Normal human embryogenesis is a stereotyped sequence with little statistical variation, but menstrual data in individual cases may be unreliable in dating this sequence’¹. An embryo of 10 postmenstrual weeks is less than half the length of an adult thumb, but already possesses several thousand named structures, practically any of which may be subject to developmental deviations². Thus, the embryonic period proper is of particular importance because the majority of congenital anomalies make their appearance during that time². These statements from embryological investigations have become highly relevant for those involved in first-trimester ultrasound scanning.

The term sonoembryology³ designates the description of the embryonic anatomy, the normal anatomic relations and the development of abnormalities as visualized by ultrasound. To confirm the presence of normal anatomy or to make the diagnosis of an anomaly, we need knowledge of the normal embryonic development, including the appearance of the normal embryo. This section is based on data from sonoembryological and embryological studies^4–13. For the ultrasound studies, 7.5-MHz transducers were used.

At 4 weeks and 3 days, a tiny gestational sac becomes visible within the decidua.

The yolk sac is first visible at 5 weeks and it is always present by 5 weeks and 4 days. There are lacunary structures at the site of implantation. The embryonic pole appears adjacent to the yolk sac, soon showing cardiac activity. Since the connecting stalk is short, the embryonic pole is found near the wall. At the end of week 5, the heart rate is about 100 bpm.

The embryonic pole, yolk sac and heart activity are now always present. The heart rate increases to 130 bpm. At the end of week 6, the first sign of the rhombencephalic cavity appears as a tiny hypoechogenic area in the cranial pole of the embryo. The amniotic cavity can be seen surrounded by a thin membrane around the embryo.

7 weeks (crown–rump length 9–14 mm)

External form

The embryonic body appears as a triangle in the sagittal section. The sides consist of (1) the back, (2) the roof of the rhombencephalon, and (3) the frontal part of the head, the base of the umbilical cord, and the embryonic tail. The embryonic body is slender in the coronal plane. The limbs are short, paddle-shaped outgrowths. 

The hypoechogenic brain cavities can be identified, including the separated cerebral hemispheres. The lateral ventricles are shaped like small, round vesicles. The cavity of the diencephalon (future third ventricle) runs posteriorly. In the smallest embryos, the medial telencephalon forms a continuous cavity between the lateral ventricles. The future foramina of Monro are wide during week 7. In the sagittal plane, the height of the cavity of the diencephalon is slightly greater than that of the mesencephalon (future Sylvian aqueduct). Thus, the wide border between the cavities of the diencephalon and the mesencephalon is indicated. The curved tube-like mesencephalic cavity lies anteriorly, its rostral part pointing caudally. It straightens considerably during the following weeks. By week 8, it is regularly identified. The relatively broad and shallow rhombencephalic cavity is always visible from 7 weeks onwards. It then has a well-defined rhombic shape in the cranial pole of the embryo.

Heart

The heart can be recognized as a beating, large and bright structure below the embryonic head at 7 weeks. The heart rate increases from 130 bpm to 160 bpm. Details of the heart anatomy are not visible, but the atrial and ventricular compartments can sometimes be distinguished by the reciprocal movements of the walls. 

The short umbilical cord shows a large celomic cavity at its insertion, where the primary intestinal loop can be identified. The first sign of herniation of the gut occurs during week 7 as a thickening of the cord and showing a slight echogenic area at the abdominal insertion. Within a few days, this echogenic structure becomes more distinct. 

The amniotic cavity becomes visible at the beginning of week 7. The mean diameter of the amniotic cavity is almost the same as the corresponding crown–rump length.

Gestational Sac and Yolk Sac

External form

The body gradually grows thicker and becomes cuboidal. At the end of the week, the elbows become obvious, the hands angle from the sagittal plane and the fingers are distinguishable.

The brain cavities are easily seen as large ‘holes’ in the embryonic head. The hemispheres enlarge, developing via thick round slices originating antero-caudally from the third ventricle into a crescent shape. The choroid plexus in the lateral ventricles becomes visible as tiny echogenic areas. The future foramina of Monro become more accentuated during week 8. The third ventricle is still relatively wide, as is the mesencephalic cavity. At this stage, the mesencephalon lies at the top of the head. The increased growth of the rostral brain structures and the deepening of the pontine flexure leads to the deflection of the brain. The rhombencephalic cavity (future fourth ventricle) has a pyramid-like shape with the central deepening of the pontine flexure as the peak of the pyramid. The first signs of the bilateral choroid plexuses are lateral echogenic areas originating near the branches of the medulla oblongata caudal to the lateral recesses. Within a short time, the choroid plexuses traverse the roof of the fourth ventricle, meeting in the mid-line and dividing the roof into two portions, about two-thirds are located rostrally and one-third caudally. In the sagittal section, the choroid plexuses are identified as an echogenic fold of the roof.

