Key Points
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Early diagnosis of structural anomalies is increasingly possible. About half of the congenital anomalies can be diagnosed in the late first trimester.
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Severe and often lethal anomalies can be diagnosed, allowing parents the options of continuing with the pregnancy or, if acceptable, termination of pregnancy.
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Women appreciate the opportunity of early reassurance or early diagnosis, making this scan an essential first step in screening for congenital anomalies.
Introduction
First trimester ultrasonography (US) was first introduced for accurate dating of pregnancy based on the crown–rump length (CRL) measurement and diagnosis of multiples. However, the rapid improvement in US imaging in the late 1980s proved that structural anomalies could already be detected in the first trimester. Key to this development was the introduction of transvaginal US, which enabled a more detailed visualisation of first trimester fetuses.
Since then numerous reports on early diagnosis of fetal anomalies have followed. The focus was initially on high-risk pregnancies but gradually extended towards more unselected populations.
After the introduction of the most powerful marker for aneuploidies – the nuchal translucency (NT) measurement – US investigation between 11 and 14 weeks has become the cornerstone of standard pregnancy care in many countries worldwide, either as part of screening programs for aneuploidies or as first global risk profile assessment in pregnancy.
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, and in 2013, the International Society of Ultrasound in Obstetrics and Gynecology (ISUOG) addressed in a guideline the various aspects of US investigation in the first trimester of pregnancy, aiming at promoting standardisation and uniformity.
Overall, in an unselected population and in a routine setting, about 40% to 50% of the structural anomalies can potentially be detected in the first trimester, although considerable variations exist among studies, reflecting operator and population characteristis. Severe and often lethal anomalies are detected in 100% of cases.
A recent systematic review concludes that 30% of structural anomalies are detectable at first trimester examination, and the detection can double to 60% when the examination follows a structured protocol.
It is clear that the yield of first trimester US goes far beyond screening for fetal aneuploidy and should therefore be considered an essential part of routine care for all women, next to noninvasive screening for aneuploidies. There is little doubt on the role of first trimester US as first step in ruling out severe congenital anomalies. What is still missing is a consensus on when this investigation should be performed (12–14 weeks), on the preferred approach (transabdominal or transvaginal) and how extended it should be. It is also important to explain to parents what can be detected and the limitations of an early US examination.
Anatomical Survey at 11 to 13+6 weeks ( Fig. 19.1 and Table 19.1 )
The mobility of the first trimester fetus can be challenging for the examiner, but it can also enable a quick visualisation of different fetal planes within a short time. The use of cine loop is crucial for this purpose and can expedite first trimester US examination. Investigation of the fetal head and of the upper thorax, in the same plane used for the NT measurement, also provides information on the nasal bone (NB) and on brain structures, including the diencephalon, the brainstem and the fourth ventricle with its choroid plexus ( Fig. 19.2 ). The fourth ventricle appears as a rectangular structure called intracranial translucency (IT) delimited by two echogenic lines. Another longitudinal midsagittal view, including the whole fetal trunk, allows visualisation of the diaphragm, of the entire abdominal wall and intraabdominal contents, including bladder filling and size. The fetal spine, although not yet completely ossified, can also be observed along its whole extension from the cervical origin to the sacrum. By tilting the probe on both sides of the fetal body, the extremities are visualised together with the long bones. A first trimester fetus has commonly open hands, easily enabling counting of fingers. The legs are often flexed and the feet close to each other so that in a single sweep, their positions can be assessed. Cross-sectional planes from cranial to caudal show in the head the image of the falx (midline) and of the choroid plexuses, filling at this stage almost entirely the relatively large lateral ventricles. Of note is that the size of the lateral ventricles (usually 6–8 mm) does not change after 12 to 13 weeks. The typical aspect of the falx and of the two-echogenic structures in the lateral ventricles has been called the ‘butterfly sign’.
