Since 1980, with the continuous improvement of the ultrasound equipment and technology, anomalies detected in the first and early second trimesters continued to increase. In the era of noninvasive prenatal testing using cell-free DNA, a comprehensive first-trimester ultrasound not only focus on the features of aneuploidies, such as thickened nuchal translucency (NT), the absence of nasal bone, but also provides clinical information that cannot be detected with noninvasive prenatal testing alone, the structural abnormalities.1,2 The early detection of certain anomalies or malformations is limited by the gestational age in which the development of such problems become evident. When scanning in the first-trimester of the pregnancy, it is important to be familiar with the normal development of the embryo and the fetus. The presence or absence of certain structures may be either normal or abnormal depending on the gestational age. Under certain condition such as patient with obesity, or patient with large fibroids, abdominal scar, and anterior placenta, it may be impossible to see these structures at this stage. Transvaginal scan shall be an alternative. This review focus on the prenatal diagnosis of fetal anomalies at 11–13+6 weeks and summarizes anomalies encountered in our practice or reported in the literature.
PubMed, MEDLINE, Cochrane Library, and Google scholar databases were searched using combinations of the terms “Fetal Structural Anomalies,” “11–13+6 weeks,” “First trimester,” “ultrasonography,” “ultrasound,” “screening,” “detection,” and “fetal abnormalities.” Reference lists of the retrieved articles were also searched for relevant articles and an additional automated search was performed using the PubMed “search for related articles” function. They were saved in the reference management software (Endnote).
Central nervous system
The fetal brain can be imaged in detail at 10–14 weeks. The cerebellum is first imaged at this stage. The choroid plexus is seen filling the ventricular cavity. The normal lateral ventricles appear relatively large and the brain mantle appears paper-thin. In addition, the falx cerebri, the thalami, the brainstem, the fourth ventricle, the posterior fossa, the cerebellum, the cerebellar peduncles, as well as the foramen magnum can be seen. It is possible to measure the biparietal diameter, head circumference, and abdominal circumference as part of the first-trimester biometric measurements.3
In 1972, anencephaly was the first malformation reported using transabdominal ultrasound at 17 weeks. Subsequently, almost 20 years later was reported with transvaginal sonography at 11+5 weeks. It is the first malformation detected in the first-trimester. In the first-trimester, the pathognomonic feature is acrania or exencephaly, so called the Micky-Mouse sign. Using transvaginal sonography and the high resolution transabdominal sonography, it is possible to make the diagnosis of anencephaly as early as 11 weeks’ gestation.4 In rare cases it can be suspected at 9 weeks of pregnancy by the altered appearance of the brain cavities with decreased fluid content.5
Cephaloceles are usually midline cranial defects in which there is herniation of the brain and meninges. The reported incidence is 0.8–3.0 per 10 000 live births. The cephalocele may also involve the occipital, frontal, parietal, orbital, nasal, or nasopharyngeal region of the head, mostly occipital. The detection of an encephalocele on ultrasound examination is often suspected in the axial view by the presence of a irregular protrusion at the anterior or posterior part of the head. As encephaloceles are often part of genetic abnormalities and syndromes, a detailed scan of fetal anatomy is recommended.6
HPE results from the failure of the prosencephalon to differentiate into the cerebral hemispheres and lateral ventricles between the fourth and eighth weeks. The incidence in abortus has been reported to be 0.4 per 1 000, with a lower incidence in live births of 0.06 per 1 000. HPE is divided into three types: alobar, semilobar, and lobar. In the first-trimester only the alobar ones can be found, with a prevalence of 0.34 per 1 000.7 Alobar HPE is the most severe type and consists of a single ventricle, small cerebrum, fused thalami, agenesis of the corpus callosum, and falx cerebri. The falx cerebri becomes sonographically apparent at 9 weeks. So alobar HPE can be detected from 9 weeks of gestation onward by expert hands, with the presence of a lack of separation of both lateral ventricles and choroid plexuses. Before this, the normal fetal brain appears to have a single ventricle similar to alobar HPE.
Ventriculomegaly is defined as dilatation of the ventricular system without enlargement of the cranium (head circumference) not caused by primary atrophy of the brain. Usually, the large echogenic choroid plexus fills the atrium and the body of the lateral ventricle. However, in ventriculomegaly, these “dangling” choroid plexus, which shrinks and detaches from its medial wall, facilitate in utero diagnosis of ventriculomegaly very early in pregnancy. The thinning choroid plexus forms an angle with the contralateral choroid plexus at degrees that depend on the severity of the ventricular enlargement.8,9
Dandy-Walker malformation (DWM)
DWM results from a cystic dilatation of the fourth ventricle, with dysgenesis or agenesis of the cerebellar vermis and hydrocephaly. When an enlarged intracranial translucency, a reduced thickness of the brainstem, and diminished visibility of the choroid plexus of the fourth ventricle in a mid-sagittal view of the fetal head was visualized, the DWM should be suspected.10 Axial and coronal views of the fetal head will show a large posterior fossa cyst separating the cerebellar hemispheres. However, one should be cautious regarding the diagnosis of DWM in the first-trimester, because an isolated enlarged intracranial translucency might be a transient sign in the early fetal life.11 There are developmental changes in the area of the cerebellum and the cerebellar vermis. The final anatomy of the vermis is formed as late as the sixteenth to twenty-ninth weeks. Therefore, at 13–14 weeks, and sometimes as late as the sixteenth week, diagnosis of DWM is difficult. One should wait until 20–22 weeks to exclude this abnormality.
