Sonographic findings associated with fetal aneuploidy

INTRODUCTION — Aneuploidy is the most common genetic abnormality detected by prenatal diagnosis [1]. The aneuploidies most frequently detected prenatally involve chromosomes 21, 18, 13, and the sex chromosomes (eg, XXX, XXY, XYY, XO), which accounted for 53, 13, 5, and 12 percent of all chromosome abnormalities in the European Surveillance of Congenital Anomalies database of cases diagnosed prenatally and before one year of age [2]. These aneuploidies are more commonly identified in the first and second trimesters than in live born infants because of an increased risk of spontaneous loss of aneuploid fetuses over the course of pregnancy and termination of some affected pregnancies [3,4].

The antepartum detection of fetal aneuploidy is one of the major goals of prenatal screening programs. Although parental risk factors for genetic disease, results of maternal cell-free DNA or biochemical marker screening, and/or sonographic findings associated with variably increased risks for aneuploidy are all considered in assessing the risk that the fetus is affected by a genetic condition, diagnostic genetic testing (typically amniocentesis or chorionic villus sampling) is required to obtain a definitive genetic diagnosis. Fetal blood or tissue sampling may be required for some conditions. (See "Diagnostic amniocentesis" and "Chorionic villus sampling".)

Sonographic findings associated with fetal aneuploidy will be discussed here. Detailed discussions of first- and second-trimester maternal screening for trisomy 21 and 18, with and without sonography, and genetic evaluation of the anomalous fetus, are reviewed separately.

●(See "Down syndrome: Overview of prenatal screening".)

●(See "First-trimester combined test and integrated tests for screening for Down syndrome and trisomy 18".)

●(See "Prenatal screening for common aneuploidies using cell-free DNA".)

●(See "Prenatal genetic evaluation of the fetus with anomalies or soft markers".)

●(See "Enlarged nuchal translucency and cystic hygroma".)

●(See "Fetal cerebral ventriculomegaly".)

FIRST TRIMESTER

Background — First-trimester measurement of nuchal translucency (NT) has been a mainstay of screening for trisomy 21 since the mid-1990s. Numerous studies have reported that its use as a component of the "combined test" (maternal age, serum total or free beta human chorionic gonadotropin [beta-hCG], serum pregnancy-associated plasma protein A [PAPP-A], and sonographic measurement of NT) detects 82 to 91 percent of cases of trisomy 21 in singleton pregnancies in the first trimester, with a fixed false-positive rate of 5 percent [5,6]. As of 2011, however, the increasing availability of cell-free DNA screening, which detects over 99 percent of fetuses with trisomy 21 and 98 to 99 percent of those with trisomies 18 and 13, with an overall screen-positive rate of 0.13 percent, has led to a decline in the use of the combined test [7]. (See "First-trimester combined test and integrated tests for screening for Down syndrome and trisomy 18" and "Prenatal screening for common aneuploidies using cell-free DNA".)

While offering all pregnant people fetal aneuploidy screening with biomarker assessment with or without measurement of NT or cell-free DNA screening or diagnostic testing is a routine part of prenatal care, identification of some first-trimester ultrasound findings, such as enlarged (also called increased) NT, cystic hygroma, absent nasal bone, megacystis, first-trimester growth delay or structural anomalies, are additional factors for individuals to consider when deciding whether to undergo genetic screening and the choice of screening test or whether to go directly to diagnostic testing.

Nuchal translucency at 11+0 to 13+6 weeks

●Diagnosis – Nuchal translucency (NT) is the clear space at the posterior fetal neck, between the spine and the skin edge (image 1). It is measured sonographically in the fetal midsagittal plane, most commonly when the crown-rump length (CRL) is 45 to 84 mm (approximately 11 to 14 weeks of gestation), but sometimes as early as CRL 38 mm (approximately 10+5 weeks of gestation).

An enlarged NT (image 2) is variably defined as measuring ≥3 or 3.5 mm or ≥95^th or 99^th percentile for gestational age by CRL.

Providers performing NT measurement as part of first-trimester combined risk assessment for common aneuploidies should be appropriately credentialed and quality performance monitored [8-10]. (See "First-trimester combined test and integrated tests for screening for Down syndrome and trisomy 18", section on 'Timing of blood sample and ultrasound' and "Enlarged nuchal translucency and cystic hygroma", section on 'Prenatal diagnosis'.).

●Significance – The risk of fetal aneuploidy and other adverse outcomes (eg, structural abnormalities, particularly congenital heart disease) increases as NT becomes progressively larger [11-13]. If an enlarged NT is identified on ultrasound examination, genetic counseling should be provided to discuss its clinical significance (residual risk of a major autosomal aneuploidy and other abnormalities) and options for further evaluation [6]. Diagnostic genetic testing (via amniocentesis or chorionic villus sampling) and performance of a detailed ultrasound evaluation at 18 to 22 weeks of gestation to assess for structural abnormalities are recommended. If the patient declines diagnostic testing, the option for primary or secondary screening with cell-free DNA can be considered, if not already performed. More detailed information on pathogenesis, fetal evaluation, management, and prognosis are available separately. (See "Enlarged nuchal translucency and cystic hygroma", section on 'Enlarged nuchal translucency'.)

Although a precise measurement of NT is an important component of the combined test, in patients undergoing cell-free DNA screening for trisomy 21, 18, and 13, a precise measurement may not be required if the NT subjectively appears normal [14]. However, evaluation of the nuchal region and NT remain important as enlargement may be associated with clinically relevant atypical chromosomal abnormalities (eg, deletion, duplication, unbalanced structural rearrangement, mosaicism, rare autosomal trisomy), submicroscopic aberrations, single gene disorders (including RASopathies [15-18]), and structural malformations [12,13,19]. (See "Enlarged nuchal translucency and cystic hygroma", section on 'Enlarged nuchal translucency'.)

Disappearance of an enlarged NT prior to 14 weeks gestation occurs in approximately 1 in 5 fetuses and is associated with an improved prognosis compared with those without regression. There is, however, a residual risk of aneuploidy (8 percent for NT >95^th percentile [20]) and adverse outcome (17 percent for NT >95^th percentile [20]).