| Organ or anatomical area | Present and/or normal |
|---|---|
| Head | Present Axial Cranial bones Midline falx Choroid plexus–filled ventricles Midsagittal Brainstem thickness a Fourth ventricle (IT) a |
| Neck | Normal appearance NT thickness if accepted after informed consent and trained or certified operator available) a |
| Face | Eyes with lens a Nasal bone Normal profile and mandible Intact lips |
| Spine | Vertebrae (longitudinal and axial) a Intact overlying skin |
| Chest | Symmetrical lung fields No effusions or masses |
| Abdomen | Stomach present in left upper quadrant Bladder Kidneys a |
| Abdominal wall | Normal cord insertion |
| Extremities | Four limbs, each with three segments Hands and feet with normal orientation |
| Placenta | Insertion (with respect to CS scar) |
| Cord | Number of vessels Insertion on the placenta |
A cross-sectional view of the thorax at the level of the four-chamber view allows visualisation of the heart axis and of the size of atria and ventricles ( Fig. 19.3A ), whereby use of colour, or even better directional power Doppler, is a crucial complement to two-dimensional imaging for rapid visualisation of cardiac structures. This includes filling of the chambers ( Fig. 19.3B ), exclusion of atrioventricular valve regurgitation (more commonly seen across the tricuspid valve), visualisation 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 (colour) flow in the same direction ( Fig. 19.3C and 
). More caudally, the fetal stomach is seen under the heart just above the level of the umbilical cord insertion. Finally, lower in the pelvis, the bladder is seen, flanked by the two umbilical arteries. The kidneys can occasionally be observed as two more echogenic oval structures on both sides of the spine. This quick and gross anatomical survey enables exclusions of major and mostly lethal structural anomalies such as acrania, exencephaly, holoprosencephaly, gross spinal anomalies, abdominal wall defects, megacystis and gross skeletal or limb deformities. Appreciation of the heart axis and of the four-chamber view and outflow tracts by colour Doppler excludes gross cardiac anomalies. Although in favourable circumstances, a transabdominal (TAI) scan performed with high-resolution US systems gives excellent images, in obese women or in case of a retroverted uterus, the transvaginal approach can be indicated and improve structure visualisation. In obese women, a transvaginal US can provide even better images than a transabdominal midtrimester scan. Recently, high-frequency linear array probes have been introduced for use in early fetal anatomical assessment. In lean women, this probe can provide excellent images, especially of the fetal heart.
The largest study to date, on 44,850 euploid fetuses examined at the time of the nuchal scan, showed that structural anomalies were observed in 1.1% of cases. 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 about 40% can potentially be detected in the first trimester. The remaining 30% cannot be detected as they become evident or develop only at later stages in pregnancy. Another study confirmed that 45% of the structural anomalies and 100% of the severe ones are amenable to early diagnoses. The NT was enlarged in 50% of cases. A recent meta-analysis of 19 studies (115,731 fetuses) on first trimester US investigation shows an overall DR for structural anomalies of 46%. In low-risk pregnancies, the DR was 32% and increased to 60% in high-risk groups and when a protocol was used.
Increased Nuchal Translucency ( Fig. 19.4 ) and Structural Anomalies
In euploid fetuses, excessive nuchal fluid accumulation (large NT, cystic hygroma) can be regarded as a strong marker for an ever-growing list of structural and genetic disorders and poor pregnancy outcomes. The chance of a poor outcome depends on the initial degree of enlargement. The strongest association exists for cardiac defects, with NT being enlarged in about 40% of the major cardiac defects.
Of all genetic syndromes, the most commonly associated with an increased NT is Noonan syndrome, a relatively common syndrome. (See more on this in the paragraph Genetic syndromes.)
An enlarged NT is a common denominator to many developmental disorders, appearing to be a nonspecific US marker shared by different pathways.
In the attempt to refine risk assessment based on NT screening, other markers have been investigated and added to the algorithm. The first one was an absent or hypoplastic NB followed by an abnormal ductus venosus (DV) flow (absent or reversed a wave). More recently, the appreciation of tricuspid regurgitation (TR) has been described.
An absent NB is common in trisomies, but some genetic syndromes also share this feature. An abnormal DV is especially associated with cardiac defects, although this association is still poorly understood.
Becker and Wegner found in 3094 fetuses investigated at the 11 + 0 to 13 + 6-week scan that an NT of more than 2.5 mm was observed in 58 of 86 (67.44%) fetuses with a structural anomaly.
Syngelaki found a highly significant association between NT above the 95th percentile and acrania ( P < .0001), diaphragmatic hernia ( P = .007), exomphalos ( P < .001), megacystis ( P < .0001), lethal skeletal dysplasia ( P = .0002), bilateral talipes ( P = .012) and body-stalk anomaly ( P < .0001) and in cases with multiple defects ( P < .0001). A large study from the United States found that an increased NT gives a threefold increased risk for hydrocephaly, lung and diaphragm anomalies, bowel obstruction and skeletal disorders.
