pregnancies or when an increased NT, with or without additional anomalies, is observed at first-trimester screening.⁸⁶ In high-risk pregnancies, a normal EFEC can provide early reassurance. The challenge is when there is uncertainty regarding the diagnosis. One should be aware that it is never advisable to undertake termination of pregnancy after an early suspicion of CHD and that repetition of the scan at a later stage is always recommended.

Accuracy of CHD detection by early US investigation

A recent systematic review and meta-analysis of 63 studies on early US detection of CHD showed a pooled sensitivity in high- and low-risk women of 68% and 56%, respectively.⁸⁷

The imaging protocol used for examination was found to have an important impact on screening performance in both populations (P <0.0001), with a significantly higher DR observed in studies using at least one outflow-tract view or color-flow Doppler imaging (both P <0.0001). Early DR varies from 16% for coarctation of the aorta (CoA) and 18% for tetralogy of Fallot (TOF) and transposition of the great arteries (TGA) to 51% for hypoplastic left heart syndrome (HLHS).⁸⁷ Another recent study, on almost 100 000 pregnancies, found that an early scan could detect >90% of hypoplastic left ventricle cases and atrioventricular septal defects (AVSD) and >60% of complex cardiac anomalies.⁸⁸

How to perform detailed early fetal echocardiography

Under normal scanning circumstances, all cardiac structures should be visible by 13 weeks (Video 16).⁸⁹ Although TA examination can allow for a satisfactory examination, in some cases, transvaginal echocardiography can give far better images, especially in women with high BMI.⁹⁰

In axial views of the chest, the cardiac apex points at 1–2 or 10–11 o’clock for cephalic or breech presentations, respectively. Heart and stomach positions are evaluated to determine the situs. The four-chamber view (4CV) is used to assess the heart axis, symmetry of the ventricles, AV valves and crux. Further tilting of the transducer cranially demonstrates two parallel lines, running from the left ventricle (LV) to the right, representing the left-outflow-tract and, more superiorly, the three-vessel views. The pulmonary artery (PA) runs straight into the ductus arteriosus (DA) and meets the left-sided aorta forming a V-sign. Modern ultrasound systems produce reasonable-quality images of the 4CV in the majority of cases. The resolution can be improved by use of high-frequency probes and of proper image magnification (chest filling at least half of the screen).

The use of color Doppler, with preference for directional power Doppler, and of correct ultrasound settings is essential in early gestation to overcome suboptimal visualization of the heart by grayscale⁹¹ (Table 4). However, color Doppler should be used if high velocity flow is suspected (like in TR or aortic stenosis). Color mapping of the great arteries reduces false-negative diagnosis in some CHD.⁸⁶ The first step is to achieve a good quality 4CV in gray-scale mode and then activate power Doppler. Ventricular filling is seen as two separate red (for apical views) stripes equal in size (Figure 9a, Video 16). The LV stripe forms the apex and is slightly longer than the right ventricle (RV) stripe. With good presets, TR is commonly visible as a blue jet originating in the RV near the interventricular septum. The observation of mild TR is a common finding in the first trimester and likely a normal variant.

By tilting the transducer cranially from the 4CV, the blue stripe of the LVOT is seen. Sometimes the blood velocity in the LVOT is below the scale and it can be better visualized by reducing the pulse repetition frequency (PRF). The next structure seen by sweeping cranially is the long blue stripe formed by the RVOT. A normal PA has a very straight course from the RV into the DA. The vessel appears vertical on the screen. By tilting the transducer further cranially it is possible to see the transverse aorta (aortic arch) on the right side of the PA (opposite to the heart). The PA–DA and Ao meet forming a blue color V-sign pointing towards the left (Figure 9b). When the PA has a straight vertical position, the Ao may not be visible on color Doppler due to the relatively slow blood flow velocity. By reducing gradually the PRF, the V-sign will appear. Earlier in gestation, at 11–12 weeks, the Ao arch is situated higher than the ductal arch and in some cases it is impossible to get a proper V-sign. However, if starting from the DA and continuing the sweep caudally, the blue stripe of the Ao will eventually be seen coming from the right.

Although, to date, no scientific organization recommends a dedicated heart investigation in the late first trimester, there is mounting evidence that some severe heart defects may be recognized at this stage of pregnancy.^90,92

The five commonest severe CHD, accounting for more than 80% of cardiac anomalies, are described below and how they can be visualized on EFEC.

