The use of ultrasound in the prenatal diagnosis of fetal genetic syndromes is rapidly evolving. Advancing technology and new research findings are aiding in the increased accuracy of ultrasound-based diagnosis in combination with other methods of non-invasive and invasive fetal testing. Ultrasound as a screening tool for aneuploidy and other anomalies is increasingly being used throughout pregnancy, beginning in the first trimester. Given the number of recorded syndromes, it is important to identify patterns and establish a strategy for identifying abnormalities on ultrasound. These syndromes encompass a wide range of causes from viral, substance-linked, chromosomal, and other genetic syndromes. Despite the ability of those experienced in ultrasound, it is important to note that not all fetal genetic syndromes can be identified prenatally, and even common syndromes often have no associated ultrasound findings. Here, we review the role of ultrasound in the diagnosis of fetal genetic syndromes.
Advancing technology
Two-dimensional ultrasonography has long been the modality of choice for diagnosis of fetal anomalies. However, the limitations of two-dimensional ultrasonography include the inability to store volume images for future manipulation, non-intuitive interpretation of the images for patients, and inability to simultaneously view images in a multiplanar view. Increasingly, because of the limitations of two-dimensional ultrasound, three dimensional and four-dimensional ultrasonography are being used to aid in diagnosing and visualising suspected fetal anomalies. Previous studies that have compared two-, three- and four-dimensional imaging to determine which has the best diagnostic ability or results in the best clinical outcomes in fetuses with anomalies have found some conflicting results. One study aimed to determine whether two-dimensional ultrasonography adds diagnostic information over three-dimensional and four-dimensional images. This study, which included 54 normal fetuses and 45 fetuses with anomalies, reported 90.4% agreement between two-, three-, and four-dimensional images. Six anomalies were missed by three- and four-dimensional imaging but observed by two-dimensional ultrasonography; however, the investigators concluded that the sensitivity and specificity of the imaging modalities were not significantly different . Another study by Dyson et al. comparing the results of two-dimensional with three-dimensional imaging found that three-dimensional ultrasonography offered additional information in 51% of cases, was equivalent in 45%, and was disadvantageous in 4%. Additional information obtained in three-dimensional imaging influenced clinical management in 5% of patients . Merz and Welter studied two-dimensional and three-dimensional ultrasound in 3472 high-risk pregnancies and discovered 1012 anomalies, excluding cardiac defects. They found that 4.2% of the malformations were correctly identified on three-dimensional ultrasound only. Although all these studies showed a benefit or at least equivalence of the imaging modalities, Scharf et al. concluded that three-dimensional visualisation was not superior to standard two-dimensional imaging, and should be restricted to specific malformations. Currently, three- and four-dimensional ultrasonography can be considered an adjunct to two-dimensional sonography, and can aid in the diagnosis of many fetal anomalies, especially those related to facial abnormalities ( Figs. 1 and 2 ), neural tube defects, and skeletal anomalies .
The use of three-dimensional ultrasound in the diagnosis of fetal oro-facial clefts when suspected on two-dimensional ultrasound greatly improves the sensitivity and specificity. In a recent systematic review, Maarse et al. found that use of three-dimensional ultrasound in women at high risk of fetal oro-facial clefts improves diagnostic accuracy. The detection rate of three-dimensional ultrasound was 100% in fetuses with cleft lip and 86–90% in fetuses with cleft lip and palate . Baumler et al. found that three-dimensional ultrasound of the fetal palate has a high accuracy in the diagnosis of cleft palate when cleft lip is identified on two-dimensional screening ultrasound .
The use of three-dimensional ultrasound in the diagnosis of neural tube defects has been advocated by the American Institute of Ultrasound in Medicine to define the upper level of the lesion . With three-dimensional ultrasound, through the use of multiple views, accuracy within one vertebral body can be achieved in 80% of cases .
For the diagnosis of skeletal dysplasias, in which a precise diagnosis can significantly affect postnatal prognosis, three-dimensional ultrasound has been found to have an improved diagnostic accuracy. In a study by Ruano et al. three-dimensional ultrasound correctly identified 77.1% of cases compared with 51.4% with two-dimensional ultrasound. Additionally, three-dimensional ultrasound can improve patient understanding of the skeletal dysplasia and aid clinicians in counselling .
Timing of ultrasound in diagnosis of fetal genetic syndromes
Ultrasound can be used throughout pregnancy to detect fetal abnormalities. First-trimester ultrasound is increasingly being used for nuchal translucency tests and also for an early limited anatomic survey. Ultrasound in the first trimester has been shown to be effective in screening for aneuploid conditions, such as trisomy 21 . The nuchal translucency measurement in the first trimester, with a cut-off of 3 mm or greater, has been shown to have a high sensitivity and specificity for identifying pregnancies at risk for chromosomal anomalies . In addition, early anatomic surveys have been shown to have good detection rates of most structures when carried out by an experienced sonographer . Picklesimer et al. , in a retrospective cohort study of aneuploid fetuses, investigated the effect of gestational age at time of ultrasound on the detection of sonographic markers of aneuploidy. The fetal ultrasounds in this study were carried out between 14 and 32 weeks’ gestation, and the investigators showed that sonographic markers of aneuploidy were present at all gestational ages. In the earlier gestational ages, a shift was observed from detection of soft markers, non-structural abnormalities, to detection of major anomalies at later gestational ages .