In another study including 6858 fetuses, Becker and colleagues found that of all the 220 anomalies (including aneuploidies) present in the cohort (prevalence, 2.8%), 111 (1.7%) were observed in fetuses with a normal NT. Therefore their conclusion was that although the association between an enlarged NT and structural fetal anomalies is a given fact, if the aim of the first trimester scan is to diagnose as many anomalies as possible, fetuses with a ‘normal’ NT should be thoroughly investigated because about 50% of the anomalies will be found in this significant group (8.3%).
The workup after an enlarged NT includes array comparative genomic hybridisation (CGH) investigation and repeat scans. Arrays reveal in these fetuses an additional 5% of pathological copy number variants. If the nuchal oedema has completely disappeared in the second trimester and the 20-week scan findings are normal, the chance of an abnormal outcome is extremely low and not dissimilar from the normal population.
Anomalies of the Central Neural System
The first publication on first trimester US examination of fetal brain appeared in 1989. The importance of early diagnosis of central neural system (CNS) anomalies lies in the fact that anomalies are common, often lethal or associated with severe mental disability or motor dysfunction. Early detection offers parents the option to terminate the pregnancy at a stage when termination may be less traumatic.
Brain development and maturation continue throughout pregnancy. 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. At the time of the first trimester scan (11–13 weeks), rudimentary brain structures are present and can be assessed by US.
First Trimester Fetal Brain and Spine Investigation
Cranial bone ossification should be completed by 11 weeks. 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 relative large and filled by the echogenic choroid plexuses in their posterior two thirds (see Fig. 19.1D ). The hemispheres appear symmetrical and separated by a clearly visible interhemispheric fissure and falx (see Fig. 19.1D ). 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 age, 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 to 13 weeks, can also be used to assess early fetal brain anatomy. The configuration of the midbrain, brainstem and fourth ventricle changes in case of open spina bifida (OSB). The IT, corresponding to the fourth ventricle, has been proposed as marker for normal brain development and intact spine. In case of OSB, the biparietal diameter is already affected from the first trimester and is relatively smaller than the head circumference. Also, cystic abnormalities of the posterior fossa (Dandy-Walker complex) can be occasionally detected.
There has been some debate as to which view, midsagittal or axial, is the most informative for early investigation of fetal brain abnormalities. The midsagittal (or preferably parasagittal or sagittal-oblique views) is useful for screening purposes, but in case of suspected intracranial findings, the use of parallel axial planes and three-dimensional (3D) neurosonography at referral centres may refine the final diagnosis.
Neurosonography can already be performed at 12 to 13 weeks, transabdominally with use of high-frequency transducers (in lean women), or transvaginally. The use of five axial views can exclude the most common anomalies amenable to early diagnosis ( Fig. 19.5 ). 3D US (box placed around the skull and sweep starting from the ‘butterfly view’) can help systematic assessment in parallel axial views (plane A), and sagittal reconstructed planes (plane C) are used for topographic orientation in the axial planes.
Most Common Brain and Neural Tube Anomalies
Acrania
Acrania ( Fig. 19.6 ) (prevalence, ∼3.7 in 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 developed, and the brain tissue is exposed to mechanical and chemical damage. Eventually, brain tissue ‘dissolves’ in amniotic fluid, producing a ‘milky’ appearance on scan ( Fig. 19.6B ). Later in pregnancy, acrania evolves into exencephaly and in the second trimester into anencephaly, in which hardly no more brain tissue is visible. Acrania can be in 12% of cases part of chromosomal or genetic condition (Meckel-Gruber syndrome) or amniotic band syndrome and is associated with aneuploidy in up to 5% of cases. Sonographic features of acrania are present from 9 weeks. The usual presentation of acrania at 11 to 13 weeks is an irregular contour of the head in sagittal plane and absent or severe deficiency of cranial bones with distortion of the brain structures ( Fig. 19.6A and 
). To not miss this condition, an early scan should be performed after 11 weeks by trained sonographers.
Other rare conditions that can be diagnosed early in gestation are iniencephaly and craniorachischisis, the latter morphologically similar to acrania.
