Enlarged nuchal translucency and cystic hygroma

INTRODUCTION — A small, thin hypoechoic space in the posterior fetal neck is a common finding in normal first-trimester fetuses. In some this space is enlarged due to mesenchymal edema (called enlarged or increased nuchal translucency [NT]) (image 1C) or a cystic hygroma. These fetuses are at increased risk for anatomic abnormalities (particularly cardiac anomalies), chromosomal and genetic abnormalities (particularly Down syndrome [trisomy 21]), and other adverse outcomes. The risk of these adverse outcomes increases as the size of the NT increases.

The diagnosis, clinical significance, and management of pregnancies complicated by enlarged NT or cystic hygroma will be discussed here. The use of NT measurement as a component of the first-trimester combined test and the full integrated test for Down syndrome screening has become uncommon because of the increasing use of cell-free DNA (cfDNA) screening for the common aneuploidies. Screening tests to detect Down syndrome and other common aneuploidies are reviewed separately:

●(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".)

ENLARGED NUCHAL TRANSLUCENCY

Terminology/anatomy — The term nuchal translucency (NT) refers to the hypoechoic region between the skin and underlying soft tissues of the posterior cervical spine (image 1A). This hypoechoic space is presumed to represent mesenchymal edema and is often associated with distended jugular lymphatic sacs on each side of the fetal neck [1,2].

A small but measurable amount of nuchal fluid can be identified in virtually all fetuses between the 10^th and 14^th week of gestation, increases with gestational age, and is considered a normal finding if below a defined threshold. Above this threshold, the fetus is considered to have enlarged NT. (See 'Diagnostic criteria' below.)

Pathogenesis — Nuchal edema is a nonspecific finding that may occur before full development of a normal lymphatic system or it may be associated with a variety of disorders (see 'Clinical significance' below). The pathogenesis is probably multifactorial and differs depending on the underlying fetal disorder [3,4]. For example:

●In trisomy 21 the collagen content of the dermis is abnormal; its hydrophilic properties may lead to the accumulation of subcutaneous fluid.

●In Turner syndrome, lymphatic dysplasia may lead to increased nuchal fluid, or narrowing of the aortic isthmus and widening of the ascending aorta may lead to overperfusion of the head and neck, thus contributing to the development of subcutaneous edema.

●In fetuses with a primary abnormality in nuchal lymphatic development, distension of the jugular lymphatic sacs, accumulation of fluid in the nuchal region, and retrograde increases in venous pressure may occur.

●In fetuses with congenital heart disease, pathogenic variants in genes encoding for endothelium and involved in both cardiac and lymphatic development may contribute to increases in nuchal fluid [5-7].

Prenatal diagnosis

Diagnostic criteria — Prenatal diagnosis of enlarged NT is based upon ultrasound measurement of an enlarged nuchal fluid space. The measurement is obtained when the crown-rump length (CRL) is 45 to 84 mm, which corresponds to approximately 11 to 14 weeks of gestation [8]. Although NT can be measured when CRL is <45 mm (most commonly at 39 mm), this is uncommon and the predictive value less certain [9].

The most commonly used thresholds for defining enlarged NT are:

●≥99^th percentile for gestational age as determined by the CRL. Calculators are available that enable clinicians to enter the NT measurement and CRL to obtain the NT percentile (calculator 1).

●Fixed cut-off ≥3.5 mm (which generally reflects an NT above the 99^th percentile at any CRL between approximately 11 and 14 weeks).

●≥95^th for gestational age as determined by the CRL.

●Fixed cut-off ≥3.0 mm (which generally reflects an NT above the 95^th percentile at any CRL between 11 and 14 weeks). This is the threshold used by the author of this topic.

●>1.5 or 1.9 multiples of the median (MoM) for gestational age as determined by the CRL. This generally reflects the ≥95^th and 99^th percentiles, respectively).