Early fetal lymphangiectasia (enlarged nuchal region/edema at 9 to 10 weeks)

●Diagnosis – Early lymphangiectasia can be defined as NT >95^th percentile for CRL 28 to 44 mm [21] or >2.2 mm [22] (image 3), but there are limited data to establish these criteria.

●Significance – In contrast to enlarged NT at 11+0 to 13+6 weeks, the significance of lymphangiectasia (fetal edema) or thickened nuchal region at 9 to 10 weeks of gestation (CRL <45 mm) is not clearly established. It has been reported to be a marker for common autosomal trisomies and monosomy X, but the magnitude of risk is unclear [21]. Patients are typically managed by offering cell-free DNA screening. A repeat scan should be performed at 11 to 14 weeks; if NT is enlarged, then diagnostic testing should be offered, as described above. (See 'Nuchal translucency at 11+0 to 13+6 weeks' above and 'Cystic hygroma' below.)

•In one study of 212 fetuses, the identification of a cystic hygroma in fetuses with CRL <45 mm was associated with a 43 percent risk of aneuploidy, which is less than the 73 percent seen in fetuses with CRL 45 to 84 mm [23]. Those with early cystic hygromas were more likely to have a normal outcome (25 percent) compared with the older group (11 percent).

•In a retrospective cohort study of 104 cases of early fetal edema, nuchal edema (>2.2 mm at CRL 28 to 44 mm) was present in 38.5 percent of cases and generalized edema was seen in 61.5 percent of cases [22]. An adverse pregnancy outcome (defined as a significant chromosomal abnormality, major structural defect, or miscarriage without genetic testing) occurred in 24 percent of cases. Overall, significant chromosomal anomalies were identified in 19.2 percent of cases (10 percent with nuchal edema and 25 percent with generalized edema).

In fetuses that reached the 11+0 to 13+6 week scan, the edema resolved (<3.5 mm) in 81.9 percent. Fetuses with NT <3.5 mm had fewer adverse outcomes than those with persistent NT ≥3.5 mm (10.9 versus 76.5 percent) [22].

Cystic hygroma

●Diagnosis – A cystic hygroma is a singular or multi-loculated fluid collection, typically along the posterior fetal neck and back (image 4).

●Significance – The cystic fluid collection is thought to represent abnormal lymphatic development with delayed communication between the lymphatic and vascular system. Communication may subsequently occur, resulting in reversal of this finding [24].

Cystic hygroma is associated with a substantially increased risk of autosomal trisomy (50 to 60 percent), copy number variants, as well as RASopathies (eg, Noonan syndrome) compared with fetuses without an enlarged NT [16,17,25,26]. Fetuses with a large septated cystic hygroma are at higher risk for monosomy X (Turner syndrome; 45,X). In euploid fetuses, 30 to 50 percent have structural anomalies, most commonly cardiac malformations [26,27].

If a cystic hygroma is identified on ultrasound examination, genetic counseling should be provided to discuss its clinical significance (residual risk of a major autosomal aneuploidy and other abnormalities) and options for further evaluation [6]. Diagnostic genetic testing (via amniocentesis or chorionic villus sampling) and performance of a detailed ultrasound evaluation at 18 to 22 weeks of gestation to assess for structural abnormalities are recommended. If the patient declines diagnostic testing, the option for primary or secondary screening with cell-free DNA can be considered, if not already performed. More detailed information on pathogenesis, fetal evaluation, management, and prognosis are available separately. (See "Enlarged nuchal translucency and cystic hygroma", section on 'Cystic hygroma'.)

Jugular lymphatic sacs

●Diagnosis – Fluid collections in the anterolateral aspect of the neck are thought to represent jugular lymphatic sacs (image 5). They are occasionally seen during the evaluation of NT and in the early second trimester.

●Significance – The fluid collections are presumed to be due to delayed communication between the primitive lateral lymphatic cysts and the jugular lymphatic veins and are most commonly seen when NT is enlarged [28-30]. When associated with an enlarged NT, structural anomaly, or nuchal fold, there is a significant risk of genetic abnormality and adverse outcome [16]. Since jugular lymphatic sacs and enlarged NT are part of the same lymphatic process, they have not been added to screening paradigms and we don't really know if there is an increased contribution to risk above the NT or other findings. (See 'Nuchal translucency at 11+0 to 13+6 weeks' above and 'First-trimester structural anomalies' below and 'Thick nuchal fold' below and 'Second-trimester structural anomalies' below.)

If they are small and noted as an isolated finding in a patient with a normal NT, they tend to resolve and outcome is typically favorable [31,32].

First-trimester absent nasal bone

●Diagnosis – When the fetal profile is viewed in the midsagittal plane, the nasal bone appears as an echogenic line within the bridge of the nose, under the skin edge. The nasal bone is considered present if this line is more echogenic than the overlying skin, and absent if it is not visualized, or less echogenic, than the overlying skin (image 6) [33].

●Significance – In one review, the frequency of an absent nasal bone in euploid, trisomy 13, trisomy 18, and trisomy 21 fetuses was 2.5, 45, 53, and 60 percent, respectively [11]. In a euploid fetus, a nonvisualized nasal bone may reflect delayed maturation, rather than true absence of the nasal bone, and is reported in 4.7 percent of euploid fetuses with CRL 45 to 54 mm, progressively decreasing to 1 percent in those with a CRL of 74 to 84 mm.

Megacystis

●Diagnosis – Megacystis (ie, an enlarged fetal bladder) is defined by longitudinal bladder length ≥7 mm at 10 to 14 weeks of gestation (image 7) [34,35].

●Significance – Megacystis occurs in approximately 1 in 1500 pregnancies. It has been associated with chromosomal abnormalities, genetic syndromes, and anomalies of the urinary tract, but also may resolve spontaneously with good outcome.

•In a retrospective cohort study of 98 patients with megacystis, the overall aneuploidy rate was 12 percent; trisomy 18 accounted for 50 percent of cases and trisomies 13 and 21 each accounted for 25 percent of cases [35]. The frequency of aneuploidy was unrelated to the magnitude of bladder distension in this and another study [36], but others have reported an association (approximately 24 percent frequency of aneuploidy at 7 to 15 mm and 11 percent frequency at >15 mm and these cases were associated with an increased risk for obstructive uropathy [34]).