Encephalocele or Cephalocele
Encephalocele or cephalocele ( Fig. 19.7 ) (1 in 5000 live births) is a neural tube defect characterised by protrusion of intracranial structures through a defect in the skull. The first trimester detection rate is 80%. 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.
By visualisation of the fetal skull defect in the axial plain, a differentiation can be made between cranial meningoceles (only protrusion of meninges; 37% of cases) and encephaloceles (protrusion of brain tissue into the cephalocele; 63% of cases) ( 
). 3D US can be helpful to clearly image the defect. Additional fetal malformations are seen in 65% of cases. The prognosis is variable and depends of associated conditions, localisation, size and anatomical structures involved. The anomaly can evolve to exencephaly. Some defects can lead to intrauterine death.
Spina Bifida ( Table 19.2 )
Open spina bifida (in Europe, ∼1 in 2000 pregnancies) is caused by failure of closure of the neural tube 24 to 27 days after conception. Typical associated brain changes are caused by leakage of cerebrospinal fluid (CSF). The developing spinal cord and exposed nerves are damaged by direct trauma and by the neurotoxicity of the amniotic fluid. In the first trimester, these secondary changes have just started and are therefore subtle. Visualisation of the spinal defect and of the myelomeningocele ( Fig. 19.8 ) is not always easy, and the defect may remain undiagnosed.
| Head or cranial structure | Sensitivity (%) |
|---|---|
| IT | 53 |
| CM (nonvisualised;<5th centile) | 50–73 |
| brainstem (>95th centile) | 97 |
| BSOB (<5th centile) | 87 |
| BS/BSOB (>95th centile) | 100 |
| Scalloping frontal bones Smaller BPD | 50–55 |
| Facial angle (<5 th centile) | 90 |
| BPD/transabdominal diameter <1 | 77 |
| IT/CM (R) | 66 |
| Posterior displacement mesencephalon | 100 |
The IT is the most known simple marker for OSB that can be measured in the same plane as the NT. It can be identified in 96% of normal fetuses by trained sonographers, and a recent meta-analysis of nine studies indicates that nonvisualisation of the IT has a sensitivity of 53.5% and specificity of 99.7% for OSB.
To increase sensitivity, other approaches have been proposed, including measurements of the cisterna magna (CM), the brainstem and the brainstem occipital bone distance (BSOB) ( Fig. 19.9 ), the posterior fossa fluid area and the four-line view ( Fig. 19.10 ). Nonvisualisation of the CM or a CM width below the fifth percentile are both suggested to have a sensitivity for OSB of 50% to 73%. 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 brainstem diameter above the 95th percentile, a BSOB distance below the 5th percentile and a brainstem to BSOB ratio above the 95th percentile have a sensitivity for OSB of 96.7%, 86.7% and 100%, respectively. In the only prospective study, the Berlin IT Multicenter Berlin study on 15,526 consecutive patients, experts were able to diagnose all the 11 OSB cases based on suspicious findings at the 11- to 13-weeks scan but only by combining all posterior fossa parameters. No single parameter showed a high sensitivity, and this varied between 18% for IT (present or absent) to 73% when CM measurements cutoffs were used.
Two other small prospective studies confirm these results. The ratio between the IT and the CM (R), a new marker for OSB, showed a sensitivity of 66%. Scalloping of the frontal bones and a smaller biparietal diameter (BPD) (50%–55% of cases), both signs of CSF leakage in OSB leading to ‘dried-up brain’, are also common in first trimester OSB. The abnormal skull shape is also reflected in a sharper facial angle that, when corrected for CRL, is about 10 degrees lower than in control participants, and it is below the 5th percentile in 90% of cases. A ratio between BPD and transverse abdominal diameter less than 1 can be easily used and detect 69% of OSB cases.
More recently there is increasing consensus about the fact that markers involving changes in the brain stem and posterior fossa configuration seem to be the most predictive of OSB.
Our opinion is that large prospective studies are still mandatory to define the role of early US in the diagnosis of OSB. A new sign proposed by the University College Hospital group (Fred Ushakov) is the ‘crash sign’, corresponding to the posterior-caudal displacement of the mesencephalon that on an axial view ‘crashes’ against the occipital bone in case of OSB ( Fig. 19.11 ), as a highly sensitive screening parameter. It is likely that only by combining sagittal and axial views of the brain high DRs of OSB can be achieved. Recently, a new promising marker for the early detection of spina bifida, the maxillo-occipital line, has been proposed.
