During the second and third trimesters of pregnancy, abnormal accumulation of fluid behind the fetal neck can be classified as nuchal cystic hygroma or nuchal edema.1–4 In the case of cystic hygromas, prenatal diagnosis by ultrasonography is based on the demonstration of a bilateral, septated, cystic structure, located in the occipitocervical region.1,2 They are thought to represent overdistention of the jugular lymphatic sacs as a consequence of failure of communication with the internal jugular vein.5 Secondary dilatation of the lymphatic channels draining the chest and limbs results in peripheral lymphedema and development of nonimmune hydrops, which is found in about 75% of affected fetuses.2 In about 75% of fetuses with cystic hygromas, there is a chromosomal abnormality, and in about 95% of cases, the abnormality is Turner syndrome.2 In the chromosomally normal fetuses, there is a high association with cardiac defects and genetic syndromes, such as multiple pterygium syndrome.2 The overall prognosis in fetuses with cystic hygromas is poor, and the survival rate is less than 5%.2 Nuchal edema is considered present if, in the midsagittal plane of the neck, there is subcutaneous edema that produces a characteristic tremor on ballotment of the fetal head.4 This constitutes the severe end of the spectrum of increased nuchal fold thickness, which is defined as soft-tissue thickening of 6 mm or more, seen in the suboccipitobregmatic view of the fetal head.3 Nuchal edema may be confined to the neck or it may be generalized, as part of hydrops fetalis. Chromosomal abnormalities are found in about one third of the fetuses, and in about 80% of these, the abnormality is trisomy 21, 18, or 13.4 Edema is also associated with fetal cardiovascular and pulmonary defects, skeletal dysplasias, congenital infection, and metabolic and hematological disorders; consequently, the prognosis for chromosomally normal fetuses with nuchal edema is poor.4
In the late 1980s and early 1990s, with the introduction of first trimester screening, several terms were used to describe the abnormal accumulation of fluid behind the fetal neck, including cystic hygroma and nuchal edema with or without internal septations. However, in the published reports on first-trimester cystic hygroma, the pattern of associated chromosomal defects, both trisomies and Turners syndrome, was suggestive that the term did not have the same pathophysiological significance as second-trimester cystic hygroma (Table 1).6–15 Furthermore, there was a wide range in the incidence of chromosomal defects from 28% to 100%.
In 1992, we introduced the term nuchal translucency (NT) thickness to standardize the technique of measuring the fluid, irrespective of whether it is septated and whether it is confined to the neck or envelopes the whole fetus.16 The rationale was that it is possible to standardize and audit the results of a measurement but not those of a subjective appearance. The NT thickness is usually measured with the fetus in the midsagittal position, in which case the appearance of the fluid is homogeneously translucent. Furthermore, increased NT is associated with trisomy 21, Turner syndrome, and other chromosomal abnormalities, as well as many fetal malformations and genetic syndromes,17,18 and the incidence of these abnormalities is related to the thickness rather than the appearance of NT.19–21
Recently, the term cystic hygroma has been reintroduced, to apparently describe a distinct entity from NT. Cystic hygroma was defined as an enlarged sonolucency with clearly visible septations extending along the fetal body axis, in contrast to NT, which was described as a nonseptated sonolucent area confined to the fetal neck.22
The aims of this study are, first, to estimate the incidence of septations in fetuses with increased NT thickness, and second, to investigate the relationship between the length and thickness of the translucency and whether the length and septations provide useful information concerning the fetal karyotype in addition to that provided by the NT thickness alone.
PATIENTS AND METHODS
In the Fetal Medicine Centre, first-trimester screening for chromosomal defects, since 1999, is performed considering a combination of maternal age, fetal NT thickness, and maternal serum-free ß-hCG and pregnancy associated plasma protein A (PAPP-A) at 110/7 to 136/7 weeks of gestation.23 Patient-specific risks are calculated by a multivariable approach in which the maternal age-related risk is multiplied with each likelihood ratio derived from the fetal NT and maternal weight-adjusted serum-free β-hCG and PAPP-A. The parents are counseled regarding the estimated risk for trisomy 21, and if they consider this risk to be high, they have an invasive diagnostic test—chorionic villus sampling or amniocentesis.
A screening study involving 96,127 pregnancies, established that the 95th percentile of vertical thickness of NT, measured in the midsagittal section of the fetus, increased linearly with fetal crown-rump length (CRL) from 2.1 mm at a CRL of 45 mm to 2.7 mm for CRL of 84 mm.19
In this study, which was performed between January 2003 and June 2005, in the cases undergoing chorionic villous sampling and in which the fetal NT thickness was equal to or above the 95th percentile for CRL, in addition to the measurement of the fetal NT thickness and CRL, we also measured NT length (Fig. 1). This was defined as the longitudinal distance between the occiput and the lower end of the sonolucency toward the fetal sacrum (NT length) and expressed as a percentage of the length between the occiput and the sacral tip (spinal length). A transverse suboccipitobregmatic section of the fetal head was also obtained to determine whether or not the sonolucency was septated.
Approval for the study was obtained from King's College Hospital Research Ethics Committee.