In the subgroup of fetuses with isolated megacystis and NT measurement <95^th percentile, no cases of aneuploidy were identified and 96 percent had resolution of the megacystis [35]. Of the 51 livebirths with resolution of the megacystis, 80 percent had normal outcome, 6 percent had vertebral defects, anal atresia, cardiac defects, tracheo-esophageal fistula, renal anomalies, and limb abnormalities (VACTERL) or imperforate anus/fistula, and 14 percent had other urologic diagnosis. In two patients with persistent megacystis, major urologic conditions were present. There were no cases of lower urinary tract obstruction among fetuses with a bladder length <12 mm.

First-trimester growth restriction

●Diagnosis – If the gestational age has been established by history and an early ultrasound examination, then the diagnosis of growth delay is made when the CRL on a subsequent first-trimester ultrasound examination performed at least one to two weeks later indicates a gestational age that is >5 to 7 days younger than expected by the initial ultrasound examination. Additional information on diagnosis is available separately. (See "Diagnosis and outcome of first-trimester growth delay", section on 'Diagnosis'.)

●Significance — Growth restriction associated with aneuploidy can occur as early as the first trimester. The severity of growth restriction correlates with the severity of the chromosomal abnormality.

•In a study that compared the CRL of 144 aneuploid and 440 euploid fetuses between 9 and 13 weeks of gestation, a shorter than expected CRL (ie, observed/expected CRL ≤0.86) increased the risk of aneuploidy more than twofold (odds ratio [OR] 2.52) [37].

•In other studies, the association between short CRL and aneuploidy was strong for trisomy 18 and 13 and triploidy, but not observed for trisomy 21 [37-39].

Additional information on the causes, evaluation, and outcome of first-trimester growth restriction is available separately. (See "Diagnosis and outcome of first-trimester growth delay", section on 'Possible etiologies' and "Diagnosis and outcome of first-trimester growth delay", section on 'Postdiagnostic evaluation' and "Diagnosis and outcome of first-trimester growth delay", section on 'Pregnancy outcome'.)

First-trimester structural anomalies

●Diagnosis – The expanded use of ultrasound in the latter part of the first-trimester fetus has led to the structured evaluation of fetal anatomic landmarks and subsequent early detection of fetal anomalies. In a systematic review, the overall detection rate for structural abnormalities among fetuses undergoing ultrasonography at 11 to 14 weeks was 51 percent (472 of 957) [40].

Some anomalies, such as holoprosencephaly, abdominal wall defects, and major abnormalities of fetal contour, should be identifiable in most cases. Other abnormalities, including major cardiac malformations (movie 1), facial clefts, and limb anomalies, are potentially identifiable, while still other anomalies, such as microcephaly or agenesis of the corpus callosum, are not seen in the first trimester due to their timing in development [41]. The utilization of a structured protocol will maximize the detection of fetal anomalies [14,42].

●Significance – The finding of a fetal structural anomaly increases the possibility of a chromosomal abnormality or genetic defect. The frequency of a chromosomal abnormality depends on the specific anomaly, the number of anomalies, and the combination of anomalies identified. (See 'Second-trimester structural anomalies' below.)

The identification of a malformation should prompt consultation with a sonologist experienced in first-trimester anatomic imaging and genetic counseling, as well as consideration of diagnostic genetic testing.

Other — First-trimester Doppler markers for aneuploidy screening are not routinely assessed in the United States as they have a limited role given the widespread availability of cell-free DNA screening. Furthermore, the measurements are challenging to obtain, require additional credentialing, and Doppler has the potential to produce biologically significant temperature rises in the first-trimester fetus. (See "Overview of ultrasound examination in obstetrics and gynecology", section on 'Safety'.)

●Abnormal flow in the ductus venosus — Abnormal ductus venosus flow velocities have been observed in both aneuploid and euploid fetuses [43]. In one review, the frequency of reversed a-wave in the ductus venosus by karyotype was: euploid fetuses (3 percent), trisomy 13 (55 percent), trisomy 18 (58 percent), and trisomy 21 (66 percent) [11].

The incorporation of ductus venosus flow into the combined first-trimester risk assessment protocol has been reported to improve screening metrics for trisomy 21 [44,45]. An abnormal flow in the ductus venosus is also associated with major congenital cardiac anomalies, and utilization may enhance early detection [46,47].

●Tricuspid regurgitation — Tricuspid regurgitation may be seen in both aneuploid and euploid fetuses. In one study, the frequency of tricuspid regurgitation at 11 to 13 weeks by karyotype was euploid fetuses (0.9 percent), trisomy 21 (55.7 percent), trisomy 18 (33.3 percent), trisomy 13 (30 percent), and monosomy X (37.5 percent) [48]. As an isolated finding, it is a poor screening tool for aneuploidy and congenital heart defects [49,50].

SECOND TRIMESTER

Background — Soft markers (described below) are sonographic findings that typically reflect normal variation in fetal anatomy but are associated with a small-to-moderate increased risk of aneuploidy. They may be transient, resolving with advancing gestational age or after birth, often with no clinical sequelae.

Historically, ultrasound findings were incorporated into a Bayes theorem to refine the patient's a priori risk for carrying a fetus with trisomy 21 based on maternal age or second-trimester screening results in what was termed a "genetic sonogram" [51-54]. At least one soft marker is identified by ultrasound in approximately 15 percent of second-trimester fetuses, with specific markers carrying different likelihood ratios with respect to trisomy 21 screening (table 1) [51-53,55]. The presence of multiple markers increases the likelihood of trisomy 21 [51-53,55], whereas the absence of markers has been associated with a 50 to 80 percent reduction in the maternal age-related risk, thus providing the parents with information that could be used to make informed choices on whether to pursue diagnostic genetic testing [51-54].