Open spinal bifida (OSB)
OSB can be detected before the twelfth week by noting irregularities of the bony spine or a bulging within the posterior contour of the fetal back. The lemon sign, the banana sign and the hanging choroid plexuses in the lateral ventricles which are the typical cranial features of OSB at mid-gestation, are rarely present in the first-trimester. In an attempt to address this diagnostic difficulty, a number of different markers of midsagittal view of the head have been proposed to allow earlier identification of OSB, such as invisible of the intercranial translucency, obliterated cisterna magna, thickened brain stem, shortening of the distance between the brainstem and the occipital bone, and the brain stem/brainstem and the occipital bone ratio more than 1.3 One study performed by 20 specialists showed the detection rate of OSB could be 100% in the first-trimester.12 Recently, in a large 10-years retrospective study of UK, the detection rate of OSB was 59%.13 Other intracranial signs reported with OSB include posterior shifting of the cerebral peduncles and aqueduct of Sylvius, an abnormal frontomaxillary facial angle and the dry brain sigh.14 All these signs are a hint to a comprehensive exam the spine, so that OSB can be diagnosed with a high sensitivity during first-trimester screening by examination of the posterior brain.12,15 It is important to understand that despite the presence of many signs of OSB in the first-trimester, the diagnosis relies on the demonstration of the actual defect in the spine.3
The face and neck
The fetal face begins to resemble that of a baby by the end of the embryonic period. Development of the face occurs mostly between the sixth to tenth weeks. Anomalies of the face can occur as an isolated finding but are frequently associated with chromosomal aneuploidy, such as trisomy 18 and 13, as well as non-chromosomal syndromes. When a facial anomaly is imaged, a targeted scan of the fetus is indicated.
Cleft lip and palate (CLP)
CLP the most common facial anomaly, with a reported incidence of 1 per 1 000 live births. In up to 80% of the cases, cleft lip is unilateral rather than bilateral. Unilateral cleft lip is more commonly on the left side. Detecting CLP in the first-trimester is challenging, as the small size of facial structure. Indeed, most cases of isolated CLP are not detected in the first-trimester.16,17 The profile and retronasal triangle (RNT) view may be an optional plane to detect CLP. When the maxillary gap sign was seen in these view, CLP is suspected. In a prospective study using three-dimensional ultrasound, the identification of CLP by visualization of the RNT in the first-trimester has been shown to have a sensitivity of 87.5% and a specificity of 99.9%.18 However, about 5% to 7% of normal fetuses can have a small maxillary gap, which related to delayed ossification of the maxilla at 11–13+6 weeks.17,19 So the diagnosis has to be confirmed in the axial or frontal views with direct observation of the facial cleft.
Conditions such as hyper- and hypotelorism, anophthalmia, and microphthalmia have been diagnosed from 12 weeks to 16 weeks by measuring the interocular distance, ocular diameter, and biocular distance. Isolated anomalies are rare, and most of the anomalies are associated with other malformations, especially those of the developing brain (alobar HPE) as well as with aneuploidy (trisomy 13) and nonchromosomal syndromes.
