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During the past 25 years, embryonic and early fetal ultrasound and diagnosis have increasingly gained attention in pregnancy care. Modern high-frequency ultrasound transducers make it possible to obtain detailed images of the early conceptus and its organs, and thus move part of the anatomy and anomaly scan from the second to the first trimester. Today, detection of embryonic and fetal structural abnormalities in the first trimester has frequently been reported. One has to distinguish between diagnosis during the early period until about 10 weeks when the embryo or early fetus is small and transvaginal ultrasound is applied, and diagnosis during the late period at the nuchal translucency screening, usually carried out using transabdominal ultrasound. Early first-trimester abnormalities are often diagnosed by chance on clinical indications, whereas late first-trimester diagnoses are the result of systematic screening using ultrasound markers.

 

Keywords

structural abnormalities; embryo; foetus; first trimester; sonoembryology
 

Introduction

The aims of any early pregnancy ultrasound scan should be to determine viability and age of the embryo or fetus, to detect multiples and describe chorionicity and amnionicity, and to detect gross abnormalities. At 10 postmenstrual weeks, an embryo is less than one-half the length of an adult thumb, but possesses already several thousands of identified structures, practically any of which may be subject to developmental deviations [1]. Holoprosencephaly, for example, develops early in embryonic life, and has been diagnosed by light-microscope in 201 cases of 44,000 early pregnancy terminations and miscarriages before 10 weeks [2]. Thus, the embryonic period proper is of importance because most congenital anomalies make their appearance during that time, and it should be possible to detect major structural anomalies by ultrasound.

 

Over the past 25 years, embryonic and early fetal ultrasound and diagnosis has gained increased attention in pregnancy care. It started with the general introduction of transvaginal ultrasound transducers, which by its improved resolution made it possible to develop the research field ‘sonoembryology’ [3], [4], [5], [6], [7] and [8]. At the same time, the first first-trimester diagnoses of structural anomalies were reported [9], [10], [11], [12] and [13].

 

When we talk about detection of first-trimester structural abnormalities, the definition of gestational age is important: a trimester corresponds to a period of 3 months, and trimesters are used to divide pregnancies into three periods of approximately equal length. An exact definition of the transition between the trimesters is not possible, because no specific developmental stages would indicate such borders [1]. The introduction of the 11–13+6 weeks scan has established a practical break of the end of the first trimester at 13+6 to 14+0 weeks. In addition, we have to make a distinction between diagnoses made during the 11–13+6 week scan in a screening situation, and those made before this period during the embryonic period on clinical indications. The prerequisite for any early diagnosis and the understanding of how and when anomalies can be detected later in pregnancy is the knowledge of the normal development of the human embryo [14] and the corresponding sonographic appearance [3], [4] and [5]. The transvaginal approach should be preferred for examinations before 11–12 weeks gestation.

 

In this chapter, we present an overview of normal development and review the relevant literature on early diagnoses of structural abnormalities. All statements of gestational age are based on the last menstrual period, expressed in completed weeks and completed days, assuming a regular cycle with ovulation at 2 weeks 0 days.

 

Normal development in the first trimester

The human embryo develops from the fertilised ovum, through the bilaminar and three-laminar disc, into a cylindrical body, and only at the end of the embryonic period does it look like an immature human being. Except for the physiological herniation of bowel into the umbilical coelom from 7–11 weeks, the body wall is already established after the folding process during weeks 4 and 5.

 

Measurement of the conceptus is important, because healthy embryos and their associated structures, such as the amniotic cavity, show virtually identical growth velocities [15]. In addition, embryos of the same size (crown-lump length [CRL]) look identical. The development of the size of embryos and the shape of the body and the brain cavities [15] are in accordance with images from the embryological literature [14]. All these facts can be used as the basis for early sonographic assessment. The synopsis in Table 1 shows the normal development of the embryo based on sonoanatomic descriptions of longitudinal two-dimensional studies [3], [4], [5] and [16] and on three-dimensional ultrasound studies [17] and [18] week by week (Table 1) [19], [20] and [21].

     
     

 

Structural abnormalities during embryonic period

There are many clinical indications for an early ultrasound examination, such as threatened abortions (e.g. bleeding, pain), suspicion of ectopic pregnancy, uncertain pregnancy length, survey after assisted fertilisation, and targeted examination of anatomy because of maternal disease (e.g. diabetes), hereditary disease, known exposition to teratogens (e.g. anti-epileptica and lithium), and previous pregnancy with fetal anomaly. The patient-in-the-patient (the embryo), is the centre of attention. The sonographer's professional aim should be to diagnose abnormal development, if it is present, to prevent unnecessary harm to the woman, embryo or fetus. Any significant deviation from the developmental schedule described in Table 1, including abnormal biometry, can be the expression of a structural abnormality.