These thresholds were chosen because they are associated with an increased risk of adverse pregnancy outcome (see 'Clinical significance' below). The choice is clinically important because the threshold is the trigger for further diagnostic evaluation (see 'Postdiagnostic evaluation' below). There is no consensus about the optimal threshold. The American College of Obstetricians and Gynecologists (ACOG) supports using either of two approaches: NT ≥3.0 mm (which corresponds to ≥95^th percentile between 11 and 14 weeks) or NT >99^th percentile for the CRL (which corresponds to ≥3.5 mm between 11 and 14 weeks) [8]. Using 3.5 mm, the 99^th percentile, or 1.9 MoM minimizes false-positives, while using 3.0 mm, the 95^th percentile, or 1.5 MoM maximizes sensitivity. Using 3.0 or 3.5 mm is convenient because it avoids the need to look up the percentile online each time NT is measured.

Ultrasound technique — The American Institute of Ultrasound in Medicine (AIUM), American College of Radiology, ACOG, Society for Maternal-Fetal Medicine (SMFM), and Society of Radiologists in Ultrasound Practice Parameter for the Performance of Standard Diagnostic Obstetric Ultrasound Examinations state the following [10]:

●The margins of the NT edges should be clear with the angle of insonation perpendicular to the NT line.

●The fetus should be in the midsagittal plane, with visualization of the tip of the nose, palate, and diencephalon.

●The fetal head, neck, and upper thorax should be magnified to fill the image.

●The fetal neck should be in a neutral position (the head in line with the spine, not flexed, and not hyperextended).

●The amnion should be seen as separate from the NT line. Care must be taken to identify the amnion since it may be separate from the chorion until 16 weeks of gestation and thus may be mistakenly identified as the posterior aspect of the fetal skin (image 1A-B).

●The electronic calipers must be placed on the inner borders of the nuchal line with none of the horizontal crossbar itself protruding into the space. The calipers must be placed perpendicular to the long axis of the fetus.

●The (+) calipers on the ultrasound screen should be used to measure NT. The measurement must be obtained at the widest space of the NT.

Pitfalls

●Lack of expertise – Expertise is important because minor changes in technique and caliper placement impact the NT measurement and, in turn, aneuploidy risk prediction when used alone or in serum-screening algorithms. There is a significant learning period for performing accurate NT measurements in the first trimester. In two large multicenter studies of first-trimester Down syndrome screening, accurate NT measurement required stringent training, formalized evaluation of sonographer’s competence, and continuing external quality control [11,12]. In the latter trial [12], adequate NT images could not be obtained in 6 percent of cases.

Measurement errors may be related to misdiagnosis of an amniotic membrane adjacent to and behind the fetal neck (as described above) or chorioamniotic separation.

●Unfavorable fetal position and maternal body habitus can make accurate measurement difficult [13].

●Change in NT measurement – NT measurements vary from week to week, and we have observed that abnormal measurements within the CRL 45 to 84 mm window can quickly revert to normal, even if the fetus is abnormal. Therefore, when an abnormal measurement is obtained, we counsel the patient according to that measurement and do not revise counseling if a subsequent measurement is normal.

Clinical significance — Enlarged NT at 11 to 14 weeks of gestation has been associated with increased risks for genetic and anatomic abnormalities (particularly congenital heart disease), which are, in turn, associated with increased risks for miscarriage, fetal demise, and neonatal death. In monochorionic twins, enlarged NT may be a sign of developing twin-twin transfusion syndrome (TTTS).

In one series of a total of 1063 pregnancies with enlarged NT, 70 percent had a favorable outcome, 20 percent ended in termination of pregnancy, 6 percent resulted in an abnormal live born child, and 4 percent ended in miscarriage or perinatal death [14]. Multiple studies have noted that greater enlargement is associated with a poorer prognosis [15-22]. In the aforementioned series, the frequency of delivery of a normal live born by NT measurement among the 834 euploid fetuses was [14]:

●95^th percentile to 3.4 mm: 92 percent

●3.5 to 4.4 mm: 90 percent

●4.5 to 5.4 percent: 79 percent

●5.5 to 6.4 mm: 45 percent

●≥6.5 mm: 18 percent

Risk for chromosomal and other genetic abnormalities

●Aneuploidy – The overall risk of a chromosomal abnormality with enlarged NT is 33 percent [21], and Down syndrome (trisomy 21) is the most common associated aneuploidy [22-25]. In one type of prenatal aneuploidy screening, the risk of Down syndrome is calculated from an equation that takes into account the NT measurement, maternal biochemical marker levels, maternal age, and gestational age. Trisomy 13 (Patau syndrome), trisomy 18 (Edward syndrome), monosomy X (Turner syndrome), and triploidy also occur with increased frequency among fetuses with enlarged NT and may be suspected from prenatal screening results. (See "First-trimester combined test and integrated tests for screening for Down syndrome and trisomy 18".)

However, when NT is >3.0 mm during screening, diagnostic testing or noninvasive prenatal testing using cell-free DNA (cfDNA) is typically discussed and suggested because the relative risk of aneuploidy rapidly rises with increasing NT at or beyond this threshold.

For example, in a population-based study including nearly 400,000 pregnancies, the prevalence and relative risk of any chromosomal anomaly by NT measurement was [26]:

•<2 mm: 0.6 percent (RR 1.0 reference)

•2.0 to <2.5 mm: 1.1 percent (RR 2)

•2.5 to <3.0 mm: 2.7 percent (RR 6)

•3.0 to <3.5 mm: 10.3 percent (RR 20)

•3.5 to <5.0 mm: 24.0 percent (RR 43)

•5.0 to <6.5 mm: 44.4 percent (RR 81)

•≥6.5 mm: 54.1 percent (RR 102)

These data are for the 90 to 97 percent of pregnancies in which an outcome was available by either prenatal or postnatal genetic testing. Approximately 50 percent of the chromosomal anomalies were potentially identifiable by cell-free DNA screening.

●Other genetic disorders — Over 100 developmental and genetic syndromes have been associated with enlarged NT [16,27]. Some, but not all, of these syndromes are associated with pathogenic copy number variants or anatomic abnormalities that can be detected prenatally and suggest a specific diagnosis [21]. For example, Noonan syndrome, multiple pterygium syndrome, Roberts syndrome, Cornelia de Lange syndrome, congenital adrenal hyperplasia, spinal muscular atrophy, DiGeorge syndrome, Smith-Lemli-Opitz syndrome, and a variety of skeletal dysplasias have been diagnosed after an enlarged NT was detected in utero [28,29].

Risk for congenital anomalies — The overall frequency of anatomic anomalies in euploid fetuses with enlarged NT ranges from 4 to 10 percent [15,30]. The frequency can be much higher in those who also have a chromosomal abnormality and depends on the specific abnormality. Even for those with low-risk NIPT, there remains a risk of structural anomalies, microdeletions, and single gene disorders in pregnancies with an increased NT [31].

Congenital heart disease — The most common anomalies associated with enlarged NT are cardiac, and septal defects are the most common cardiac abnormality. The overall frequency of congenital heart disease increases with increasing NT [32-34]. Depending on the cutoff used (95^th versus 99^th percentile), the overall frequency of a critical cardiac anomaly in a euploid fetus with enlarged NT ranges from approximately 2 to 6 percent, which is severalfold higher than the 0.6 percent baseline risk of moderate and severe forms of congenital heart disease in the general obstetric population [34,35]. Approximately 45 percent of euploid fetuses with congenital heart disease have NT >95^th percentile and 20 percent have NT >99^th percentile [35]. The ≥99^th percentile appears to be more sensitive than an absolute cutoff of ≥3.5 mm [34].

Enlarged NT is an early marker of cardiac anomalies and may be detected before diagnosis of the anomaly. In a series of 211 fetuses with enlarged NT and subsequently diagnosed with a major cardiac anomaly, the cardiac diagnosis was made at the 11- to 13-week scan in approximately 54 percent, at the 18- to 24-week scan in approximately 39 percent, at a third-trimester scan in approximately 5 percent, and postnatally in less than 3 percent [36].  