Micrognathia is a rare facial anomaly that is described by a small, underdeveloped mandible. Only the severe ones may be detected in the first-trimester. In the retronasal triangular view, the normal fetus will show an obvious gap between the right and left bodies of the mandible. The absence of the mandibular gap or failure to identify the mandible in the RNT view is highly suggestive of micrognathia.20
Cystic hygroma is a fluid-filled cystic structure located in the soft tissue, commonly the neck, which the prevalence is reported at 1:285 in the first-trimester.21 There is currently a controversy on whether cystic hygroma is an entity that is distinct from an enlarged NT, because septations can be seen in both conditions.22 Given the common association with other fetal malformations and chromosomal abnormalities, a detailed ultrasound evaluation of the fetus is warranted when a cystic hygroma is diagnosed in the first-trimester.23
Malformations of the chest
Malformations of the heart
Congenital heart defect (CHD) account for approximately 25% of all congenital anomalies. The reported incidence of congenital heart disease is two to eight per 1 000 live births. In the first-trimester, with the development of technology, the detection rate of major CHD has been greatly improved. Several indirect sonographic markers were proposed for cardiac screening at 11–13+6 weeks gestation including increased NT, abnormal flow in ductus venosus, tricuspid regurgitation and abnormal cardiac axis, which created a group at increased risk for CHD. The different combination of these indirect markers can allow the detection rate of cardiac anomalies around 50%.24–27 Recently, several studies proposed a new scheme for direct cardiac screening in the first-trimester, which is based on the direct visualization four-chamber view and three-vessel and trachea view using two-dimensional and color Doppler.28,29 The sensitivity was 88.57% with a specificity of 100% for the detection of major CHDs between 11 and 13+6 weeks gestation in a low-risk population. Some experts suggest adding upper abdomen view to this scheme, so that better to rule out most major cardiac malformation.3 Among the high-risk pregnancies, early fetal echocardiography shall be recommended. Early fetal echocardiogram is a highly specialized, targeted cardiac examination performed between 11+0 and 16+0 weeks gestation, which is similar to the approach in later pregnancy.13,30 The detection rate varies according to the type of the cardiac abnormality, for example, from nearly 100% for tricuspid atresia, pulmonary atresia, hypoplastic left heart syndrome to under 20% for tetralogy of Fallot and transportation of great arteries.13
Congenital diaphragmatic hernia (CDH)
It is the only common congenital abnormality of the diaphragm, occurring in approximately 1 of 2 000 to 1 of 4 000 live-born infants. The defect more commonly affects the left hemidiaphragm compared to the right. Failure of the pleuroperitoneal membrane to fuse with the other diaphragmatic components before the intestines return to abdominal cavity results in the intestines passing into the thoracic cavity. The diagnosis of CDH is possible at 12–14 weeks. The association of increased NT at 11–14 weeks and CDH has been reported. And enlarged NT thickness in CDH is associated with a poor outcome, as it's related to an early intrathoracic compression.31 The upturned superior mesenteric artery sign may help to detect first-trimester CHD.32
Malformations of the abdominal wall and gastrointestinal tract
Omphalocele is a median abdominal wall defect through which the bowel and liver or bowel alone have herniated through into a peritoneal sac after 12 weeks of gestation. Most experts agree that the physiological midgut herniation is present between the 6th and 11th weeks of gestation and at crown-rump length of less than 45 mm. However, there is 5% physiological midgut herniation could be observed at 12 weeks by three-dimension ultrasound.33 Previous studies suggested that larger defects or cases with the extracorporeal liver were less likely to be associated with aneuploidy than smaller lesions and cases with intracorporeal liver. In a recent study, the contents and size of the omphalocele showed no significant contribution to the likelihood of aneuploidy.34,35 Spontaneous resolution of the first-trimester omphalocele containing the only bowel was reported. With the lower incidency in other studies, a spontaneous resolution has not been observed in cases with the herniated liver.35,36
A diagnosis of gastroschisis should be considered if a lateral anterior abdominal wall defect without bowel herniation remote from the cord insertion. There are multiple reports in the literature on first-trimester ultrasound diagnosis of this defect. Gastroschisis usually occurs to the right of the umbilicus through which the intestinal organs eviscerate. The anterior abdominal wall can be consistently imaged from 9 weeks. Gastroschisis has been diagnosed as early as the twelfth week. It is the result of a vascular compromise of either the umbilical vein or the omphalomesenteric artery. Recent theories challenge this pathogenesis and propose that gastroschisis results from faulty embryogenesis with failure of incorporation of the yolk sac and vitelline structures into the umbilical stalk, resulting in an abdominal wall defect, through which the midgut egresses into the amniotic cavity. Gastroschisis is more common in pregnant women of young age.30 Unlike omphalocele, gastroschisis has little association with chromosomal abnormalities. Large series of fetal gastroschisis have shown chromosomal aneuploidy and additional unrelated fetal malformations in 1.2% and 12%, respectively.37,38
The body stalk anomaly
The body stalk anomaly is a lethal malformation due to failure of fusion of the lateral folds during the sixth week. The incidence was 0.32 per 10 000 births. In this malformation, the abdominal organs lie outside the cavity. The organs are contained within a sac, which is covered by an amnio peritoneal membrane and is attached directly to the placenta. The umbilical cord in these cases may be totally absent or significantly shortened and severe kyphoscoliosis may be present. This malformation has been reported in the first-trimester. The earliest in utero diagnosis was made at 9 weeks. In a study involving 17 cases of body stalk anomalies diagnosed at a median gestational age of 12+3 weeks, liver and bowel herniation into the coelomic cavity, along with an intact amniotic sac containing the rest of the fetus and normal amount of amniotic fluid, was noted in all fetuses. Additionally, absent or short umbilical cord and severe kyphoscoliosis and positional abnormalities of the lower limbs were common associated findings.39
Malformations of the genitourinary tract
Visualization of the fetal urogenital system in the first-trimester is performed by the identification of the bladder, adrenal, and kidneys. The fetal bladder is seen on ultrasound in about 88% of fetuses at 12 weeks of gestation and in 92% to 100% of fetuses at 13 weeks of gestation. The fetal kidneys have obtained their adult form and position within the renal fossa by approximately the 10th–12th gestational week. The fetal kidneys can first be visualized by transabdominal sonography at 9 weeks, which can be identified in 86%–99% of fetuses at 12 weeks of gestation and in 92%–99% of fetuses at 13 weeks of gestation. The fetal adrenal during the first and early second trimester is relatively large in comparison to the kidneys, but the adrenal-to-kidney length ratio decreases linearly between 12 and 17 weeks.