 

All first-trimester miscarriages usually show sonographic abnormalities, such as the yolk sac being too large or too small, the amniotic cavity being too large, or the embryonic pole being too small, abnormal, or the heart rate being too slow. Of interest, are those abnormalities in which the embryo continues to live and develop. In such cases, we might expect the following ultrasound findings: abnormal contours of head, body wall and limbs; abnormal decrease in fluid amount in brain cavities; abnormal increase in fluid amount in brain cavities, thorax, abdomen, and intestinal tract; abnormal number of limbs, fingers and toes; and abnormal biometry of CRL, biparietal diameter (BPD), heart rate, amniotic cavity, and yolk sac.

 

By looking at the embryo and keeping these guidelines in mind, one should be able to detect embryos with major anomalies where survival into the fetal period or even until and after birth is possible.

 

Central nervous system anomalies

Most embryonic and fetal diagnoses must be expected from the developing central nervous system because it is the most impressive organ system of the embryo and fetus [22]. It is not surprising that the first report of a first-trimester ultrasound diagnosis was an anencephaly [13], 25 years after its earliest description in the third trimester [23]. The abnormal shape of the head in this condition is relatively easy to detect. In such a fetus, where the CRL and BPD cannot be normal, the abdominal diameter will represent a useful biometric parameter. In acrania (exencephaly), only a thin layer, if any, covers the brain. Ultrasound images usually show an abnormally shaped cephalic pole [24] and [25]. In our experience, the striking feature of acrania at 8–9 weeks gestation is the altered appearance of the brain cavities with decreased fluid content [24], [26] and [27]. If one consequently measures the head width (BPD), one cannot overlook serious brain defects.

 

Both neural tube defects and the amniotic rupture sequence may develop into an encephalocele. Occipital encephalocele, caused by amniotic rupture sequence, was described in a 9-week-old embryo [24]. An irregular protrusion at the posterior part of the head was found. In addition, it was not possible to identify the brain cavities, as they were empty [28].

 

Encephalocele is also a well-known part of the Meckel–Gruber syndrome. In two cases of Meckel–Gruber syndrome at 8 weeks, an encephalocele was not seen, but the cavity of the rhombencephalon was enlarged [29]. In another 9-week 0 day-old embryo (CRL 22 mm), a dysraphic defect at the occiput and a significantly enlarged rhombencephalic cavity were demonstrated [24]. The additional finding of polydactyly helped to diagnose Meckel–Gruber syndrome [28]. Thus, it seems that the occipital encephalocele in Meckel–Gruber syndrome becomes visible at the end of the embryonic and early fetal period. Encephalocele may also be associated with other inherited conditions. In a case of cerebro–oculo–muscular–syndrome, a significant protrusion of the mesencephalic roof could be shown at 10.5 weeks, which successively developed into an encephalocele during the following weeks [28].

 

Holoprosencephaly is a heterogeneous entity of central nervous system anomalies that results from a primary defect in induction and patterning of the rostral neural tube (basal forebrain). This defect leads to varying degrees of incomplete separation of the cerebral hemispheres and facial anomalies. Holoprosencephaly is graded according to the severity of the brain anomaly as alobar, semi-lobar, lobar and middle interhemispheric variant [30] and [31]. The development of the telencephalon into cerebral hemispheres becomes visible during week 7. Thus, the diagnosis of alobar holoprosencephalon can be expected at 8 weeks.

 

Spina bifida can be detected during the embryonic period at 9 weeks, as described in a case series in 2000 [32]. The sonographic appearance of bifid spine in embryos is a significant irregularity of the contours of the spine and back [32]. The detection of such an embryonic or fetal malformation is usually made by two-dimensional ultrasound, but three-dimensional ultrasound may enhance the abnormality (Fig. 1). Another recent case report using two-and three-dimensional ultrasound showed a large cystic structure at the caudal part of the spine representing a large myelomeningocele [33].

 

     

 

Facial anomalies

At the end of the embryonic period, the eyes, the maxille, and the mandible are identifiable. Major anomalies that involve these structures should be detectable as shown in a case with amniotic rupture sequence [24]. The typical facial anomalies associated with alobar holoprosencephaly, such as proboscis and extreme hypotelorism or cyclopia have been diagnosed by ultrasound in the embryonic period [34] and [35]. Anyplane slicing in the three-dimensional mode helped to enhance imaging of hypotelorism [34]. An example of van der Woude syndrome with bilateral cleft lip and palate was described in a 10-week, 3 day-old fetus [28].