Noncardiac anomalies — In a population-based study of euploid live born infants without critical congenital heart anomalies, those with NT measurements ≥95^th percentile, ≥99^th percentile, or ≥3.5 mm were at greater risk of having a noncardiac major anatomic anomaly than infants with NT <90^th percentile (relative risk [RR] 1.5, 2.2, and 3.1, respectively) [37]. The risk of the following anomalies was increased approximately threefold in infants with NT measurements ≥95^th percentile compared with those <95^th percentile:

●Hydrocephalus

●Agenesis, hypoplasia, and dysplasia of the lung

●Atresia and stenosis of the small intestine

●Osteodystrophies

●Diaphragm anomalies

Risk for second-trimester miscarriage or fetal demise — In euploid fetuses, the incidence of fetal death increases with increasing NT enlargement. In pooled data from three studies and a total of nearly 5000 euploid fetuses with enlarged NT, miscarriage or fetal death occurred in 1.6 percent of those with NT between the 95^th and 99^th percentiles and in approximately 20 percent with NT ≥6.5 mm [27]. Pregnancy loss and fetal death may be related to fetal anomalies, especially those that cause hydrops.

Additional issues in multiple gestations — Diagnostic criteria for enlarged NT are the same for singletons and fetuses in a multiple gestation. The clinical significance of enlarged NT is also similar (eg, fetal aneuploidy, genetic syndromes, anatomic abnormalities, demise), with the following specific issues:

●Aneuploidy – NT measurement as a marker for aneuploidy is particularly useful in multiple gestations as enlargement can be seen related to a specific fetus, who can undergo diagnostic testing. By comparison, maternal biochemical serum markers and most cfDNA screening tests pool contributions from all fetuses of a multiple gestation, thus requiring diagnostic testing of all of the fetuses.

In dichorionic twins, the trisomy 21 risk is calculated separately for each fetus using its NT measurement. In monochorionic twins, the average of the NT measurements of both fetuses is used to calculate an overall pregnancy risk. (See "Twin pregnancy: Routine prenatal care", section on 'Screening for Down syndrome (trisomy 21)' and "Triplet pregnancy", section on 'Aneuploidy screening and diagnosis'.)

●Twin-twin transfusion – Enlarged NT or >20 percent discordance between NT measurements in monochorionic twins is predictive of twin-twin transfusion syndrome (TTTS) [38]. In one study, discordance >20 percent was associated with a >30 percent risk of early fetal death or development of severe TTTS compared with a <10 percent risk when discordance was <20 percent [39]. (See "Twin-twin transfusion syndrome: Screening, prevalence, pathophysiology, and diagnosis" and "Twin-twin transfusion syndrome: Management and outcome".)

Postdiagnostic evaluation — After a diagnosis of enlarged NT, a typical postdiagnostic evaluation includes:

●Detailed fetal anatomic survey at the time of NT measurement and at 18 to 22 weeks of gestation

●Fetal echocardiography at 18 to 22 weeks of gestation

●Genetic counseling, including options for fetal genetic testing

Detailed fetal anatomic survey — An initial early anatomic survey is performed at the time of NT measurement. Experienced ultrasonographers using high-resolution transvaginal ultrasound can detect many major anomalies in the first trimester [40]. However, the sensitivity for diagnosis of congenital anomalies, especially cardiac anomalies, is higher at 18 to 22 weeks of gestation, so the survey should be repeated at that time. (See "Overview of ultrasound examination in obstetrics and gynecology", section on 'Obstetric sonography'.)

The specific fetal anomaly, particularly when correlated with the patient’s personal and family history, may suggest a specific diagnosis or syndrome.

An enlarged NT in the first trimester may persist into the second trimester (called an increased nuchal fold) and is a strong sonographic marker of aneuploidy [41-47]. If genetic testing was not performed previously, then counseling and testing should be offered again. Likewise, if a fetal anomaly is first detected at the second-trimester anatomic survey and genetic testing was not performed previously, then counseling and testing should be offered again. (See "Prenatal genetic evaluation of the fetus with anomalies or soft markers".)