Hypoplastic left heart syndrome (HLHS): the typical sonographic appearance of HLHS in the first trimester (Video 17) is absence of a normal 4CV with significant RV > LV disproportion and deviation of the heart axis. On color Doppler, either only the RV filling (Video 17) is seen or both inflows, but with significant RV > LV disproportion. Sometimes the appearance can be complicated by TR and/or mitral valve regurgitation(s). In HLHS the PA is enlarged and straight, there is no V-sign, and retrograde flow in the transverse aorta is seen just above the ductal arch. The velocity of the retrograde flow in the Ao is generally low and, if this is not visible, the PRF and ultrasound power should be gradually reduced. Not all cases of HLHS are amenable to first-trimester diagnosis, as some may result from progression of aortic stenosis into atresia and become apparent only later in pregnancy. Suspicious signs can be RV > LV inflow disproportion and recognition of high velocity flow at the stenotic AV, which can be easily confused with TR. If these signs are observed, the case should be closely followed-up to see whether there is evolution towards HLHS. In expert hands, diagnosis of the most severe forms of HLHS can be as high as 90%, although pooled data report around 73%.^11,86,93

Atrioventricular septal defects (AVSD) are commonly associated with trisomy 21 (1 in 3) and left atrial isomerism (LAi).⁸⁷ The condition varies in severity, but a complete AVSD is characterized by a common atrioventricular (AV) junction with a fused multileaflet AV valve. Large AV septal defects are visible on the 4CV (Videos 18a and b). Careful observation of the movements of the common AV valve, especially during diastole, is a diagnostic hint. Color Doppler shows a single ventricular inflow with angled ventricular filling strips, instead of two normal parallel strips. This arrangement is termed ‘trousers sign’ (Video 18). Insufficiency of the common valve is frequent in AVSD and the jet originates from the middle of the heart. In cases of AVSD with normal karyotype, it is important to exclude LAi. This includes complex types of AVSDs, heart block, interrupted IVC with azygos continuation and right-sided stomach.⁸⁹

Transposition of the great arteries (TGA) is one of the most challenging diagnoses even at the mid-trimester scan with less than a 50% DR.⁹⁴ A great proportion of TGAs have essentially a normal 4CV and normal size of the great arteries. There is interfetal variability regarding the plane in which the parallel course of the great arteries can be visualized (Video 19). Detection of TGA at 11–13 weeks is quoted to be 18%.⁸⁶ Grayscale US is not helpful in the diagnosis of TGA at 11–13 weeks due to limited resolution and normal 4CV. There are two different presentations of TGA: (1) parallel vessels seen at the level of the outflow tracts and (2) the impression of a 'single' vessel, due to the ‘fusion’ of the color Doppler stripes of the pulmonary artery–ductal arch and the aorta in a sagittal or oblique view. To improve diagnostic ability, we suggest following the course of the great vessels, rather than to look at the three-vessel view. 

Tetralogy of Fallot (TOF) (Video 20) is commonly associated with chromosomal and genetic conditions and extracardiac anomalies. This CHD has typically normal 4CV and normal filling of the ventricles by two parallel stripes. The landmark of TOF is visualization of a large and usually abnormally curved vessel, which arises from the middle of the heart and forms the aortic arch (Video 20). The vessel is seen by grayscale, but even better with color Doppler. Visualization of the PA and DA is often difficult due to their hypoplasia and insufficient resolution. When a VSD and a single overriding vessel are seen at 11–13 weeks, the diagnostic possibilities include TOF, pulmonary atresia, DORV and arterial trunk. These are all severe conotruncal CHD and exclusion of 22q.11 microdeletion is recommended. The pooled early detection rate of TOF is around 40%.⁸⁷

Coarctation of the aorta (CoA) is a challenging diagnosis at any stage of gestation, due to high rate of false-negative and -positive diagnoses. Suspicion of CoA can arise by observation of disproportion of the ventricles at 11–13 weeks. In 40% of the cases, there is an associated VSD and disproportion may not be evident. Distinction between CoA and interrupted aortic arch at 11–13 weeks may be difficult. The pooled detection rate is around 37%.⁸⁷

Hypoplastic right heart syndrome (HRHS)

This severe anomaly, much less frequent than HLHS, should be suspected when a single ventricular filling is seen on the right side of the heart. The anomaly is usually caused by pulmonary atresia. Reversed flow in the pulmonary artery trunk may also be present. Despite reported high detection rates (90–100%), this remains an infrequent first-trimester diagnosis.^86,87