 

Heart anomalies

So far, a complete and detailed diagnosis of complicated heart defects is reserved for the end of the first and the second trimester.

 

Body wall defects

Because of the physiological “abdominal wall defect” that is clearly visible by ultrasound until 10–11 weeks, we have to be cautious in making diagnoses such as omphalocele before 12 weeks. The normal size and development of the physiological mid-gut herniation is described longitudinally from 7–12 weeks [5], and may aid in differentiating normal and abnormal body wall development. Contemplations about the pathogenesis of body wall defects tend to categorise these defects according to their location in relationship to the umbilicus [36] and [37]. We may divide the ventral wall defects into cranial defects (e.g. ectopia cordis, Cantrell's pentalogy, and epigastric omphalocele); central defects (e.g. central omphalocele, gastroschisis); caudal defects (e.g. bladder exstrophy, cloacal exstrophy, omphalocele-exstrophy-imperforate anus-spinal defects complex); and complex defects (e.g. limb–body–wall–complex), including body stalk anomaly, and body wall defect caused by amniotic rupture sequence [28] and [38].

 

Before 12 weeks gestation, differentiation by ultrasound according to these sub-groups seems inappropriate. Although there exist only a few case reports, large complex defects, such as limb–body–wall–complex and ectopia cordis should be detectable [39] and [40] before 10 weeks. Even the early diagnosis of gastroschisis at 9 weeks has been described, in which the addition of colour Doppler was helpful [41].

 

Gastrointestinal and genitourinary anomalies

Most of congenital gastrointestinal anomalies are obstructive conditions of the gastrointestinal tract. Such anomalies are atresia, stenosis, and duplication of the gastro-intestinal tract, cysts or tumours, and hepatic, splenic, or pancreatic diseases. Alteration of the amniotic fluid amount owing to possible imbalance of production and resorption by the fetal gastrointestinal and urinary system do not become significant until the second trimester. The fluid that can be found in the embryonic stomach as early as 8 weeks does not present swallowed amniotic fluid, but originates probably from gastric secretion [5]. Therefore, one cannot expect oligo- or polyhydramnios as markers for gastrointestinal or urogenital anomalies. Surprisingly, a case of oesophageal atresia showed increased fluid amount in the stomach and bowel at 10 weeks gestation, and first after 12 weeks, the typical feature of empty stomach occurred [28]. As with the gastrointestinal tract, the development of the genitourinary tract is not complete before the post-embryonic period. Genitourinary tract anomalies are usually not detected before the 11–13+6 week scan. Gross anomalies, such as persistent cloaca, however, may present as large cystic areas in the lower abdomen. Diagnoses of gastrointestinal and genitourinary anomalies during the embryonic period have not been described.

 

Musculoskeletal anomalies, poly- and oligodactyly, limb defects

Many skeletal disorders can cause abnormal shape and size of the skeleton. The spectrum ranges from absence of a finger to the major lesions of the skeleton caused by amniotic adhesions. One limb may have reduced growth owing to vascular compromise, or general dwarfism caused by serious congenital osteochondro-dysplasia.

 

In severe anomalies, such as amniotic rupture sequence or limb-body-wall complex, the reduction defects of an extremity and the kyphoscoliosis may be easily detected at 9 weeks [28] or even at the end of week 8. A sign for the diagnosis is the abnormal shape of the amniotic cavity, which, during 8 and 9 weeks, usually looks like a well-demarcated balloon with the embryo inside. Small anomalies, such as polydactyly, can be seen in Meckel–Gruber syndrome as demonstrated in an embryo of only 22 mm CRL [28]. Caution must be practised with the diagnosis of polydactyly, as reflections of the ultrasound beam from both sides of fingers and toes may give the false impression of hexadactyly.

 

The normal embryonic and early fetal development of the skeleton has been described by ultrasound in a small study [42]. Diagnosis of a rare skeletal dysplasia that might lead to the termination of a pregnancy must be based on reliable and unambiguous images. The size of the measured long bones in embryos and young fetuses are near the limit of the ultrasound resolution. Thus, improvements of the image quality will be necessary before accurate measurements can be made [43]. In serious dysplasias, such as achondrogenesis, significant bone shortening may not be obvious before 11 weeks [44].

 

Conjoined twins is obviously an easy diagnosis during the embryonic period. Chen et al. [45] presented a review of first-trimester diagnoses up to 2010. They identified reports of three cases at 7 weeks, five cases at 8 weeks, and 12 cases at 9 weeks [45].