Clinical setting

Enlarged NT identified before/during aneuploidy screening — In patients who are planning to have a screening test for aneuploidy, it is reasonable to offer a diagnostic genetic test instead of the planned screening test when an enlarged NT is identified before/during screening. These patients are at high risk of aneuploidy and many will be screen positive (ie, have a high-risk result). For example, in a large observational study, 92 percent of patients with NT ≥3.0 mm were screen positive on the combined test and were offered invasive testing [48]. Screening with a cfDNA test of maternal blood has higher sensitivity and specificity than the combined test for the common aneuploidies (trisomy 21, trisomy 18, trisomy 13, and sex chromosome aneuploidies), but will still fail to detect some genetic causes of enlarged NT since it only detects the common aneuploidies. In patients with NT ≥3 mm who choose to undergo cfDNA screening, the residual risk of a significant chromosomal abnormality is 1.0 percent in those who have low-risk cfDNA results [49]. Patients with NT ≥3.5 mm have a higher residual risk, especially at maternal ages under 35 years since the risk for the common aneuploidies is less in younger patients [50]. The abnormalities comprising the residual risk include pathogenic copy number variants (which can be detected by microarray) and RASopathies (eg, Noonan syndrome).

Enlarged NT as an incidental finding after a low-risk cfDNA result — In patients who undergo cfDNA screening for Down syndrome and have a low-risk result, ultrasound examination specifically for NT assessment is not recommended [49]. However, an enlarged NT may be an incidental finding on an ultrasound performed to obtain an early anatomic survey at 12 to 14 weeks of gestation [40]. Such patients should have genetic counseling to discuss prognostic implications and consideration of diagnostic genetic testing and they should undergo fetal echocardiography at 18 to 22 weeks to evaluate for congenital heart disease. (See 'Fetal echocardiography' below.)

Genetic testing (microarray) — We offer microarray genetic analysis rather than a G-banded karyotype to all patients undergoing diagnostic genetic studies for enlarged NT. In a systematic review of pooled data from 17 studies and 1696 pregnancies, the incremental yield of microarray over G-banded karyotyping was 4 percent among fetuses with isolated enlarged NT and 7 percent among those with enlarged NT associated with abnormalities diagnosed by first-trimester ultrasound [51]. The most common pathogenic copy number variants detected by microarray were 22q11.2 deletion, 22q11.2 duplication, 10q26.12q26.3 deletion, and 12q21q22 deletion, and approximately 1 percent were variants of uncertain significance. (See "DiGeorge (22q11.2 deletion) syndrome: Clinical features and diagnosis" and "Microdeletion syndromes (chromosomes 12 to 22)".)

Patients with normal microarray — Exome or whole genome sequencing is an option in cases of euploid fetuses with enlarged NT. The yield is highest in fetuses with multiple anomalies. In nonanomalous fetuses with NT >99^th percentile, a meta-analysis found that exome or whole genome sequencing had a 4 percent incremental diagnostic yield over microarray [52]. Among the 15 fetuses with a syndrome or other disorder identified by sequencing, Noonan syndrome accounted for four cases and was the only syndrome identified in more than one fetus. It is reasonable to offer testing for pathogenic variants associated with Noonan syndrome in cases of euploid fetuses with NT ≥3.0 mm; we suggest testing when NT is ≥5 mm given the strong association between very enlarged NT and RASopathies [53,54]. Noonan syndrome can present with enlarged NT (the only sonographic abnormality in 20 percent of fetuses with RASopathies), cystic hygroma, and/or congenital heart abnormalities. The karyotype is euploid, but the syndrome can be identified by exome or whole genome sequencing of amniocytes or chorionic villi. Many diagnostic laboratories now offer a "Noonan syndrome" or "RASopathy" panel test, which includes many or all of the genes known to be associated with the syndrome. Clinical manifestations, diagnosis, and prognosis of Noonan syndrome are discussed in more detail separately. (See "Noonan syndrome".)

Targeted molecular genetic testing is an option in cases where fetal anatomic abnormalities or personal or family history suggest a specific monogenic disorder. These patients should be referred to a genetic counselor or other individual with relevant expertise as the choice of genomic test and pre- and posttest counseling are complex.