Second-trimester soft markers include:

●Echogenic intracardiac focus (EIF)

●Choroid plexus cysts (CPCs)

●Single umbilical artery (SUA)

●Urinary tract dilation

●Slightly shortened long bones (humerus, femur)

●Hyperechoic bowel

●Thickened nuchal fold

●Absent or hypoplastic nasal bone

Because of the increased risk for fetal aneuploidy (table 1), the identification of a soft marker warrants a detailed sonographic evaluation of fetal anatomy to exclude the presence of additional markers, structural malformations, and growth restriction. The contemporary use of soft markers alone in screening for or excluding aneuploidy is inefficient compared with the first-trimester combined screening test and clinically negligibly contributive with respect to the major autosomal trisomies when cell-free DNA screening results are low risk. Even reporting the presence of some soft markers (EIF, CPCs) is controversial in a low-risk patient because this information is anxiety-provoking, requires considerable clinician time for counseling, and may lead to unwarranted diagnostic genetic testing.

The Society for Maternal-Fetal Medicine (SMFM) does not support diagnostic testing for aneuploidy in a patient solely for the indication of an isolated soft marker in the setting of a low-risk cell-free DNA screen [56,57]. This is because of the high specificity of cell-free DNA screening (near zero residual risk of trisomy 21) and the typically low or moderate increased risk conferred by the presence of an isolated marker (table 1) does not increase the risk estimate of aneuploidy sufficiently to warrant a recommendation for diagnostic testing [57]. However, in the setting of multiple soft markers, genetic counseling by a specialist provider is recommended as the residual risk depends on the specific marker and diagnostic genetic testing, including chromosomal microarray, may be reasonable [57,58]. Some soft markers, as described below, may have clinical implications other than aneuploidy; thus, amniocentesis may be recommended to evaluate for these other clinical conditions.

The genetic evaluation of the fetus with an isolated or multiple soft markers is reviewed separately. (See "Prenatal genetic evaluation of the fetus with anomalies or soft markers", section on 'Approach to the evaluation of the fetus with "soft markers" and no structural anomalies'.)

Soft markers

Echogenic intracardiac focus

●Diagnosis – An echogenic intracardiac focus (EIF) is a punctate echogenic area that is typically seen in the left cardiac ventricle but may be seen in either or both ventricles. To be considered an EIF, it must be as bright as bone and seen in two imaging planes (image 8).

●Significance – EIFs are not associated with myocardial dysfunction or structural cardiac anomalies [59]. An isolated EIF in the setting of an otherwise normal detailed structural survey (table 1) is considered a normal variant in the setting of a low-risk cell-free DNA screen.

The location and number of EIFs do not significantly affect the risk of aneuploidy. In the second trimester, 21 to 28 percent of fetuses with trisomy 21 have an EIF, compared with 3 to 5 percent of euploid fetuses [51]. The incidence varies across races (present in up to 30 percent of fetuses of Asian descent) and decreases with advancing gestational age [60,61]. It is thought to be related to microcalcification and fibrosis of the papillary muscle or chordae. In an autopsy study of abortuses, stillbirths, and perinatal deaths, discrete central papillary muscle calcification was more common in fetuses with trisomy 13 than trisomy 21 (39 and 16 percent, respectively, versus 2 percent of euploid controls) [62].

EIF is different from diffuse, extensive myocardial calcification, which is rare and associated with myocardial dysfunction [63].

For pregnant people with no previous aneuploidy screening and an isolated EIF, the SMFM recommends counseling to estimate the probability of trisomy 21 and a discussion of options for noninvasive aneuploidy screening with cell-free DNA, or quad screen if cell-free DNA is unavailable or cost-prohibitive [57]. For those with negative serum or cell-free DNA screening results and an isolated EIF, they recommend no further evaluation (ie, no indication for fetal echocardiography, follow-up ultrasound imaging, or postnatal evaluation).

Choroid plexus cysts

●Diagnosis – Choroid plexus cysts (CPCs) are typically small (<10 mm in diameter) sonolucent structures with well-delineated borders within the choroid plexus of the cerebral lateral ventricles (image 9). They have a wide range of appearances, from unilateral single simple cysts to septated, bilateral, or multiple cysts.

●Significance – Isolated CPCs in the setting of an otherwise normal detailed obstetrical ultrasound and low-risk aneuploidy screening are considered a normal variant [56]. They are not associated with adverse long-term developmental outcomes [64]. Those that persist beyond the second trimester are typically asymptomatic and benign.

CPCs are thought to result from filling of the neuroepithelial folds with cerebrospinal fluid [65]. The majority of studies suggest that a CPC that is isolated after a detailed anatomic survey (including examination of the face, heart, great vessels, and extremities including open hands) is highly reassuring of a normal karyotype [66,67]. In a meta-analysis, there were no cases of trisomy 18 among 1016 fetuses with isolated CPCs and maternal age less than 35 years [68].

Nonisolated CPCs increase the chances of aneuploidy. CPCs are present in 30 to 50 percent of fetuses with trisomy 18 compared with 0.6 to 3 percent of all second-trimester fetuses [69,70]; the frequency of CPCs is not increased in fetuses with trisomy 21 [71,72]. (See 'Trisomy 18 (Edward syndrome)' below.)

For pregnant people with no previous aneuploidy screening and isolated CPCs, the SMFM recommends counseling to estimate the probability of trisomy 18 and a discussion of options for noninvasive aneuploidy screening with cell-free DNA, or quad screen if cell-free DNA is unavailable or cost-prohibitive [57]. For those with negative serum or cell-free DNA screening results and isolated CPCs, they recommend no further aneuploidy evaluation and no follow-up ultrasound imaging or postnatal evaluation.

Single umbilical artery

●Diagnosis – Prenatal diagnosis of single umbilical artery (SUA) is based on ultrasound examination showing two instead of three vessels in the umbilical cord (cross section or longitudinally) (image 10). Color flow Doppler in the region of the bifurcation of the fetal aorta shows intra-abdominal umbilical vessels on only one side of the fetal bladder, which is pathognomonic of SUA (image 11). (See "Single umbilical artery", section on 'Prenatal diagnosis'.)

●Significance – Aneuploidy is rare in a fetus with an isolated SUA after a detailed anatomic survey, and chromosomal analysis is not typically performed when no other malformations or indications for genetic amniocentesis are present [73]. However, when additional fetal malformations are detected, an association between SUA and risk of aneuploidy (trisomy 18) has been reported. For fetuses with an isolated SUA, the SMFM recommends no additional evaluation for aneuploidy, regardless of whether previous results of aneuploidy screening were low risk or testing was declined [57].