Megacystis is a condition that the longitudinal length of the normal bladder be more than 7 mm in the first-trimester and is reported in 0.06% of pregnancy. Lower urinary tract obstructions is the main cause, but may more than it only, including complex conditions with poor prognosis such as chromosomal abnormalities or anorectal malformations, as well as merely a sign of isolated urological anomalies with an overall good prognosis.40–42 The cases with bladder diameter between 7 mm and 12 mm often showed spontaneous resolution.40,43
Bilateral renal agenesis (BRA)
BRA is usually diagnosed by ultrasound in the second-trimester: (a) absence of the fetal bladder; (b) bilateral absence of the fetal kidneys; (c) oligohydramnios. It is a rare and lethal malformation, with a prevalence of 1:4 000 to 1:7 000 pregnancy at routine obstetric ultrasound examination.44 The diagnosis has been made in first-trimester, by the identification of an absent kidney. When BRA is suspected in the first-trimester, follow-up ultrasound in the early second trimester is recommended to confirm the diagnosis by the onset of anhydramnios.
Autosomal dominant polycystic kidney disease, autosomal recessive polycystic kidney disease, and multicystic dysplastic kidney
When the enlarged hyperechogenic kidneys are noted in the first-trimester, polycystic kidney disease should be suspected. Though autosomal recessive polycystic kidney disease also has been diagnosed in first-trimester, follow-up examination in the second-trimester is needed to confirm the diagnosis. The presence of normal kidneys in the first- and second-trimester of pregnancy is common even with a family history of autosomal dominant polycystic kidney disease. Since oligohydramnios may not be present before 13 weeks and fetal urinary bladder may or may not be imaged in the first-trimester, nonvisualization of the fetal bladder at 13–16 weeks should trigger a careful evaluation of the fetal kidneys and lower abdominal wall. A follow-up scan after 16 weeks is indicated to rule out any anomalies, especially those involving the kidneys. Multicystic dysplastic kidney has not yet been diagnosed in the first-trimester.
Malformations of the skeleton
The limbs begin to develop toward the end of the sixth week. The upper limbs develop before the lower limbs.45 With the new high-resolution transducers, they can be visualized from 9 weeks onward. The fetal spine is difficult to image before the 11th week of gestation because of a lack of bone ossification. After 12 weeks of pregnancy, the spine is imaged on ultrasound with such details to allow for the diagnosis of major spinal deformities.14 Skeletal dysplasia is found in about 1 per 4 000 births. There is one study demonstrates that the majority of limb abnormalities can be detected in the first-trimester.46 Several case reports have described the prenatal diagnosis of a wide range of skeletal defects in the first-trimester of pregnancy, and they are usually associated with increased NT thickness. However, some limb anomalies, for example, clubfoot, may be transient during the normal development of the lower limbs, and the diagnosis should not be made in the first-trimester of pregnancy.47
The 11–13+6 week scan is effective in identifying a large variety of fetal defects, but there are some important possible disadvantages compared with second-trimester ultrasound examination. First, the small size of anomalies results that a number of major anomalies can be detected through a systematic scan only in experienced hands. Second, the method as the anatomy is at an early stage of development. Undetectable anomalies mostly relate to structures not yet fully developed prior to 14 weeks, for example, cerebellar anomalies and echogenic lung cysts. The third some anomalies, such as aortic and pulmonary stenosis, can progress into more severe malformations with advancing gestation, so may not have been obvious at this period. The last is the detection of defects that may resolve in utero, such as ventricular septal defects.48
An increasing number of congenital anomalies have been diagnosed in the first-trimester. Through the abdominal or vaginal approach, we can now see much more than ever before. Given the present technology, the earliest time to perform a targeted scan for anomalies is 11–13+6 weeks. The reason for not all structures being visible is not the failure of the resolution of the ultrasound, but the fact that several structures are not yet formed and therefore, cannot be seen. This examination; however, could not replace the mid-trimester scan and the 16–20 weeks follow-up examination by conventional second-trimester transabdominal scan should always be performed.
Conflicts of Interest
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