It is advised that all pregnant women undergo a fetal anatomic survey in the second trimester. Fetal anatomy is assessed systematically through ultrasound after about 18 weeks. Specifics of standard fetal anatomic evaluations are detailed in the American Institute of Ultrasound in Medicine practice guidelines . It is important to use a methodical routine in the execution and evaluation of the anatomic survey to assure complete assessment of fetal anatomy. The first trimester ultrasound largely focuses on nuchal translucency measurement in the assessment of chromosomal syndrome risk; however, the second trimester ultrasound can identify much more specific defects that follow a different pattern for each genetic syndrome. Importantly, some fetal anatomy is more easily visualised later in the second trimester. A prospective randomised study by Schwärzler et al. evaluated three different groups of fetuses distinguished by gestational age at time of anatomic survey for the outcome of need for additional ultrasound to complete the evaluation. The investigators concluded that fetuses that underwent an anatomic survey at 20–22 6/7 weeks are less likely to need repeat examination than women who have an ultrasound 18–18 6/7 weeks’ gestation.
Third-trimester ultrasound can also be used as an adjunct to second-trimester anatomic survey to follow the evolution of identified fetal abnormalities. Third-trimester ultrasound as a screening tool for fetal genetic syndromes, however, has limited utility. In 2008, it was concluded in a Cochrane review that routine use of third-trimester ultrasound screening in an unselected population of women does not confer benefit.
Timing of ultrasound in diagnosis of fetal genetic syndromes
Ultrasound can be used throughout pregnancy to detect fetal abnormalities. First-trimester ultrasound is increasingly being used for nuchal translucency tests and also for an early limited anatomic survey. Ultrasound in the first trimester has been shown to be effective in screening for aneuploid conditions, such as trisomy 21 . The nuchal translucency measurement in the first trimester, with a cut-off of 3 mm or greater, has been shown to have a high sensitivity and specificity for identifying pregnancies at risk for chromosomal anomalies . In addition, early anatomic surveys have been shown to have good detection rates of most structures when carried out by an experienced sonographer . Picklesimer et al. , in a retrospective cohort study of aneuploid fetuses, investigated the effect of gestational age at time of ultrasound on the detection of sonographic markers of aneuploidy. The fetal ultrasounds in this study were carried out between 14 and 32 weeks’ gestation, and the investigators showed that sonographic markers of aneuploidy were present at all gestational ages. In the earlier gestational ages, a shift was observed from detection of soft markers, non-structural abnormalities, to detection of major anomalies at later gestational ages .
It is advised that all pregnant women undergo a fetal anatomic survey in the second trimester. Fetal anatomy is assessed systematically through ultrasound after about 18 weeks. Specifics of standard fetal anatomic evaluations are detailed in the American Institute of Ultrasound in Medicine practice guidelines . It is important to use a methodical routine in the execution and evaluation of the anatomic survey to assure complete assessment of fetal anatomy. The first trimester ultrasound largely focuses on nuchal translucency measurement in the assessment of chromosomal syndrome risk; however, the second trimester ultrasound can identify much more specific defects that follow a different pattern for each genetic syndrome. Importantly, some fetal anatomy is more easily visualised later in the second trimester. A prospective randomised study by Schwärzler et al. evaluated three different groups of fetuses distinguished by gestational age at time of anatomic survey for the outcome of need for additional ultrasound to complete the evaluation. The investigators concluded that fetuses that underwent an anatomic survey at 20–22 6/7 weeks are less likely to need repeat examination than women who have an ultrasound 18–18 6/7 weeks’ gestation.
Third-trimester ultrasound can also be used as an adjunct to second-trimester anatomic survey to follow the evolution of identified fetal abnormalities. Third-trimester ultrasound as a screening tool for fetal genetic syndromes, however, has limited utility. In 2008, it was concluded in a Cochrane review that routine use of third-trimester ultrasound screening in an unselected population of women does not confer benefit.