Midline Defects
Holoprosencephaly
Holoprosencephaly (1:1300 pregnancies) is characterised by maldevelopment of the prosencephalon into two hemispheres, resulting in a single ventricle ( Fig. 19.12 and 
). The anomaly is reported in and is often associated with severe skull and facial defects and with more than two thirds of cases associated with chromosomal abnormalities, mainly trisomies 13 and 18.
Absence of the butterfly sign and the presence of a single brain cavity anteriorly on the axial plane are specific for alobar holoprosencephaly with a high sensitivity.
Lobar or semilobar holoprosencephaly, however, is more subtle to diagnose and usually is not be detected in the first trimester.
Agenesis of the Corpus Callosum
Agenesis of the corpus callosum (ACC) represents a spectrum of different CNS anomalies occurring in 0.3% to 0.7% of the population, often as part of a syndrome. The corpus callosum develops relatively late during fetal life, and the earliest sonographic visualisation is possible from 16 weeks’ gestation onwards and about 1 week earlier in female fetuses. Visualisation of the pericallosal artery is possible in more than 95% of normal fetuses at the 11 to 13 weeks’ scan ; however, we strongly discourage use of Doppler on a developing fetal brain before 14 weeks’ gestation.
Dandy-Walker Malformation
In Dandy-Walker malformation (DWM) (1:30,000 live births), the anomaly may be suggested by a markedly enlarged intracranial translucency and BSOB, with absence of the septum separating the fourth ventricle and the CM. Direct assessment of the cerebellar vermis is not possible because it is only completed at around 18 weeks’ gestation. DWM can be associated with chromosomal anomalies or other fetal abnormalities. Also, in case of suspected vermian anomalies, the final diagnosis should not take place in the first trimester. The presence of suspicious findings may prompt repetition of the US scan to after 18 weeks’ gestation.
Ventriculomegaly
Lateral ventricles measuring more than 10 mm are mainly a second and third trimester diagnosis. Although normal ranges for the fetal ventricular system in the first trimester are available, mild ventriculomegaly may still be a normal variant. However, lateral ventricle can appear already enlarged in the first trimester in case of chromosomal anomalies, especially trisomies 18 and 13, in some genetic syndromes and in aqueduct stenosis ( Fig. 19.13 ). An abducted thumb may suggest X-linked hydrocephalus.
In conclusion, 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 specialist centres with detection rates of 50% to 100% and very low-false positive rates (FPRs). However, there is controversy as to the best test and how it will perform in low-risk populations. All other brain anomalies cannot be diagnosed in early gestation (mild ventriculomegaly, ACC, migration disorders, tumours, schizencephaly).
Facial Anomalies
Recently, a number of studies have suggested that facial anomalies, such as micrognathia and labiopalatum cleft, can already be diagnosed in the first trimester. Besides direct appreciation on the fetal profile of severe micrognathia and bilateral cleft, the use of angles can assist in the diagnosis in less obvious cases. Visualisation of an interrupted maxillary bone, defined as ‘maxillary gap’, is suggestive of a cleft palate. Although useful in specific cases, it is unlikely that these markers will be used routinely.
Congenital Heart Defects
Congenital heart defects (CHDs) are the most common malformations (8–10/1000 live births). About 30% are severe and responsible for significant mortality and morbidity in the neonatal period and infancy.
Since the widespread use of NT screening and the recognition of other early markers, paralleled by the improvements in resolution of US systems, first trimester diagnosis of CHD has been extensively investigated. 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. The importance of an early diagnosis of major CHD is that it allows additional investigations and, in case of certain diagnosis, for early, less traumatic and safer termination of pregnancy (TOP), well before the legal term of 24 weeks (in many countries). The challenge is when there is uncertainty of the diagnosis or clinical significance requiring assessment at a later gestation, this can increase parental anxiety. In high-risk pregnancies, a normal EFEC can provide early reassurance.
Early Markers for Congenital Heart Disease
After the initial suggestion of a strong association between an increased NT and CHD, a recent meta-analysis showed an NT at the 95th percentile or above and at the 99th percentile or above, 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. 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 64% when NT is 8.5 mm or greater. All kinds of CHDs can be associated with an increased NT, without preference for one defect above another.