Whether an isolated SUA is associated with other adverse outcomes such as fetal growth restriction (FGR) or stillbirth is unclear; however, given this possibility, a third-trimester scan for fetal growth is suggested and consideration of antenatal testing for fetal well-being [57]. Evaluation, management, and prognosis are discussed in more detail separately. (See "Single umbilical artery", section on 'Postdiagnostic evaluation' and "Single umbilical artery", section on 'Pregnancy management' and "Single umbilical artery", section on 'Pregnancy outcome'.)

Urinary tract dilation

●Diagnosis – Mild (grade 1) antenatal (A) urinary tract dilation (UTD-A1; previously known as mild pyelectasis), is usually defined as a renal pelvic diameter of 4 to <7 mm pelvic dilation at 16 to 27 weeks of gestation (image 12 and figure 1). The maximal anterior-posterior dimension of the intrarenal pelvis should be measured with the fetal spine at 6 or 12 o'clock [74].

●Significance – UTD-A1 is seen in 1 to 2 percent of fetuses overall, but 11 to 17 percent of fetuses with trisomy 21 (image 13) [51,74]. However, the presence of both a detailed anatomic survey and a low-risk cell-free DNA screen for fetal aneuploidy is reassuring. For pregnant people with no previous aneuploidy screening and isolated UTD-A1, the SMFM recommends counseling to estimate the probability of trisomy 21 and a discussion of options for noninvasive aneuploidy screening with cell-free DNA, or quad screen if cell-free DNA is unavailable or cost-prohibitive; diagnostic genetic testing solely for the indication of UTD is not recommended in these cases [57]. For those with a negative serum or cell-free DNA screening results and UTD, they recommend no further aneuploidy evaluation. (See "Prenatal screening for common aneuploidies using cell-free DNA".)

In most fetuses with UTD-A1, the finding is physiologic and transient, resolving over the course of gestation or in the postnatal period. Approximately 12 percent of fetuses with UTD-A1 have a postnatal urologic condition, and therefore follow-up imaging is recommended around 32 weeks gestation; if not resolved, postnatal follow-up is recommended [57,74]. For fetuses with more severe urinary tract dilation (antenatally categorized as UTD-A2 or 3), follow-up imaging and care should be individualized based on sonographic features and clinical circumstance. Prenatal and postnatal management are discussed in detail separately. (See "Fetal hydronephrosis: Etiology and prenatal management".)

Slightly short long bones

●Diagnosis – Various criteria have been published for determining whether a femur or humerus is short with respect to aneuploidy screening [51,54]. The criteria are usually based on observed-to-expected ratios or multiple of the median with respect to biparietal diameter (BPD) [51,54]. We consider an observed-to-expected length ratio <0.9 to be abnormal (the expected length for gestational age is based on the 50^th percentile for long bone length at the BPD-based gestational age) [51,54].

The femur must be measured meticulously with an angle of insonation perpendicular to the bone and the calipers at the end of the diaphysis. It is reported that as many as 13 percent of fetuses with a slightly short femur will have a normal femoral length on follow-up sonography within a short interval of time (false positive) [75].

●Significance – The criteria for slightly short long bones overlap the range observed in unaffected fetuses and vary among different populations. A slightly short femur is detected in approximately 28 percent of fetuses with trisomy 21 and 6 percent euploid fetuses [51]. A shortened humerus is a slightly better predictor of trisomy 21 than a shortened femur (positive likelihood ratio 4.8 and 3.7, respectively) [51]. These two markers often occur in conjunction with each other [51,52].

For pregnant people with no previous aneuploidy screening and isolated shortened humerus, femur, or both, the SMFM recommends counseling to estimate the probability of trisomy 21 and a discussion of options for noninvasive aneuploidy screening with cell-free DNA, or quad screen if cell-free DNA is unavailable or cost-prohibitive [57]. For those with negative serum or cell-free DNA screening results, they recommend no further aneuploidy evaluation but a third-trimester ultrasound examination for reassessment and evaluation of growth.

In contrast, a very short femur (<5^th percentile) or abnormal appearing long bones may be a sign of a skeletal dysplasia, early onset FGR, and presence of pathogenic copy number variants [58,75-77]. (See "Approach to prenatal diagnosis of the lethal (life-limiting) skeletal dysplasias".)

Echogenic bowel (hyperechoic bowel)

●Diagnosis – Fetal hyperechoic bowel refers to increased echogenicity (brightness) of the fetal bowel noted on second-trimester sonographic examination (image 14A-B). To be considered hyperechoic, the bowel must be as bright as bone using a transabdominal transducer with a frequency of ≤5 MHz, with harmonics turned off and lower gain. This is important because higher frequency transducers and harmonics may result in the bowel appearing echogenic when it is not.

●Significance – Hyperechoic bowel is seen in 13 to 21 percent of fetuses with trisomy 21 and 1 to 2 percent of euploid fetuses [51]. In fetuses with hyperechoic bowel, trisomy 21 is the most common aneuploidy identified. Isolated hyperechoic bowel has been reported with sex chromosome aneuploidies, which are potentially detectable with cell-free DNA screening [7]. (See "Prenatal screening for common aneuploidies using cell-free DNA", section on 'Sex chromosome aneuploidies'.)

For pregnant people with no previous aneuploidy screening and isolated echogenic bowel, the SMFM recommends counseling to estimate the probability of trisomy 21 and a discussion of options for noninvasive aneuploidy screening with cell-free DNA, or quad screen if cell-free DNA is unavailable or cost-prohibitive [57]. For those with negative serum or cell-free DNA screening results, they recommend no further aneuploidy evaluation.

Hyperechoic bowel is transient, regressing or disappearing in up to 72 percent of fetuses [78], but it also can be associated with a variety of fetal and pregnancy complications, including cystic fibrosis, congenital infection, intraamniotic bleeding, FGR and gastrointestinal pathology. Clinical evaluation for these entities is discussed separately. (See "Fetal echogenic bowel".)

Because of the association with FGR, follow-up imaging in the third trimester is recommended to assess fetal growth. The appearance of an echogenic loop of large bowel in the third trimester is normal.