Fetal echocardiography — Fetal echocardiography at 18 to 22 weeks of gestation is appropriate for fetuses with enlarged NT at 11 to 14 weeks. The AIUM Practice Parameter for the Performance of Fetal Echocardiography states fetal echocardiography is indicated when NT is ≥3.5 mm or ≥99^th percentile for gestational age and states it may be considered for NT 3.0 to 3.4 mm [55]. ACOG recommends echocardiography when NT is ≥3.5 mm and states it may be considered for NT 3.0 to 3.4 mm [8].

Specialized centers can perform fetal echocardiography as early as 13 or 14 weeks of gestation with a complete cardiac evaluation possible in over 90 percent of cases [56]. The sensitivity of early fetal echocardiography is over 50 percent in high-risk patients but not sufficiently high to allow omitting the 18- to 22-week evaluation if the early evaluation is normal [33]. The major benefit of early evaluation is early reassurance in at-risk pregnancies. If an early examination is performed, it is particularly important that the duration of interrogation is as short as possible to limit fetal exposure to Doppler. (See "Congenital heart disease: Prenatal screening, diagnosis, and management" and "Overview of ultrasound examination in obstetrics and gynecology", section on 'Safety'.)

Follow-up after diagnostic evaluation

Positive findings on diagnostic evaluation — Counseling and management of these patients is based on the specific findings (genetic abnormality, congenital anomaly). The suspected diagnosis, additional evaluation when appropriate, prognosis, resources, reproductive options, and pregnancy, delivery, and neonatal management should be discussed.

Negative findings on diagnostic evaluation — Enlarged NT commonly resolves spontaneously after 14 weeks in anatomically and chromosomally normal fetuses, and may also resolve in abnormal fetuses [16,18,21,57,58]. Although most fetuses with resolution of nuchal edema will have a normal outcome, there is an increased risk of fetal demise, particularly if the NT is large and/or persists [27]. No studies have specifically addressed the optimal management of these pregnancies. We perform a fetal growth scan early in the third trimester. If growth restriction is diagnosed, then surveillance is according to usual obstetric standards for monitoring these pregnancies (see "Fetal growth restriction: Evaluation" and "Fetal growth restriction: Pregnancy management and outcome"). In the absence of growth restriction, we order antenatal fetal testing (nonstress test or biophysical profile) weekly starting at 36 weeks, although the risk of demise and the benefit of antenatal testing in this setting are unknown.

In children with enlarged NT in utero, normal karyotype, and no anatomic anomalies or other characteristics associated with genetic syndromes, a systematic review including 17 studies found that the prevalence of developmental delay was 28 in 2458 (1.4 percent), which is not higher than the rate in the general population [59]. The pooled rate of developmental delay did not significantly differ according to the cutoff used to define enlarged NT (95^th percentile, 3.0 mm, or 99^th percentile). These and subsequent data from large studies [60,61] are reassuring for patients with fetuses who have no abnormalities after postdiagnostic evaluation. However, there are several limitations to the available data, including lack of a standard definition of developmental delay, often inadequate methods for ascertainment of cases and developmental assessment, and incomplete identification of syndromes. Additional standardized pediatric evaluations and long-term neurodevelopmental follow-up studies are needed to better define these risks.

CYSTIC HYGROMA

Anatomy and pathogenesis — Cystic hygroma is a congenital malformation resulting from lymph accumulation in the jugular lymphatic sacs due to obstruction of the lymphatic system, most commonly in the fetal neck. Cystic hygromas may be septated or simple (nonseptated or biseptate).

Incidence — In the first trimester, the overall incidence of cystic hygroma is approximately 1 in 100 fetuses; the incidence of septated cystic hygroma is approximately 1 in 285 fetuses [28,62].