 

Many cases of aneuploidy are missed during an early scan if they do not present obvious major structural abnormalities. Detectable differences have been found between euploid embryos and trisomies using biometric markers (e.g. CRL, heart rate, and yolk sac diameter); however, these deviations from the norm in embryonic heart rate in trisomies 13 and 18, and in yolk sac diameter in trisomy 21 pregnancies observed at 6–10 weeks, were small and unlikely to provide the basis for a method of screening [46]. Examples of embryonic diagnoses made by transvaginal ultrasound before 10 weeks' gestation are presented in Table 2.

 

     

 

Structural abnormalities during the early fetal period at 10–11 weeks, and 11–13+6 weeks scan

Size of fetus

It is obvious that the size of an embryo and fetus affects the detection of anomalies. During the embryonic period, the CRL is less than 31 mm, and most developing structural anomalies still have a small size at the limit of the ultrasound resolution, such that it cannot be expected to detect these defects. A few weeks later at the 11–13+6 scan, the fetus has doubled or trebled its length compared with the size at 9 weeks, and significantly more fetal conditions with structural abnormalities have further developed and become detectable as shown in reviews by Souka et al. [56] and ∗[57] and Bilardo et al. [58] In the second trimester at 18–20 weeks, the size of most abnormal structures is in the range of the transabdominal examination, and functional consequences of, for example, obstructions in the urinary or gastrointestinal tract become evident in many cases such as dilatations, or poly- or oligohydramnios.

 

Clinical indication versus screening

Although early diagnosis during the embryonic period is based on direct transvaginal sonographic identification of structural abnormalities, more or less by chance on clinical indications, are later diagnoses between 10 and 11 and 13+6 weeks often mediated through ultrasound markers. Then the approach is generally transabdominal, but once a structural anomaly is suspected, a supplementary transvaginal scan with a high-resolution transducer is usually carried out.

 

Sonographic markers

The most powerful ultrasound marker is nuchal translucency, which in 1990 was recognised as having an association with trisomy 21 [59]. Extensive research during the past 2 decades was introduced by Nicolaides [60], [61] and [62], who established that the measurement of nuchal translucency thickness provides effective screening for chromosomal defects. Even in the absence of aneuploidy, nuchal translucency is relevant because it is associated with an increase in adverse perinatal outcomes caused by a variety of fetal conditions, such as cardiac defects [63], dysplasias, deformations, disruptions, and genetic syndromes [44], [56], ∗[57], [64] and [65]. The likelihood for associated anomalies increases with the thickness of nuchal translucency. Today numerous studies on nuchal translucency have been conducted, which analyse various aspects together with other possible sonographic markers for aneuploides and structural abnormalities. Such markers are absent nasal bone [66], ductus venosus [67], tricuspid regurgitation [68], and fronto-maxillary angle [69]. Exomphalos, megacystis and single umbilical artery are abnormal findings that are other possible markers for aneuploidy in the first and also second trimester.

 

Efficacy of screening

In many countries, the detection of major fetal anomalies is part of guidelines for a second-trimester routine scan. A systematic review of studies in the 1990s on the efficacy of detecting fetal anomalies at the routine second trimester scan reported overall prevalence of fetal anomalies of 2.1%, ranging from 0.8 to 2.5% in individual studies, and including major and minor anomalies [70]. Overall use of late-pregnancy ultrasound scanning yielded detection of fetal anomaly of 44.7%, with a range between 15.0 and 85.3% [70]. Borrell et al. [71] analysed data from 36,237 pregnancies generated at the 11–13+6-week screening in eight centres; these data suggest that the overall detection rate of major congenital anomalies during the 11–13+6-week ultrasound evaluation is 29% (95% confidence interval 25 to 33).

 