Thick nuchal fold

●Diagnosis – The nuchal fold refers to the skin in the back of the fetal neck evaluated in the second trimester. The skin thickness is measured in an axial plane of the fetal head where the cavum septi pellucidum, thalami, cerebral peduncles, and the cerebellar hemispheres are demonstrated (image 15). The measurement is made from the outer edge occipital bone to the skin edge. A nuchal fold is considered thick if the measurement is ≥6 mm.

●Significance – Increased thickness of the nuchal fold is one of the most sensitive markers for trisomy 21 in the second trimester, detected in at least 20 to 50 percent of fetuses with trisomy 21 and 0.5 to 2 percent of euploid fetuses. As an isolated finding, it carries a likelihood ratio for trisomy 21 of between 3 and 11 [51,52,55,79-82]. Although the thickened nuchal fold can revert to normal with advancing gestation, the risk of trisomy remains. (See 'Trisomy 21 (Down syndrome)' below.)

The SMFM recommends that pregnant people with no previous aneuploidy screening and isolated thickened nuchal fold receive counseling to estimate the probability of trisomy 21 and discuss options for noninvasive aneuploidy screening via cell-free DNA or quad screen if cell-free DNA is unavailable or cost-prohibitive, or diagnostic testing via amniocentesis, depending on clinical circumstances and patient preference [57]. For those with negative serum screening results and isolated thickened nuchal fold, they recommend counseling to estimate the probability of trisomy 21 and a discussion of options for no further aneuploidy evaluation, noninvasive aneuploidy screening via cell-free DNA, or diagnostic testing via amniocentesis, depending on clinical circumstances and patient preference. For those with low-risk cell-free DNA screening results and an isolated thickened nuchal fold or absent or hypoplastic nasal bone, they recommend no further aneuploidy evaluation.

A thick nuchal fold has also been observed with sex chromosome anomalies [83].

Second-trimester absent nasal bone

●Diagnosis – Different methods have been proposed for determining a nasal bone to be short or hypoplastic; the most commonly utilized are a nasal bone length of ≤2.5 mm or a gestational age threshold of <2.5^th or 5^th percentile or <0.75 multiples of the median for gestational age (image 16) [84].

●Significance – The reported sensitivity of absent nasal bone for trisomy 21 varies but is generally lower in the second than in the first trimester [85,86]. In the second trimester, the nasal bone is absent in approximately 30 to 40 percent of fetuses with trisomy 21 and 0.3 to 0.7 percent of euploid fetuses [51,87]. It is hypoplastic in approximately 50 to 60 percent of fetuses with trisomy 21 and 6 to 7 percent of euploid fetuses [87].

The finding of an isolated absent or hypoplastic nasal bone carries a likelihood ratio of 6.6 for trisomy 21 (table 1) [51]. For pregnant people with no previous aneuploidy screening and isolated absent or hypoplastic nasal bone, SMFM recommends counseling to estimate the probability of trisomy 21 and a discussion of options for noninvasive aneuploidy screening via cell-free DNA or quad screen if cell-free DNA is unavailable or cost-prohibitive, or diagnostic testing via amniocentesis, depending on clinical circumstances and patient preference [57]. For those with negative serum screening results and isolated absent or hypoplastic nasal bone, they recommend counseling to estimate the probability of trisomy 21 and a discussion of options for no further aneuploidy evaluation, noninvasive aneuploidy screening via cell-free DNA, or diagnostic testing via amniocentesis, depending on clinical circumstances and patient preference. For those with negative cell-free DNA screening results and isolated absent or hypoplastic nasal bone, they recommend no further aneuploidy evaluation.

Other markers

Mild to moderate ventriculomegaly

●Diagnosis – Ventriculomegaly is identified on a transventricular view of the fetal head. The atria is measured at the level of the parieto-occipital sulcus with the calipers on the internal margin of the medial and lateral walls of the ventricle (image 17). Ventriculomegaly is diagnosed when the atrial diameter is ≥10 mm (irrespective of gestational age), which is 2.5 to 4 standard deviations above the mean, depending on the study. It is usually classified as mild: 10 to 12 mm; moderate: 13 to 15 mm; or severe: >15 mm (image 18).

●Significance – The risk of an abnormal outcome in fetuses with mild ventriculomegaly depends on the cause (eg, trisomy 21, infection [eg, cytomegalovirus, toxoplasmosis], idiopathic) and increases with the degree of ventriculomegaly, progression over time, and presence of other anomalies. Mild to moderate ventriculomegaly is detected in 4 to 13 percent of fetuses with trisomy 21 and 0.1 to 0.4 percent of euploid fetuses [51].

The diagnosis, etiology, evaluation, pregnancy management, and prognosis of fetal ventriculomegaly are discussed in detail separately. (See 'Trisomy 21 (Down syndrome)' below and "Fetal cerebral ventriculomegaly".)

Second-trimester structural anomalies

●Diagnosis – Sonographic examination is routinely performed at 18 to 20 weeks of gestation to evaluate the fetus for structural anomalies. (See "Overview of ultrasound examination in obstetrics and gynecology", section on 'Obstetric sonography'.)

●Significance – As in the first trimester, the frequency of chromosomal abnormalities is increased in fetuses with sonographic evidence of structural anomalies. The magnitude of risk for a chromosomal abnormality is highly dependent upon both the specific malformation and the number of malformations. (See 'First-trimester structural anomalies' above.)

In retrospective series of prenatally detected anomalies on second- or third-trimester ultrasound that prompted genetic studies, an isolated fetal anomaly was associated with chromosome abnormalities in 2 to 18 percent of cases; multiple anomalies were associated with a fetal chromosome abnormality in 13 to 35 percent of cases [88-90]. By comparison, approximately 0.5 to 0.7 percent of all live born infants have a karyotypic abnormality [91,92]. Refer to individual topic reviews on specific congenital abnormalities for information on the risk of abnormal karyotype with each abnormality.

A low-risk result on cell-free DNA screening may be falsely reassuring in the setting of a structural anomaly and further diagnostic genetic testing (eg, genetic amniocentesis for microarray on amniocytes) may be indicated [93,94]. (See "Prenatal genetic evaluation of the fetus with anomalies or soft markers".)

Second-trimester growth restriction

●Diagnosis – Sonographic estimation of either fetal weight <10^th percentile for gestational age or abdominal circumference <10^th percentile for gestational age is the best finding on which to base the diagnosis of FGR. (See "Fetal growth restriction: Screening and diagnosis".)