The heart rate has increased to 160 bpm. Occasionally it is possible to identify the atrial and ventricular walls moving reciprocally as early as at the end of week 8. The atrial compartment appears wider than the ventricular compartment, and the heart covers about 50% of the transverse thoracic area. A kind of four-chamber view of the heart can then be obtained, where the atrial compartment is wider than the ventricular part. 

There is no sign of the stomach during week 7. In some cases, it is possible to recognize the fluid-filled stomach as a small hypoechogenic area on the left side of the upper abdomen below the heart at the end of week 8.

The body develops an ellipsoid shape with a large head. The soles of the feet touch in the mid-line at the end of the week. At the same time, it is possible to obtain acceptable images of the profile; thus, it should be possible to examine the mouth. The ventral body wall is well defined. 

The lateral ventricles are always visible. They are best seen in the parasagittal plane, where the C-shape becomes apparent. The cortex is smooth and hypoechogenic. The bright choroid plexuses of the lateral ventricles are regularly detectable at 9 weeks 4 days. They show rapid growth, similar to the hemispheres, and soon fill most of the ventricular cavities. The width of the diencephalic cavity narrows gradually, while the width of the mesencephalon remains wide. A distinct border (‘isthmus prosencephali’) has developed between the cavity of the mesencephalon and the third ventricle. The wall of the diencephalon, initially very thin, thickens considerably starting from week 8 to 9. The isthmus rhombencephali is always distinct. The cavity of the mesencephalon remains relatively large, especially the posterior part. The height and the width are about the same size. During weeks 8 and 9, the rhombic fossa becomes deeper due to the progressive flexure of the pons. The lateral corners of the rhombencephalic cavity, called the lateral recesses, are easily identified at weeks 7 and 8. During this period, the distance between these recesses increases (rhombencephalon width). Later, during weeks 9 and 10, the lateral recesses often become covered by the enlarging cerebellar hemispheres. Thus, only the central part of the hypoechogenic fourth ventricle, which is divided by the choroid plexuses, is visible. The choroid plexuses of the fourth ventricle are bright landmarks, dividing the ventricle into rostral and caudal compartments. The cerebellar hemispheres are easily detectable. The primordia of cerebellar hemispheres are clearly separated in the mid-line during the embryonic period.

During week 9, the heart rate reaches a maximum of mean 175 bpm. 

From 8 weeks 3 days to 10 weeks 4 days of gestational age, all embryos have herniation of the midgut, most distinctive during weeks 9 and 10. At this stage, the midgut herniation presents as a large hyperechogenic mass. The stomach can be detected in 75% of the embryos before 10 weeks.

The human features of the fetus become clearer. The fetal body elongates, the arms and the legs develop into upper and lower arms and legs, the hands and fingers and the feet and toes. In the largest fetuses, the soles of the feet rotate from the sagittal plane. The head is still relatively large with a prominent forehead and a flat occiput. The future skull can be distinguished; ossification starts at about 11 weeks with the occipital bone¹⁴.

Central nervous system

The thick crescent-shaped lateral ventricles fill the anterior part of the head and conceal the diencephalic cavity. The thickness of the cortex is about 1 mm at the end of the first trimester. The diencephalon lies between the hemispheres, and the mesencephalon gradually moves towards the center of the head. After an initial increase, the width of the third ventricle becomes narrow towards the end of the first trimester. The cerebellar hemispheres seem to meet in the mid-line during weeks 11–12. After 10 weeks 3 days, the choroid plexuses of the fourth ventricle can always be visualized. The distance between the choroid plexuses and the cerebellum becomes shorter during weeks 9–11 because of cerebellar growth. The onset of ossification of the spine occurs at the end of the first trimester. 

At 10 weeks, the moving valves and the interventricular septum can be identified. The heart rate slows down to 165 bpm at the end of week 11. The ventricles, atria, septa, valves, veins and outflow tracts become identifiable.

Midgut herniation has its maximal extension at the beginning of week 10 and returns into the abdominal cavity during weeks 10–11. The gut retracts into the abdominal cavity between 10 weeks 4 days and 11 weeks 5 days. Fetuses which are older than 11 weeks 5 days usually do not demonstrate any sign of the herniation. The esophagus can be identified as an echogenic double line anterior to the aorta, leading into the stomach. The stomach is visible in all specimens before 11 completed weeks.