Infectious syndromes: ultrasound findings
Antepartum ultrasound can aid in the diagnosis of several intrauterine congenital infections. These infectious syndromes all have the potential to cause devastating in-utero and postnatal consequences, and even demise. Fortunately, the infectious syndromes rarely occur in developed nations. If identified prenatally, many of the infections can be treated. Therefore, it is important to understand the applications and limitations of ultrasound in the diagnosis of infectious syndromes. Additionally, it is important to note that infants with symptomatic congenital infections at birth do not always have abnormalities on prenatal ultrasound. The incidence and ultrasound findings most often associated with individual infectious syndromes are listed in Table 1 . Although ultrasound can be a clue in the diagnosis of infectious syndromes, the findings are not diagnostic, and definitive diagnosis should be determined by other means.
| Infection | Incidence of acute maternal infection | Most common ultrasound findings |
|---|---|---|
| Cytomegalovirus | 0.2–2.2% | Neurological intracranial calcifications periventricular echogenicities Gastrointestinal echogenic bowel hepatosplenomegaly Cardiac cardiomegaly Other intrauterine growth restriction placentomegaly ( Fig. 3 ) hydrops . |
| Parvovirus | 1–4% | Hydrops, elevated middle cerebral artery dopplers |
| Toxoplasmosis | 0.2–1% | Neurological ventriculomegaly intracranial calcifications periventricular calcifications microcephaly Gastrointestinal hepatomegaly Cardiac myocardial calcifications Other hydrops placentomegaly |
| Varicella | 0.01–0.4% | Neurological microcephaly ventriculomegaly or atrophy microcalcifications micropthalmia Gastrointestinal echogenic bowel hepatic calcifications Musculoskeletal Clubfeet abnormal position of hands limb hypoplasia flexed limbs Other intrauterine growth restriction hydrops |
| Syphilis | 0.4-1.3% | Gastrointestinal Hepatosplenomegaly Other Placentomegaly Hydrops |
Chromosomal syndromes
Invasive testing is the gold standard for prenatal diagnosis of chromosomal syndromes. Although the risks of invasive genetic testing are relatively low, chorionic villus sampling and amniocentesis both increase the risks of pregnancy loss, preterm labour, and premature rupture of membranes, among other risks . Therefore, genetic screening tests have been developed and implemented in the general obstetric population to stratify women by risk category. The available genetic screening tests include first-trimester serum and nuchal translucency, second-trimester serum screening, and maternal plasma cell-free fetal DNA testing. The sensitivities and specificities of these screening tests vary. Often, patients use the addition of ultrasound markers of aneuploidy to determine whether they desire invasive diagnostic testing. Although a normal second-trimester anatomic survey does not eliminate possibility of aneuploidy, the absence of any marker can convey a significant risk reduction . Ultrasound can be used to identify structural anomalies, and also to detect soft markers of aneuploidy. The use of soft markers alone in the decision to pursue diagnostic testing in otherwise low-risk women can lead to unnecessary invasive procedures. On the other hand, a normal anatomic survey can give false reassurance to patients at high risk of aneuploidy . Therefore, although we must acknowledge that aneuploidy can be present with a normal sonographic exam, ultrasound performs an important role in the diagnosis of fetal chromosomal syndromes . Among the most common chromosomal syndromes that are identified through screening in pregnancy are trisomy 21, trisomy 18, and trisomy 13. The associated ultrasound findings that have been found are included in Table 2 . Many of the chromosomal syndromes have similar sonographic findings, and definitive diagnosis cannot be determined on the basis of ultrasound alone.
| Organ system | Trisomy 21 (Down syndrome) | Trisomy 18 (Edwards syndrome) | Trisomy 13 (Patau syndrome) |
|---|---|---|---|
| Cardiac | Echogenic intra-cardiac focus ( Fig. 4 ); atrial-ventricular canal defect; atrial septal defect; ventricular septal defect; and other cardiac defects | Ventricular septal defect; atrial-ventricular canal canal defect; hypoplastic left heart syndrome; other cardiac defects . | Ventricular septal defect; hypoplastic left heart syndrome; double outlet right ventricle; and other cardiac defects . |
| Neurological | Choroid plexus cyst; and ventriculomegaly | Ventriculomegaly, choroid plexus cyst; Dandy–Walker malformation; and neural tube defects | Microcephaly, Holoprosencephaly . |
| Gastrointestinal | Hyperechoic bowel; duodenal atresia; oesophageal atresia | Omphalocele, diaphragmatic hernia; tracheoesophageal fistula; duodenal atresia; and hyperechoic bowel . | Omphalocele . |
| GU | Pyelectasis ( Fig. 5 ) . | Pyelectasis . | Hyperechoic kidneys, polycystic kidneys . |
| Facial | Absent or hypoplastic nasal bone | Micrognathia, cleft lip/palate | Cleft lip/palate |
| Musculoskeletal | Short humerus, short femur, clinodactyly | Clenched hands, overlapping digits, radial dysplasia, foot abnormalities | Post-axial polydactyly |
| Other | Thickened nuchal fold; and intrauterine growth restriction . | Thickened nuchal fold; single umbilical artery; and intrauterine growth restriction . | Thickened nuchal fold; and intrauterine growth restriction . |
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