Prenatal diagnosis — Prenatal diagnosis of cystic hygroma is based on ultrasound examination, typically in the first trimester, showing a single or multilocular fluid-filled structure in the nuchal region or extending along the entire length of the fetus (image 2). When imaged in multiple planes, multiple internal septae or trabeculae may be identified (image 3A-B), and distended jugular lymph sacs may be visualized on either side of the fetal neck (image 4).

Differential diagnosis — Differential diagnosis of the ultrasound findings described above include:

●Enlarged NT – A biseptate nuchal fluid collection could represent either a simple cystic hygroma or enlarged NT with visualization of the midline ligamentum nuchae [63]. Features that suggest a cystic hygroma are large size, extension of the lesion along the entire length of the fetus, and identification of multiple septae. The mean size of first-trimester cystic hygromas has been reported to be 8 mm with some measuring over 30 mm [64]. Enlarged NT (image 1B-C) tends to be smaller than a cystic hygroma (image 3A-B) and more likely to be confined to the nuchal region between the occiput and upper spine [28]. Sonographically, it is not possible to distinguish a completely nonseptate cystic hygroma from enlarged NT and the distinction is clinically unimportant since postdiagnostic evaluation and management are the same. (See 'Prenatal diagnosis' above.)

●Neural tube defect – Both cystic hygromas and neural tube defects protrude from the fetal surface. Cystic hygroma can be distinguished from a neural tube defect, such as a posterior encephalocele or cervical meningocele, by visualizing an intact skull and spine on high-resolution transvaginal ultrasonography. (See "Neural tube defects: Prenatal sonographic diagnosis".)

●Cystic teratoma – A cystic hygroma can be distinguished from a cystic teratoma protruding from the fetal surface by the presence or absence of solid components in the lesion: A cystic hygroma has only cystic components while a cystic teratoma tends to have both cystic and solid components.

●Hemangioma – A cystic hygroma often has internal septae while a hemangioma does not. On color-flow mapping, a hemangioma will have robust vascularity whereas a cystic hygroma has only a limited vascular supply.

Clinical significance — Cystic hygromas are associated with an increased risk for fetal aneuploidy and anatomic abnormalities, both of which increase the risk for miscarriage, hydrops, fetal demise, and neonatal death. Increasing size is associated with an increasing risk of abnormal outcome [22,25,65]. Nuchal septations during first-trimester sonography is a risk factor for chromosomal anomalies, even in the absence of enlarged NT [66].

Aneuploidy — In the first trimester, cystic hygromas are associated with an increased risk for fetal trisomy, especially trisomy 21 [28,64]. In the second trimester, a cystic hygroma may be the clinical presentation of monosomy X [24].

Aneuploidy appears to be more frequent with septated than simple cystic hygromas. In one study, the frequency of aneuploidy with septated and simple cystic hygromas was 57 and 21 percent, respectively [67]. In another study, however, 60 percent of simple cystic hygromas ≥2 mm were associated with an abnormal karyotype, with trisomy 21 occurring in one-fourth of cases [68]. The lack of a standard definition of cystic hygroma and differences in cystic hygroma size among study populations likely contribute to disparities among studies in reported risk for aneuploidy.

Anatomic abnormalities — Approximately one-third of euploid fetuses with first-trimester septated cystic hygromas have major anatomic anomalies, primarily cardiac and skeletal [28,64].

Natural history — In euploid fetuses, over 80 percent of simple cystic hygromas resolve within four weeks of diagnosis, and the vast majority of these neonates are phenotypically normal [68]. Septated cystic hygromas also often resolve between 15 and 30 weeks of gestation.

There may be a link between large cystic hygromas in utero and postnatal webbed neck, which can occur with Turner syndrome. Anecdotally, the author has seen newborns with thickened neck/redundant nuchal folds at birth who had large second-trimester cystic hygroma that resolved before birth.

Postdiagnostic evaluation — Postdiagnostic evaluation is the same as for enlarged NT. (See 'Postdiagnostic evaluation' above.)

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 genetic screening and diagnosis".)