Other serious CHDs that can be detected in the first-trimester with an abnormal 4CV are Ebstein anomaly (25%) and tricuspid atresia (88%).⁸⁶ In contrast, diagnosis of DORV, common arterial trunk and right aortic arch may be more challenging as it relies on appreciation of abnormal outflow tracts.⁸⁶ The use of 4D-spatiotemporal image correlation (STIC) has been proposed as helpful in EFEC. However, with the very active first-trimester fetus, STIC is only feasible with shorter acquisition time.⁹⁵

To summarize, diagnosis of major CHD at 11–13 weeks is increasingly feasible. Use of a standardized protocol, color flow mapping and training of operators improves early detection of CHD. We expect that, in the future, CHD screening at 11–13 weeks will be based on direct examination of the cardiac morphology, rather than on examination of markers. In all cases, repetition of the scan at 16 weeks and, when there is uncertainty, also later in gestation, is mandatory to reduce false-positive and -negative diagnoses.

Early markers of CHD

The most well-known early marker for CHD is a thickened NT (Figure 16) in the presence of a normal karyotype.²² Other markers such as abnormal ductus venosus (DV) flow and tricuspid regurgitation (TR) are also associated with CHDs.^96,97 In some settings, cases with abnormal DV or TR are referred to specialized centers for early detection of CHD. In a meta-analysis, NT ≥95th and ≥99th centile had a pooled sensitivity and specificity for major CHD of 45.6% and 94.7% and of 21% and 99.2%, respectively, with a positive likelihood ratio of 30.²² The risk for CHD increases with increasing NT measurement from 1.6% when the NT is between 2.5 and 3.4 mm, 3.4% when between 3.5 and 4.4 mm, 7.5% when between 4.5 and 5.5 mm, 15% when between 5.5 and 6.4 mm, 19% when between 6.5 and 8.4 mm, and becomes 64% when NT is ≥8.5 mm. All kinds of CHD can be associated with an increased NT, without preference for one defect over another.⁹⁸

Abnormal ductus venosus (DV) flow 

Abnormal ductus venosus (DV) flow (Video 21) and tricuspid regurgitation (TR) (Video 22) are also commonly seen in fetuses with CHD and increase the sensitivity of NT alone in screening for CHD. The DV can be evaluated by its A-wave (positive, absent, reversed) or PI. Our group found an abnormal DV-PI (≥95th percentile) in two-thirds of fetuses with an increased NT, normal karyotype and CHD with a sensitivity and specificity for detection of CHD of 70% and 62%, respectively.⁹⁹ There is now consensus that DV-PI measurement is superior to A-wave assessment only, as part of screening algorithms.¹⁰⁰ Abnormal DV flow (absent or reversed A-wave during atrial contraction) is a sign of cardiac dysfunction in the second and third trimester.¹⁰¹ A recent study including over 90 000 apparently normal fetuses and 211 with CHD reports that an abnormal DV flow was present in 27.5% of fetuses with CHD.⁸⁸

Tricuspid regurgitation (Video 22) is also frequently observed in euploid fetuses with CHD.^87,97 The mechanism for this association is not clear but it may be related to the reduced diastolic function and high afterload at this gestational age. A recent study found TR in 29% of fetuses with major CHD.⁸⁸

Another marker, more recently proposed as sensitive early screening test for CHD, is measurement of the cardiac axis. Normal mean cardiac axis measures 44.5 ± 7.4°. In the CHD group, 74.1%, had an abnormal cardiac axis (110 with left deviation and 19 with right deviation). This marker is suggested to be more sensitive than other first-trimester markers, used alone or in combination, for the detection of major CHD.¹⁰²

In summary, any one of NT ≥99th percentile, abnormal DV or TR is present in 47% of fetuses with a heart defect and in 3.8% of those without a heart defect. Deviated cardiac axis is seen in ¾ of fetuses with CHD. All these findings should prompt referral for EFEC in specialized centers, even when the NT is normal. The risk of CHD is reduced if these findings are absent.