A selection of large studies reported over the past 8 years is presented in Table 3[72], ∗[73], ∗[74], [75], [76] and [77]. The designs of these studies are not identical: the gestational age at examination varies from 10–14 to 13–14 weeks. The populations vary from low risk, non-selected to selected, the design from retrospective to randomised-controlled trial. Chen et al. [74] compared two methods for first-trimester and second-trimester scanning, where the study group in addition to nuchal translucency screening was offered a detailed anatomy scan. The first-trimester examinations of both groups are included in this overview. Also, the definition of anomalies varied: Taipale et al. [72] drew from a low-risk population, and included only anomalies that were assumed to be detectable at the mid-trimester scan; Saltvedt et al. [73], Syngelaki et al. [76] and Grande et al. [77] considered pregnancies with normal fetal karyotype; and Saltvedt et al. [73] and Hildebrand et al. [75] included only moderate to severe anomalies. In many cases, the assignment to the degree of severity of a condition and to a specific organ system in fetuses with multiple anomalies or abnormal karyotype is difficult and varies in these studies. Such varying inclusion and exclusion criteria explain the differences of prevalence as, for example, in the studies by Taipale et al. [72] (0.7%) and Grande et al. [77] (3.2%), (P = 0.0001). Therefore, comparisons as presented in Table 3 must be interpreted with caution. Significant differences have also been observed between studies with normal karyotype only (subtotal 1), and the studies that include all pregnancies (subtotal 2), in the detection rate of 'all' anomalies, skeletal and ‘other’ anomalies. Also, these differences are most probably caused by selection and assignment biases. Overall, the prevalence of structural anomalies is 1.4%, and the detection rate is about 34%. The latter is still 10% less than the detection rate of overall late pregnancy ultrasound scanning from the 1990s [70]. The highest detection rate of 67% is found in the thorax/abdomen group excluding cardiac lesions, followed by a detection rate of 45% in the central nervous system group. The detection rate of spina bifida in these studies was only 8 out of 43 (18.6%), and detection of heart defects was low, namely 62 out of 297 (20.9%).

 

     
      
     

 

 

Although the detection of spina bifida is possible during the embryonic period proper before 10 weeks [32], its detection rate is still poor at the 11–13+6 week scan (see above). The typical findings ‘lemon shape’ and ‘banana sign’ [78] do not appear before the end of the first trimester [32]. Buisson at al. [79] described in two cases at 12 weeks a slight retraction of the frontal bones, resulting in an acorn-shaped head, the cerebral peduncles appearing parallel to each other. In 2009, Chaoui et al. [80] reported the possibility of detecting spina bifida by using internal translucency as a new sonographic marker [80]. The findings of an absent internal translucency in spina bifida, however, are subtle and require evaluation by highly experienced sonographers, especially when three-dimensional ultrasound is required to obtain the correct mid-sagittal plane. The measurement of the brain stem and brain stem to occipital bone diameter in the mid-sagittal view of the face and brain was suggested as a possible tool to evaluate the presence of open spina bifida [81], or a similar sonographic landmark in the axial scan plane of the head, namely the aqueduct of sylvius-to-occiput distance [82]. Recently, it was shown that fetuses with spina bifida had a smaller BPD than normal fetuses, and that 50% had a BPD less than the 5th centile [83]. Combination of BPD with alphafetoprotein and beta human chorionic gonadotropin seems to increase the detection rate of open spina bifida to 59% [84].

 

Apart from these suggested screening tools, a thorough standard examination of the spine itself should increase the detection rate of spinal pathology.

 

The prenatal detection of heart defects is typically carried out at the mid-trimester routine examination. The screening performance for heart defects in the first trimester is relatively poor, because only 30% of fetuses with heart defects have an increased nuchal translucency, when the 99th centile is used as a cut-off [85]. Borrell et al. [86] reported recently that, by including ductus venosus blood flow measurements (absent or reversed A-wave) in the nuchal translucency screening programme, the detection rate of congenital heart defects increased to 47%, with a 2.7% false-positive rate [86].

 

A recent study reported improved detection rate of structural abnormalities in two centres, including 5472 consecutive pregnancies, based on an extended examination protocol with systematic detailed assessment of fetal organ systems [87]. Here, the prevalence of lethal and severe malformations was 1.39%. Overall, 40.9% of abnormalities were detected in the first trimester, and 76.3% of the major structural defects.

 

Conclusion

Examination of the fetal anatomy is part of ultrasound screening programmes. It is desirable to identify anomalies, if present, as early as possible. The time of detection of many structural abnormalities has moved from the second trimester to the first trimester and, today, a significant amount of anomalies of the young fetus are detected during the nuchal translucency screening programme, and even ‘by chance’ during the embryonic period proper. The detection rate at the end of the first trimester is steadily increasing, but there is still a long way to go. A reasonable way to increase detection rates of anomalies is improving further the skills of the sonologists by teaching and training and by using detailed examination protocols. Such protocols, including standard biometry, encourage the sonologist to follow a systematic approach of the anatomy assessment even in the early period of the first trimester.

 

Nevertheless, structural abnormalities occur, such as obstructions in the gastrointestinal tract and the urinary system, and hydrocephalus, which usually do not become visible before the second or even third trimester.

 

Conflict of interest

None declared.