●Significance – Although the most common etiologies for small fetal size are uteroplacental insufficiency and constitutional factors, aneuploidy has been detected in 20 percent of pregnancies referred for further evaluation of a small fetus [95,96]. Most growth-restricted fetuses with chromosomal anomalies have associated findings, however, 2 to 6 percent of fetuses with isolated growth restriction have an abnormal karyotype [97]. Chromosomal microarray increases the detection of chromosomal abnormalities by 4 percent in nonanomalous fetuses and by 10 percent in those with structural abnormalities [98].

The incidence of growth restriction also varies with the type of aneuploidy. Among fetuses with trisomy 21, 13, and 18, growth restriction has been reported in 30, 50, and 90 percent of cases, respectively [99].

The SMFM suggests a detailed obstetrical ultrasound evaluation, genetic counseling, and offering diagnostic testing for patients with unexplained growth restriction before 32 weeks or anytime in gestation when noted in combination with a fetal malformation or polyhydramnios [96].

Other findings

●Although more prevalent in fetuses with trisomy 21 than euploid fetuses, historical markers, such as a sandal gap, short ear length, and a hypoplastic wedge-shaped middle phalanx of the fifth digit that causes it to curve toward the fourth finger (clinodactyly), are common normal variants [100] and are not useful for aneuploidy screening.

●An aberrant right subclavian artery is more common in fetuses with trisomy 21, being seen in 19 to 28 percent compared with 1 percent of euploid fetuses. In fetuses with trisomy 21, it is typically not an isolated finding [101,102]. It is also not usually associated with cardiac anomalies [103].

SONOGRAPHIC FEATURES OF SELECTED ANEUPLOIDIES

Trisomy 21 (Down syndrome) — Trisomy 21 is the most common aneuploidy to result in a live birth, occurring in 1 of 730 live births. (See "Down syndrome: Clinical features and diagnosis" and "Down syndrome: Management".)

Approximately one-third of fetuses with trisomy 21 have one or more sonographically detectable structural malformations (major or minor) in the following systems [104]:

●Cardiovascular, notably endocardial cushion defects and ventricular septal defects (40 to 50 percent)

●Central nervous system (eg, mild ventriculomegaly)

●Gastrointestinal system (eg, duodenal atresia [after 22 weeks] (image 19))

●Craniofacial (eg, cystic hygroma, brachycephaly)

●Hydrops fetalis (image 20)

Historically, identification of affected fetuses was achieved by utilizing Bayes theorem and genetic sonography (see 'Background' above) to modify a patient's a priori risk based on age and/or second-trimester maternal serum screening results. This approach is now obsolete, as it has been replaced by more sensitive and specific screening methods, including first-trimester combined screening and, more recently, cell-free DNA screening. The small-to-moderately increased risk of trisomy 21 conferred by the presence of an isolated soft marker is a negligible contributor to aneuploidy risk assessment after a low-risk cell-free DNA screen [57]. (See "Down syndrome: Overview of prenatal screening".)

Trisomy 18 (Edward syndrome) — Trisomy 18 is the second most common autosomal trisomy detected in the second trimester, occurring in 1 of 5000 live births. (See "Congenital cytogenetic abnormalities", section on 'Trisomy 18 syndrome'.)

Sonographic abnormalities include structural anomalies and markers (image 21):

●Cardiovascular anomalies (complex congenital heart defects, ventriculoseptal defects, and valvular defects)

●Central nervous system anomalies (neural tube defects, abnormal cisterna magna, agenesis of the corpus callosum, cerebellar anomalies, ventriculomegaly)

●Facial anomalies (clefts, micrognathia, low-set ears, microphthalmia)

●Gastrointestinal anomalies (omphalocele, diaphragmatic hernia)

●Urogenital anomalies (horseshoe kidney, hydronephrosis)

●Limb abnormalities (upper limb reduction [eg, radial ray defect]), clenched hands with overlapping index finger, clubbed feet, rocker bottom feet)

●Nuchal fold thickening or cystic hygroma

●Choroid plexus cyst(s) (CPC)

●Strawberry shaped calvarium (pointed front and a flat occiput)

●Single umbilical artery (SUA), umbilical cord cysts

●Fetal growth restriction (FGR)

The frequency of sonographically detected anomalies in fetuses with trisomy 18 varies depending on gestational age, with anomalies detected in 76 percent of those less than 20 weeks and 93 percent at 20 weeks and beyond [105]. Some authorities have opined that by 19 to 20 weeks of gestation, genetic ultrasounds (detailed obstetrical ultrasounds) by experienced imagers should have 100 percent sensitivity (no false negatives) for detecting trisomy 18 [66,106]. (See "Prenatal screening for common aneuploidies using cell-free DNA".)

In the third trimester, fetuses with trisomy 18 may have the unusual combination of polyhydramnios and FGR. In one series, 21 percent of trisomy 18 fetuses had FGR and polyhydramnios [107]. Trisomy 18 is especially likely when both findings are observed and associated with abnormal hand positioning.

Trisomy 13 (Patau syndrome) — Trisomy 13 occurs in 1 of 5000 live births, is the least common of the three major autosomal trisomies, and is associated with more severe and extensive structural malformations than trisomy 21 or 18. (See "Congenital cytogenetic abnormalities", section on 'Trisomy 13 syndrome'.)

Trisomy 13 is sonographically detectable in >95 percent of cases due to the presence of multiple major structural malformations of numerous organ systems, including [108-110]:

●Central nervous system (alobar holoprosencephaly, neural tube defects, posterior fossa abnormalities, agenesis of the corpus callosum, ventriculomegaly)

●Severe midline facial abnormalities (cyclopia, midline facial clefts, anophthalmia, hypoplastic nose)

●Cardiac anomalies (complex congenital heart defects, ventriculoseptal defects)

●Gastrointestinal anomalies (omphalocele, diaphragmatic hernia)

●Renal anomalies (polycystic kidneys, enlarged echogenic kidneys, horseshoe kidneys)

●Skeletal anomalies (postaxial polydactyly, club feet, rocker bottom feet)

Triploidy — Fetuses with triploidy have an extra haploid set of chromosomes (69). It affects 1 to 2 percent of conceptuses, with the majority resulting in first-trimester pregnancy loss. The prevalence decreases with advancing gestational age and is rare in live births. It is not associated with advancing maternal age.