Other sometimes detectable anomalies

Facial anomalies

Facial anomalies, such as micrognathia (Video 23) and cleft lip/palate, can be diagnosed in the first trimester.^{11 12} Especially severe cases are readily recognized and the use of angles and other markers can assist in identifying more subtle cases.^103,104,105 As micrognathia can resolve later in pregnancy, caution should be used in managing this condition, especially if the genetic work-up is normal. Visualization, on a sagittal view of the face, of an interrupted maxillary bone, the ‘maxillary gap’,¹⁰⁶ or absence of the ‘superimposed line’ representing the vomeral bone, have been suggested as markers for a cleft of the palate.¹⁰⁷ However, there is still controversy as to which plane, axial or sagittal, is more informative for the first-trimester diagnosis of an isolated cleft of the palate.¹⁰⁸ In view of the prevalence and nature of the anomaly, these screening strategies need to be assessed in large prospective studies.

Anomalies of the chest, diaphragm, abdominal wall and bowel

Unilateral or total lung agenesis and laryngeal or tracheal occlusion are rare anomalies, potentially amenable to early prenatal diagnosis in view of their impact on the anatomy of the thorax,¹¹ whereas lesions characterized by an echogenic appearance of the lung, currently grouped under the name congenital pulmonary airway malformation (CPAM), have not been reported earlier than 16 weeks.¹⁰⁹ Chronic high airway obstruction syndrome (CHAOS), due to laryngeal or tracheal occlusion, is a usually lethal condition (especially if hydrops is present) leading to increased volume and echogenicity of the lungs, with a visible fluid-filled trachea and flattening or inversion of the diaphragm. The heart appears small and squeezed by the enlarged hyperechoic lungs (Figure 22) and the impaired venous return leads sequentially to ascites, hydrops and heart failure.¹¹⁰ In less severe forms of occlusion, pulmonary enlargement may resolve later in pregnancy. The finding of apparently normal lungs at 11–13 weeks does not exclude CHAOS, because the condition can have delayed manifestations. The association between an enlarged NT and diaphragmatic hernia (CDH) was described in 1997.¹¹¹ Severe CDH can be associated with nuchal edema, probably owing to impaired venous return due to increased intrathoracic pressure. In left-sided CDH, the stomach can occasionally be seen next to the heart although, in milder cases, it may still be situated intra-abdominally and herniate into the thorax only when, later in pregnancy, the increased intra-abdominal pressure pushes it upwards. In right-sided CDH, the stomach in the first trimester is invariably situated intra-abdominally. In Syngelaki et al. ’s study,⁷ 3/8 cases of CDH in the cohort (37.5%) had an enlarged NT and 4/8 were diagnosed at the 11–13-week scan.

Anomalies of the abdominal wall have been discussed earlier in this Chapter.

Bowel anomalies can usually only be diagnosed later in pregnancy, however the presence of an intra-abdominal cyst, even if it resolves, may be an early sign of anal atresia.¹¹²

Urinary tract and kidney anomalies

Advanced first-trimester examination requires visualization of the kidneys, in addition to assessing normal bladder filling.¹³ First-trimester kidneys can occasionally appear mildly echogenic (Figure 15), which is a normal variant.

A normal amount of amniotic fluid in early pregnancy does not exclude a severe genitourinary anomaly with no urine production. It is only after 16 weeks that the major contribution to the volume of amniotic fluid is fetal urination and therefore oligohydramnios can only become apparent from the 17th week.¹¹³ Fetal bladder filling should be visible from 10–11 weeks onwards. Megacystis was discussed earlier in this Chapter.

First-trimester examination detects the majority of lower urinary tract obstruction and a few cases of bilateral or unilateral renal agenesis and polycystic kidneys. Overall, about 70% of these anomalies are diagnosed in the first trimester, but none of multicystic kidneys, hydronephrosis, duplex or horseshoe kidneys, megaureter or renal cysts is amenable to first-trimester diagnosis.^11,12

When bilateral large hyperechoic kidneys are seen, variably associated with an occipital encephalocele and postaxial polydactyly, Meckel-Gruber syndrome should be suspected.¹¹⁴ The diagnosis of Meckel-Gruber syndrome is supposed to be easier at this stage, since later in pregnancy the presence of oligohydramnios may hinder visualization of polydactyly and encephalocele.

Skeletal anomalies

Severe skeletal anomalies can be suspected in the first trimester. These conditions are often associated with thickened NT.^11,12,115 Non-invasive diagnosis of skeletal anomalies is also becoming increasingly available and this can be applied as soon as the suspicion arises.¹¹⁶ Non-invasive prenatal sequencing for multiple Mendelian monogenic disorders (NIPS-M) is currently also experimented among fetuses with skeletal abnormalities or increased nuchal translucency (NT), although the last group may have already undergone invasive prenatal diagnosis in most cases.¹¹⁷

Genetic syndromes

Some typical phenotypic expressions of known genetic syndromes may be visible by the time of the early US scan. When parents are known carriers of genetic syndromes with a dominant or recessive inheritance pattern, expert US investigation from the first trimester, alone or in combination with targeted genetic testing, may help to confirm or exclude the (re-) occurrence of the syndrome in offspring and reduce the period of uncertainty.