SUMMARY AND RECOMMENDATIONS

●Background – Some nuchal fluid is a normal finding in all first-trimester fetuses (image 1A); however, abnormal accumulations, such as a cystic hygroma or enlarged (increased) nuchal translucency (NT), are associated with an increased risk of chromosomal and anatomic abnormalities. (See 'Terminology/anatomy' above and 'Anatomy and pathogenesis' above.)

●Enlarged nuchal translucency (NT)

•Prenatal diagnosis – Prenatal diagnosis of enlarged NT is based on ultrasound measurement of the nuchal fluid space when the crown-rump length (CRL) is 45 to 84 mm, which corresponds to approximately 11 to 14 weeks of gestation. The most commonly used thresholds for diagnosis are the 95^th and 99^th percentiles for gestational age (NT normally increases with gestational age) (image 1B). Calculators are available that enable clinicians to enter the CRL and NT measurement to obtain the NT percentile (calculator 1). (See 'Prenatal diagnosis' above.)

•Risks/prognosis

-Enlarged NT has been associated with increased risks for aneuploidy (particularly trisomy 21) and anatomic abnormalities (particularly congenital heart disease), which can result in miscarriage, fetal demise, or neonatal death. Enlarged NT may also be associated with developmental and genetic syndromes and, in twins, twin-twin transfusion syndrome (TTTS). Increasing NT is associated with an increasingly worse prognosis. (See 'Clinical significance' above.)

-In normal fetuses, enlarged NT commonly resolves spontaneously by the second trimester. A large or persistent nuchal fluid accumulation appears to be a poor prognostic factor, even in euploid nonanomalous fetuses. (See 'Negative findings on diagnostic evaluation' above.)

-Some studies have reported an increased prevalence (up to 8.7 percent) of neurodevelopmental delay in children with a fetal history of enlarged NT; however, others have found no excess risk of developmental delay in children with normal karyotype and no congenital anomalies in those in whom increased first-trimester NT resolved. (See 'Risk for chromosomal and other genetic abnormalities' above.)

•Postdiagnostic evaluation – After a prenatal diagnosis of enlarged NT, postdiagnostic evaluation includes:

-Genetic counseling, including options for fetal genetic testing (see 'Clinical setting' above). Noonan syndrome or an associated RASopathy can present with enlarged NT (typically ≥3 mm), cystic hygroma, and/or congenital heart defects and a euploid karyotype. Targeted molecular genetic testing or exome sequencing of amniocytes or chorionic villi can establish the diagnosis. (See 'Patients with normal microarray' above.)

-Fetal anatomic survey at the time of NT measurement and at 18 to 22 weeks of gestation. (See 'Detailed fetal anatomic survey' above.)

-Fetal echocardiography at 18 to 22 weeks of gestation. (See 'Fetal echocardiography' above.)

-Periodic assessment of fetal well-being. (See 'Follow-up after diagnostic evaluation' above.)

●Cystic hygroma

•Prenatal diagnosis – Prenatal diagnosis of cystic hygroma is based on ultrasound examination, typically in the first trimester, showing a single or multilocular fluid-filled structure in the nuchal region or extending along the entire length of the fetus (image 2). When imaged in multiple planes, multiple internal septae or trabeculae may be identified (image 3A-B) and distended jugular lymph sacs may be visualized on either side of the fetal neck (image 4). (See 'Prenatal diagnosis' above.)

•Risks/prognosis – Cystic hygromas are associated with an increased risk for fetal aneuploidy (particularly trisomy 21) and anatomic abnormalities (particularly congenital heart defects), both of which increase the risk for miscarriage, hydrops, fetal demise, and neonatal death. Increasing size is associated with an increasing risk of abnormal outcome. In general, the risk of aneuploidy and congenital anomalies is higher with cystic hygromas than enlarged NT (table 1). (See 'Clinical significance' above.)

•Postdiagnostic evaluation – Fetal genetic analysis should be offered to any patient with a first-trimester cystic hygroma or significantly enlarged NT, given the relatively high risk of aneuploidy. (See 'Clinical setting' above.)

Postdiagnostic evaluation of cystic hygroma is the same as for enlarged NT. (See 'Postdiagnostic evaluation' above.)