An abnormal DV and TR is seen more commonly in fetuses with CHDs and increases the sensitivity of NT alone as a screening test for CHD.
Abnormal DV flow (absent or reversed A-wave during atrial contraction) is a sign of cardiac dysfunction in the second and third trimesters. A meta-analysis of seven studies, including 600 chromosomally normal fetuses with NT at the 95th percentile or greater, found that an abnormal DV flow at 11 to 14 weeks’ gestation in the presence of a NT of 3.5 mm or greater, was associated with a threefold increased risk for CHDs, but a normal DV flow halved the CHD risk. Another recent meta-analysis reports that an abnormal DV A-wave, in association with an increased NT, can detect 83% of CHDs with an FPR of 20% as opposed to 19% with a FPR of 4% when the NT is normal.
The DV can be evaluated as A-wave (positive, absent or reversed) or pulsatility index (PI). Our group (CB) found an abnormal ductus venosus PI (DVPI) (≥P95) in two thirds of the fetuses with an increased NT, normal karyotype and CHD with a sensitivity and specificity for CHDs of 70% and 62%, respectively. There is now consensus that DVPI measurement is superior to A-wave assessment only as part of screening algorithms.
The mechanism of the abnormal DV flow in the presence of CHD is unclear, but the predominance of right-sided obstructive lesions, atrioventricular septal defects (AVSD) with atrioventricular (AV) valve regurgitation and hypoplastic left heart syndrome (HLHS) suggest that altered both right atrial pressure and diastolic dysfunction may be involved.
Tricuspid regurgitation is frequently observed in trisomic fetuses at 11 to 14 weeks and in euploid fetuses with CHDs. The mechanism is not clear but may be related to the reduced diastolic function and the high afterload at this gestational age.
A recent study of 40,990 fetuses found a NT at the 95th percentile or above, TR or reversed A-wave in the DV in 35.3%, 32.9% and 28.2% of the 85 fetuses with major CHD, respectively, and in 4.8%, 1.3% and 2.1% of those without CHD. Any one of the three markers was found in 57.6% of the fetuses with CHD (95% confidence interval (CI), 47%–67.6%) and in 8% of those with normal hearts (95% CI, 7.7%–8.2%).
Recently, early measurement of the cardiac axis has been suggested as a very sensitive screening test for CHD. The first trimester normal mean cardiac axis is 44.5 ± 7.4 degrees. In the CHD group, 74.1%, had an abnormal cardiac axis (110 with left deviation and 19 with right deviation). Cardiac axis measurement is suggested to be significantly better than enlarged NT, TR or reversed a-wave in DV, used alone or in combination, for the in detection of major CHDs.
In conclusion, an abnormal DVPIV in the first trimester can detect about 70% of the major CHDs and is an indication for referral for specialised EFEC even when the NT is normal. EFEC is also recommended for TR. The risk for CHD increases with increasing NT measurement and is further increased in the presence of an abnormal DV flow or TR but is reduced if these findings are absent. However, the use of Doppler in early pregnancy should be limited in time and performed only in high-risk cases.
Accuracy of Congenital Heart Disease Detection by Early Ultrasound Investigation
A recent review by Khalil and Nicolaides, based on 24 screening studies for CHD, shows a first trimester DR between 2.3% and 56%. DRs at any stage depend mainly on the experience of the sonographers and, in nonexpert hands the DR does not differ greatly if screening is performed at 12 or 18 weeks (11% vs 15%).
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 HLHS. In another systematic review, Rossi and Prefumo report a 48% DR for CHD with 43% of the CHDs detected by nontargeted first trimester US examination, as opposed to 53% when specialised EFEC is carried out. When EFEC is performed by experts and in high-risk fetuses, sensitivity and specificity can reach 85% and 99%, respectively, and even higher after 13 to 14 weeks.
How to Perform a Complete Early Fetal Echocardiography
Under normal scanning circumstances, all cardiac structures should be visible by 13 weeks. Initially, the transvaginal approach was used, but with the advent of the NT screening, the transabdominal approach became the preferred method. Transvaginal echocardiography can still be superior in obese patients, but reduced flexibility in obtaining different scanning planes limits its accuracy.
The main reason for preferring the transabdominal approach is that the first trimester fetus often lies in a prone position, probably because of gravity and shape of the uterine cavity. This position enables standardisation of cardiac examination.