CNS

In this phase the development of the ventricular system, cerebellum, cisterna magna (the posterior fossa). At this time the vermis is not completely closed. The complete development of the cerebellum will be completed at 17 weeks gestation.

Prenatal ultrasonographic diagnosis of anencephaly during the second and third trimesters of pregnancy is based on the demonstration of an absent cranial vault and cerebral hemispheres¹⁵. Animal studies have shown that, in the absence of the cranial vault, there is progressive degeneration of the exposed cerebral tissue to anencephaly¹⁶.

In normal human fetuses, there is histological evidence that the onset of ossification of the cranial vault is at 10 weeks of gestation¹⁷ and that, ultrasonographically by 11 weeks, there is hyperechogenicity of the skull in comparison to the underlying tissues¹⁸. Ultrasound reports have demonstrated that in the human, as in animal studies, there is progression from acrania to exencephaly and finally anencephaly (Table 1)^19–23. In the first trimester, the pathognomonic feature is acrania, the brain being either entirely normal or at varying degrees of distortion and disruption.

Goldstein et al. reported the difficulties with early diagnosis of anencephaly; the 12-week scan showed no defects but repeat examination at 26 weeks demonstrated anencephaly²⁴. Rottem et al. reported a fetus at 9 weeks with an abnormal shape of the cephalic pole and cervical spine; at 11 weeks, the diagnosis of anencephaly and open cervical spina bifida was made²¹. Kennedy et al. described a case of acrania at 10 weeks in which the brain was of normal volume but appeared echogenic and disorganized; at 14 weeks, the fragmented and degenerating brain was visualized²². Bronshtein and Ornoy reported a case with no abnormal findings at 9 and 11 weeks, but at 12 weeks there was acrania and at 14 weeks there was anencephaly²³.

In an ultrasound screening study of 622 high-risk pregnancies at 10–13 weeks and 16–18 weeks of gestation, all three fetuses with acrania/anencephaly were correctly identified at the first scan²⁵. Another screening study examined 3991 patients by ultrasound at 11–14 weeks and again at 18–20 weeks; there were two cases of exencephaly (one associated with spina bifida and another with iniencephaly) and they were both diagnosed at the early scan²⁶. Two screening studies for chromosomal abnormalities by fetal nuchal translucency at 10–14 weeks in a total of 6861 pregnancies correctly diagnosed all seven cases of anencephaly in the first-trimester scan^27,28.

In a multicenter study of screening for chromosomal abnormalities, by assessment of fetal nuchal translucency thickness at 10–14 weeks of gestation, there were 53 435 singleton and 901 twin pregnancies²⁹. There were 47 fetuses with anencephaly, including three from twin pregnancies. The diagnosis of anencephaly was made at the early scan in 39 cases and at the 16–22-week scan in a further eight cases. During the first phase of the study, 34 830 fetuses were examined. In this group, there were 31 cases of anencephaly but the diagnosis was made at the early scan in only 23 (74%) of the cases²⁹. Subsequently, the sonographers from the participating centers were informed of the different diagnostic features of anencephaly in the first compared to the second trimester and they were instructed to specifically look for and record the presence or absence of acrania at the early scan. In the second phase of the study, 20 407 fetuses were examined and all 16 cases of anencephaly were diagnosed at the early scan²⁹.

These findings demonstrate that anencephaly can be reliably diagnosed at the routine 11–14-week ultrasound scan, provided the sonographic features for this condition are specifically searched for.

This is a cranial defect with protrusion of meninges (meningocele) and brain (encephalocele). In about 75% of cases, the lesion is occipital but alternative sites include the frontoethmoidal and parietal regions. It is often associated with microcephaly, hydrocephaly, spina bifida and Meckel–Gruber syndrome.

A prerequisite for the diagnosis of encephalocele (in contrast to nuchal cystic hygroma) is the demonstration of an associated bony defect in the skull and, therefore, the diagnosis may not be possible before the onset of cranial ossification at about 10 weeks of gestation. However, van Zalen-Sprock et al. have reported that, at least in some cases, the first sign for possible encephalocele is enlargement of the rhombencephalic cavity from about 9 weeks³⁰.

van Zalen-Sprock et al. described a fetus at 11 weeks of gestation with two translucent areas in the occipital region³². A repeat scan at 13 weeks demonstrated a bony defect and protrusion of the brain. The diagnosis of occipital encephalocele was made and this was confirmed by pathological examination after termination of the pregnancy.