Triploidy is associated with severe fetal anomalies and high mortality [111,112]. Fetal structural anomalies are seen in 84 percent of affected fetuses and are heterogeneous [111,112]:

●Central nervous system anomalies (posterior fossa malformations, holoprosencephaly neural tube defects, ventriculomegaly)

●Facial defects

●Cardiac anomalies (complex congenital heart defects, tetralogy of Fallot, and transposition of great arteries)

●Renal anomalies (agenesis and multicystic kidneys)

●Syndactyly of the third and fourth digits, clenched hands

●Clubbed feet

●Absent gallbladder

●Single umbilical artery (SUA)

Two phenotypic types are identifiable (image 22). When the extra set of chromosomes is maternal (digynic), FGR is associated with a normal size or large head, small trunk and limbs, a small placenta, and oligohydramnios. Abdominal circumference lagged behind head circumference by two weeks in one report of 21 cases between 12 and 16 weeks [113]. The nuchal translucency (NT) in fetuses with digynic triploidy is typically normal.

By comparison, when the extra set of chromosomes is paternal (diandric), FGR is symmetric and moderate and the placenta is usually large, cystic, and hydropic, suggesting a partial mole [113,114]. Fetuses with diandric triploidy may have a thickened NT. The additional paternal haploid complement is associated with maternal complications, including early onset hypertension, theca lutein cysts, hyperemesis gravidarum, and hyperthyroidism [112,115]. (See "Congenital cytogenetic abnormalities", section on 'Triploidy syndrome' and "Gestational trophoblastic disease: Pathology", section on 'Genetics of molar pregnancy'.)

Monosomy X (Turner syndrome) — Monosomy X (45,X) occurs in 1 in 2000 live born females. In contrast to trisomy 21, 18, and 13, which occur as a result of nondisjunction and increase in incidence with increasing maternal age, monosomy X is caused by several different mechanisms and the incidence does not increase with increasing maternal age. Most conceptuses with monosomy X are spontaneously aborted in the first trimester. Those that survive pregnancy most often have either placental or fetal mosaicism of a 45,X and a euploid cell line.

Sonographic findings include [116,117]:

●Large septate cystic hygroma (image 23)

●Thickened nuchal fold

●Hydrops fetalis, total body lymphangiectasia

●Cardiac abnormalities (coarctation of aorta, ventriculoseptal defects, tetralogy of Fallot)

●Short femur

Sixty percent of affected fetuses develop signs of hydrops [118]. Generalized hydrops associated with large septate cystic hygromata has a very poor prognosis, with only 1 percent surviving to infancy [119].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Prenatal screening and diagnosis".)

SUMMARY AND RECOMMENDATIONS

●First trimester

•Background – Although the combined test (first-trimester measurement of nuchal translucency [NT] and assessment of serum analytes [total or free beta human chorionic gonadotropin, pregnancy-associated plasma protein A]) has been a mainstay of first-trimester screening for trisomy 21, cell-free DNA has superior performance metrics for the targeted major aneuploidies and its utilization is increasing dramatically. (See 'Background' above.)

•Sonographic findings associated with aneuploidy – First-trimester sonographic findings associated with, but not diagnostic of, major aneuploidies include NT >3 or 3.5 mm, cystic hygroma, absent nasal bone, megacystis, growth delay, and structural anomalies. (See 'Nuchal translucency at 11+0 to 13+6 weeks' above and 'Cystic hygroma' above and 'First-trimester absent nasal bone' above and 'Megacystis' above and 'First-trimester structural anomalies' above.)

•Approach to pregnancies with sonographic findings associated with aneuploidy – While offering all pregnant people fetal aneuploidy testing (screening or diagnostic) is part of routine care, the identification of ultrasound findings associated with aneuploidy is an additional factor when a patient assesses the options for genetic testing. (See 'Background' above.)

●Second trimester

•Risk of aneuploidy in fetuses with an isolated soft marker (echogenic intracardiac focus [EIF], choroid plexus cyst [CPC], single umbilical artery [SUA], urinary tract dilation [UTD], thickened nuchal fold, or absent/hypoplastic nasal bone) – The presence of one of these isolated soft markers alone is not an indication for diagnostic genetic testing for aneuploidy in patients with a low-risk cell-free DNA screen. (See 'Background' above.)

•Risk of aneuploidy in fetuses with multiple soft markers – In the setting of multiple soft markers and a low-risk cell-free DNA screen, genetic counseling by a specialist provider is recommended as the residual risk will be dependent on the specific markers present. (See 'Background' above.)

•Evaluation of fetuses with urinary tract dilation, echogenic (hyperechoic bowel), slightly short long bones (<5^th percentile), and mild to moderate ventriculomegaly – Fetuses with any of these findings are at increased risk for adverse outcomes in addition to aneuploidy and thus have additional indications for diagnostic genetic testing (karyotype or microarray), other types of testing (eg, cystic fibrosis, infection), and structured follow-up. (See 'Urinary tract dilation' above and 'Echogenic bowel (hyperechoic bowel)' above and 'Slightly short long bones' above and 'Mild to moderate ventriculomegaly' above.)

•Evaluation of fetuses with growth restriction – A detailed obstetrical ultrasound evaluation, genetic counseling, and the offer of diagnostic genetic testing for aneuploidy are indicated for patients with unexplained growth restriction before 32 weeks or anytime in gestation when noted in combination with a fetal malformation or polyhydramnios. (See 'Second-trimester growth restriction' above.)

•Fetuses with sonographic evidence of a structural anomaly – These fetuses are at increased risk of having a genetic abnormality. The magnitude of risk is dependent upon the specific malformation and whether isolated or multiple structural anomalies are identified. The finding of a structural anomaly should prompt genetic counseling and a recommendation for diagnostic testing. Cell-free DNA screening is a less informative option for those declining diagnostic genetic testing. (See 'Second-trimester structural anomalies' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Beryl R Benacerraf, MD (deceased), who contributed to earlier versions of this topic review.