Many fetal syndromes have been diagnosed in fetuses with a, usually severely, increased NT and normal chromosomes.^23,29 Thus far, a clear association with thickened NT has been confirmed for Noonan syndrome (NS) and other RASopathies, and diagnostic protocols have been suggested.^24,28 Some of the phenotypic features typical of NS may already be visible from early in pregnancy (Figure 23). Typical patterns of NT and serum markers have also been proposed for the early diagnosis of 22q11 deletion.¹¹⁸ A breakthrough in the early diagnosis of fetal syndromes has been the introduction of trio whole exome sequencing (WES) in the prenatal work-up of fetuses with structural anomalies, although experience with anomalies diagnosed in the first trimester is still limited.^119,120

SAFETY AND ETHICAL CONSIDERATIONS

Thanks to continuous improvement in US technology (high-frequency probes with excellent resolution) and the widespread use of ultrasound at 11–14 weeks, early diagnosis of structural anomalies is increasingly possible. Transvaginal US often provides even better imaging. Importantly there is no scientific evidence that US in the first trimester may be harmful, provided that the thermal indices are kept within acceptable ranges and color and spectral Doppler modalities are used under the principle of ‘as low as reasonably achievable’ (ALARA).¹³ Exposure of young fetuses to prolonged Doppler examination should always be avoided. The advantages of an early diagnosis are evident, as it allows time for repeat US scans, additional genetic investigations and for parents to consider their options, including termination of pregnancy. It is important to know that certain findings, such as a thickened NT, bowel herniation or megacystis may be transient and not associated with an unfavorable outcome. Caution in making certain diagnoses or excluding anomalies at such an early stage is recommended as the situation may change at repeat examinations.

Experience, training and adherence to protocols, are key to good performance of first-trimester US.^12,13,92

Women greatly value the opportunity of early diagnosis of structural anomalies or early reassurance. However, they should be informed of the shortcomings of ultrasound diagnosis at this early stage of pregnancy.¹²¹

FUTURE OF THE EARLY ANATOMY SCAN

Current worldwide practice regarding the performance of first-trimester anatomy scans is still very variable and more uniformity is warranted.¹²² The decrease in cost of cfDNA will inevitably lead to the widespread adoption of this screening method as an integral part of prenatal screening, from as early as 10 weeks’ gestation. It is important for practitioners to understand that this test cannot replace and should be combined with a first-trimester scan for the diagnosis of fetal structural anomalies and evaluation of the NT, undoubtedly the strongest marker of abnormal fetal development.^23,123,124

Further developments in elaboration of US data and other technologies, such as virtual reality and artificial intelligence will no doubt soon be available, from as early as the first trimester.^125,126 These and similar developments will facilitate detection of abnormal embryological and fetal development, from an increasingly earlier stage (9–10 weeks’ gestation).¹²⁷

We expect that, in the future, tailored genetic and (preconceptional) risk-profile assessment, combined with early US investigations, cfDNA and, where indicated, invasive testing to perform advanced genetic diagnostic methods (WES), will provide at-risk couples with timely information regarding the health of their offspring, and also regarding the chance of future pregnancy complications.

CONCLUSION

The performance of first-trimester diagnosis for anomalies is good, provided experienced sonographers follow a protocol and the examination takes place beyond 12 weeks’ gestation. Training programs and certification for first-trimester US, as for second-trimester US, should become available. The number of false positives is not high at this first-trimester scan and, with increasing experience, fewer referrals may be necessary.^14,128

Many severe and often lethal anomalies are amenable (always detectable) to early diagnosis and increasingly more of the sometimes detectable are diagnosed early in pregnancy.^14,92 This enables couples to make reproductive choices at an earlier stage, when termination of pregnancy, in addition to being less traumatic, is safer¹²⁹. Even in the era of cfDNA, an early fetal anatomical evaluation (including NT assessment) remains an essential component of screening for congenital defects and early risk assessment for pregnancy complications.

PRACTICE RECOMMENDATIONS

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