This is a lethal, autosomal recessive condition characterized by the triad of encephalocele, bilateral polycystic kidneys and polydactyly.

Pachi et al. described the sonographic features of the syndrome in a high-risk pregnancy at 13 weeks of gestation³³. There was an occipital bony defect accompanied by encephalocele and abnormally enlarged kidneys. Pathological examination, after termination at 13 weeks, detected all three features of the syndrome. Sepulveda et al. examined nine high-risk pregnancies at 11–13 weeks and correctly diagnosed the four affected fetuses by the presence of the characteristic triad of the syndrome³⁴. Similarly, van Zalen-Sprock et al. examined five high-risk pregnancies and correctly identified the three affected fetuses at 11–14 weeks³⁰. 

An ultrasound screening study for fetal abnormalities at 12–14 weeks of gestation, involving 1632 pregnancies correctly identified the one case of Meckel–Gruber syndrome; there was an occipital bony defect with a small encephalocele at 12 weeks and enlarged cystic kidneys at 13 weeks³⁵. The parents chose to continue with the pregnancy and at 15 weeks there was enlargement of the encephalocele. Serial scans from 18 weeks demonstrated the presence of anhydramnios, making visualization of the fetal abnormalities difficult. The diagnosis was confirmed after delivery at 37 weeks and neonatal death³⁶. Sepulveda et al. detected the triad of the syndrome in a 13-week fetus during screening for chromosomal abnormalities by measurement of fetal nuchal translucency thickness in 21 477 pregnancies³⁴.

These findings suggest that the phenotypic expression of the syndrome is evident from at least 11 weeks of gestation. Consequently, all affected cases could potentially be diagnosed by the early scan, provided that systematic examination of both the skull/brain and the renal fossae is carried out routinely. Indeed, the diagnosis is likely to be easier at 11–14 weeks, when the amniotic fluid is normal, than during the second trimester when the presence of the associated oligohydramnios could easily cause encephalocele and certainly polydactyly to be missed. Additionally, at 11–14 weeks, the fingers are easier to examine because they are invariably extended, whereas in the second trimester the hands are often clenched.

This condition, which complicates about 10% of cases with hydrocephalus, is characterized by complete or partial absence of the cerebellar vermis and cystic dilatation of the fourth ventricle. The Dandy–Walker complex is a non-specific end-point of chromosomal abnormalities (usually trisomy 18 or 13 and triploidy), more than 50 genetic syndromes, congenital infection or teratogens such as warfarin, but it can also be an isolated finding.

Ulm et al. reported a 14-week fetus with an apparently isolated Dandy–Walker malformation but fetal karyotyping demonstrated triploidy³⁹.

In a screening study involving ultrasound examinations at 11–14 weeks of gestation and again at 18–20 weeks in 3991 patients, there was one case of the Dandy–Walker malformation and this was not diagnosed in the first-trimester scan²⁶. In another screening study for chromosomal abnormalities by fetal nuchal translucency in 1473 pregnancies, there was one case of Dandy-Walker malformation and this was correctly diagnosed in the first-trimester scan²⁷.

This is a lethal, sporadic condition characterized by absence of the cerebral hemispheres with preservation of the mid-brain and cerebellum. It is thought to result from widespread vascular occlusion of the internal carotid arteries or their branches, prolonged severe hydrocephalus, an overwhelming infection, or defects in embryogenesis. About 1% of infants thought to have hydrocephalus are later found to have hydranencephaly.

Lin et al. reported a 12-week fetus with a large head, small hemispheres and a fluid-filled intracranial cavity with no mid-line echo⁴⁰. A repeat scan at 18 weeks demonstrated a cystic fetal head with no cerebral hemispheres and falx; the brain could be seen protruding into the cystic cavity. Unlike alobar holoprosencephaly, there was no rim of cortex present. The pregnancy was terminated and pathological examination confirmed the diagnosis. 

Holoprosencephaly, with a birth prevalence of about 1 in 10 000, is characterized by a spectrum of cerebral abnormalities resulting from incomplete cleavage of the forebrain. There are three types according to the degree of forebrain cleavage. The alobar type, which is the most severe, is characterized by a monoventricular cavity and fusion of the thalami. In the semilobar type, there is partial segmentation of the ventricles and cerebral hemispheres posteriorly with incomplete fusion of the thalami. In lobar holoprosencephaly, there is normal separation of the ventricles and thalami but absence of the septum pellucidum. The first two types are often accompanied by facial abnormalities.