In axial views of the chest, the cardiac apex points at 1 to 2 or 10 to 11 o’clock positions for cephalic or breech presentations, respectively. Heart and stomach positions are evaluated to determine the situs. The four-chamber view is used to assess the heart axis, symmetry of the ventricles, AV valves and crux (see Fig. 19.3A ). Further tilting of the transducer cranially demonstrates two parallel lines, running from the LV to the right, representing the left outflow tract and, more superiorly, the three-vessel view. The pulmonary artery (PA) runs straight into the ductus arteriosus (DA) and meets the left-sided aorta, forming a V sign. Modern US systems produce reasonable quality image of the four-chamber view in the majority of cases. The resolution can be improved by the use of high-frequency probes and of proper image magnification (chest filling at least half of the screen).
The use of colour Doppler is essential in early gestation to overcome suboptimal visualisation of the great arteries by grey-scale, with preference for directional power Doppler. However, colour Doppler should be used if high velocity flow is suspected (like in TR or aortic stenosis). Mapping of the great arteries reduces false-negative diagnosis in some CHDs. The first step is to achieve a good-quality four-chamber view on grey-scale mode and to activate power Doppler. Ventricular filling is seen as two separate red (for apical views) stripes equal in size (see Fig. 19.3B and 
). The LV stripe forms the apex and is slightly longer than the RV stripe. With good presets, TR is commonly visible as a blue jet originating in the RV near the interventricular septum. A bit of TR is a very common in the first trimester and is likely a normal variant.
By tilting the transducer cranially from the four-chamber view, the blue stripe of the left ventricular outflow tract (LVOT) is seen. Sometimes the blood velocity in the LVOT is below the scale, and it can be better visualised by reducing the pulse repetition frequency (PRF). The next structure seen by sweeping cranially is the long blue stripe formed by the right ventricular outflow tract (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 farther 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 aorta meet, forming a blue colour V-sign pointing towards the left (see Fig. 19.3C ). When the PA has a straight vertical position, the aorta may be not visible on colour Doppler because of the relatively slow blood flow velocity. By gradually reducing the PRF, the V-sign will appear. Earlier in gestation, at 11 to 12 weeks, the aorta 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, the sweep is continued caudally, and eventually, the blue stripe of the aorta will be seen coming from the right.
To simplify CHD screening at EFEC, we propose an approach aimed at detecting the five commonest severe CHD, accounting for more than 80%: HLHS, AVSD, TGA, TOF and CoA.
The typical sonographic appearance of this severe HLHS (see Fig. 19.3D ) is absence of a normal four-chamber view with significant right ventricle–left ventricle (RV–LV) disproportion and deviation of the heart axis. On colour Doppler, either only the RV filling (see Fig. 19.3E ) is seen or both inflows but with significant RV–LV disproportion. Sometimes the appearance can be complicated by TR or MR regurgitation(s). The PA is enlarged and straight (see Fig. 19.3F ). There is no V-sign, and retrograde flow in the transverse aorta is seen just above the ductal arch (see Fig. 19.3G) . The velocity of the retrograde flow in the aorta is generally low, and if this is not visible, the PRF should be gradually reduced. Some cases of HLHS are associated with progression of aortic stenosis into atresia can become apparent only in the second trimesters. Suggestive signs are RV–LV inflow disproportion and recognition of high velocity flow at the stenotic AV, which can be easily confused with TR. We advise a follow-up scan 2 weeks later to confirm or exclude HLHS.
In HLHS, a transvaginal scan gives additional information about a restricted foramen ovale flow by visualisation of reversed A-wave in the pulmonary veins.
Atrioventricular septal defect is commonly associated with trisomy 21 (1 in 3) and left atrial isomerism (LAi). The condition varies in severity, but a complete AVSD is characterised by a common AV junction with a fused multileaflet AV valve. Large AVSDs are visible on the four-chamber view ( Fig. 19.14 and 
). Careful observation of the movements of the common AV valve, especially during diastole, is a diagnostic hint. Colour Doppler shows a single ventricular inflow with angled ventricular filling strips instead of two normal parallel strips. This arrangement is termed the ‘trousers sign’ ( Fig. 19.14A ). Insufficiency of the common valve is frequent in AVSD, and the jet originates from the middle of the heart ( Fig. 19.14D ).