Toth et al. observed a floating membranous structure in place of the skull of an 11-week fetus⁴¹. At 12 weeks, they noted acrania and a floating, balloon-like, membranous brain substance. At 16 weeks, the diagnosis of acrania and holoprosencephaly with cyclops was made and these findings were confirmed at postmortem examination after termination at 18 weeks⁴¹. Bronshtein and Weiner described a case of alobar holoprosencephaly during routine ultrasound examination at 14 weeks; there were a single cerebral ventricle, fused thalami and a crescent-shaped frontal cortex⁴². The fetal karyotype was normal. Gonzalez-Gomez et al. described a 10-week fetus with a single ventricular cavity, absence of the orbits and mid-facial cleft⁴³. The karyotype was normal. Pathological examination after termination at 11 weeks demonstrated alobar holoprosencephaly, anophthalmia, arrhinia and facial cleft⁴³. Sakala and Gaio diagnosed alobar holoprosencephaly in a 13-week fetus with absent falx, large single ventricle and fused thalami; the karyotype was 69,XXY⁴⁴. Turner et al. reported a case of alobar holoprosencephaly (single ventricle and fused thalami), exomphalos and increased nuchal translucency at 10 weeks; the karyotype was trisomy 18⁴⁵. Wong et al. reported three cases of alobar holoprocencephaly (single ventricle and fused thalami) at 10–13 weeks; there was one case each of trisomy 18, triploidy and mosaic 18p deletion and duplication⁴⁶.

Snijders et al. reported on the sonographic features of 46 trisomy 13 fetuses at 10–14 weeks of gestation⁴⁷. In 76% there was increased nuchal translucency thickness, 64% were tachycardic, 24% had holoprosencephaly and 10% had exomphalos. There was no significant difference in nuchal translucency thickness between those with and those without holoprosencephaly or exomphalos⁴⁷. 

In spina bifida, there is failure of closure of the neural tube, which normally occurs by the 6th week of gestation. In the spine of normal fetuses, there are three ossification centers, two pedicles and the spinal body, and these are present from the 10th week of gestation, allowing ultrasonographic visualization of the neural canal from this gestation. Braithwaite et al. assessed the fetal anatomy at 12–13 weeks of gestation, by a combination of transabdominal and transvaginal sonography, and they reported successful examination of the vertebrae and overlying skin in both the transverse and coronal planes in all cases⁴⁹.

In the 1990s, improvements in the quality of ultrasound equipment have led to the diagnosis of spina bifida during the first trimester of pregnancy. Blumenfeld et al. described the evolution of the cranial and cerebellar signs of spina bifida in an affected fetus that was scanned at 10, 12 and 15 weeks of gestation⁵³. In the first scan, there was a sacral irregularity but the cerebellum appeared normal; at 12 weeks, the banana sign was detected and, at 15 weeks, when the diagnosis of sacral meningocele was made, the lemon sign was identified. Sebire et al. described that, in three cases of lumbosacral spina bifida diagnosed at 12–14 weeks of gestation, there was an associated lemon sign⁵⁴. Similarly, Bernard and colleagues reported the diagnosis of spina bifida in a 12-week fetus with narrowing of the frontal bones and flattening of the occiput⁵⁵.

These findings demonstrate that, at least in some cases of spina bifida, the characteristic lemon and banana signs are present from the first trimester of pregnancy. However, the prevalence of these signs at the 11–14-week scan remains to be determined.

Abnormalities of the heart and great arteries are the most common congenital defects and the birth prevalence is 5–10 per 1000. In general, about half are either lethal or require surgery and half are asymptomatic. The first two groups are referred to as major. Specialist echocardiography at around 20 weeks of gestation can identify most of the major cardiac defects, but the main challenge in prenatal diagnosis is to identify the high-risk group for referral to specialist centers. Currently, screening is based on examination of the four-chamber view of the heart at the 20-week scan, but this identifies only 26% of the major cardiac defects⁵⁶.

Examination of the four-chamber view of the heart can now be carried out at the 11–14-week scan (Table 2)^57–60. At 12–13 weeks of gestation, the four-chamber view can be examined successfully by transabdominal ultrasound in 76% of the cases and transvaginally in 95%⁴⁹. Bronshtein et al. reported that the diameters of the two ventricles were similar and increased linearly with gestation from about 1.5 mm at 11 weeks to 3 mm at 14 weeks; the diameter of the heart was about one-third that of the chest and the ratio did not change with gestation⁵⁸. In contrast, Blaas et al. examined the ratio of the heart diameter to that of the abdomen and reported a decrease with gestation from 51% at 8 weeks to 42% at 12 weeks¹¹.