Regression analysis was used to examine the significance of the association between NT thickness and percentage of NT length to spinal length. The prevalence and distribution of chromosomal defects were estimated for each NT category: between the 95th percentile for CRL and 3.4 mm, 3.5–4.4 mm, 4.5–5.4 mm, 5.5–6.4 mm, and 6.5 mm or more. The patients were subdivided into those with abnormal and normal karyotype, and logistic regression analysis was used to investigate the effect on abnormal karyotype of gestational age in days, fetal CRL in millimeters, fetal NT in millimeters, NT length to spinal length as a percentage, and presence or absence of septations. Multiple logistic regression analysis was subsequently performed to determine the significant independent contribution of those variables yielding a P < .05 in the univariable analysis.
Fetal karyotyping was carried in 386 singleton pregnancies with increased NT thickness. The median maternal age was 36 (range 22–46) years and the median fetal CRL was 65 (range 45–84) mm. A transverse suboccipitobregmatic plane of the fetal head was successfully imaged in 378 (97.9%) fetuses, and septations within the translucency were observed in all cases (Fig. 2).
The NT length and spinal length were measured in all 386 fetuses. There was a significant association between NT thickness and percentage of NT length to spinal length (r = 0.791, P < .001; Fig. 3). In all fetuses with NT thickness of 6 mm or more, the percentage of NT length to spinal length was 80% or more, except in two of the fetuses with Turner syndrome, in which the increased NT thickness was confined to the neck and thorax (Fig. 4).
The fetal karyotype was abnormal in 83 (21.5%, 95% confidence interval 17.4–25.6%) pregnancies, including 52 cases of trisomy 21 (Table 2). Univariable regression analysis demonstrated that significant predictors of abnormal karyotype were gestational age, fetal CRL, fetal NT, and NT length to spinal length, but multiple regression showed that the only significant independent predictor was fetal NT (Table 3).
The findings of this study confirm that, first, there is a high association between increased NT and trisomy 21 as well as other chromosomal defects, and second, the incidence of chromosomal defects increases with NT thickness.16,19–21 In a previous, more extended study of 11,315 pregnancies with increased NT, the fetal karyotype was abnormal in 2,168 (19.2%), and the incidence of chromosomal defects increased with NT thickness from about 7% for those with NT between the 95th percentile for CRL and 3.4 mm to 20% for NT of 3.5–4.4 mm, 50% for NT of 4.5–6.4 mm, and 75% for NT of 6.5 mm or more.21 Furthermore, the distribution of NT was different for each type of chromosomal defect; in the majority of fetuses with trisomy 21 the NT thickness was below 4.5 mm, whereas in the majority of fetuses with trisomies 13 or 18 it was 4.5–8.4 mm, and in those with Turner syndrome it was 8.5 mm or more.
The data demonstrate that septations within the translucency can be seen in all fetuses with increased NT, provided the fetal neck is examined in the transverse suboccipitobregmatic plane. The ability to observe such septations is simply dependent on, first, obtaining the correct transverse plane of the fetal head and neck with the septations being parallel to the transducer, and second, on the use of the appropriate gain on the settings of the machine.
The data also demonstrate that the length of extension of NT from the cervical toward the sacral region is related to the thickness of NT. This is not surprising and it is comparable to ankle edema in postnatal life, which like increased NT, has a multifactorial etiology; the more the edema, the higher up the legs it can be demonstrated. The study has also shown that, whatever association there is between the length of NT and abnormal fetal karyotype, this association is a mere consequence of the fact that a higher NT thickness corresponds to a greater length.
In the early 1990s, the term “increased NT thickness” was introduced to describe the abnormal accumulation of fluid under the skin behind the fetal neck. The methodology for measuring NT thickness is reproducible, and the measurement can be subjected to external quality assurance.20 However, those performing the NT scan should receive training and acquire expertise in doing so.20 Extensive research in the last 15 years has established that increased NT is associated with chromosomal defects, many fetal malformations, and genetic syndromes, and the incidence of these abnormalities is related to the thickness, rather than the appearance, of NT.17–21 The likelihood ratios for trisomies 21, 18, and 13, for deviations in the measured NT from the normal median for CRL, have been validated by prospective screening studies involving many hundreds of thousands of patients.20 The measurement of fetal NT can be combined with maternal serum-free ß-hCG and PAPP-A at 11–136/7 weeks to give accurate patient-specific risks and provide the most effective method of screening for trisomy 21, with a detection rate of 90% for a false positive rate of 5%.20,23 Further improvement in first-trimester screening can be achieved by the inclusion of assessment of the nasal bone and flow in the tricuspid valve and ductus venosus, with a detection rate of more than 90% for a false-positive rate of less than 3%.24 During the second trimester, increased NT usually resolves, but in a few cases, it evolves into nuchal edema or true cystic hygromas.1,2
It was recently suggested that first-trimester cystic hygroma constitutes such a unique and easily identifiable marker that, in contrast to NT, it can be implemented in population screening without the need for sonographers to receive special training and ongoing surveillance to confirm accuracy of diagnosis.22 Furthermore, it was recommended that, after the diagnosis of cystic hygromas, it is unnecessary for maternal serum-free ß-hCG and PAPP-A to be measured and for software to be used for calculation of patient-specific risk of chromosomal defects. Instead, the parents should be counseled that 50% of fetuses will have a chromosomal abnormality.22 However, the findings of the present study have demonstrated that, first, when visualized appropriately all increased NTs contain septae, second, the length of NT correlates with its thickness, and third, the risk of a chromosome abnormality is not dependent on the length of the translucent area once its thickness is accounted for. Consequently, cystic hygroma does not constitute a distinct entity in the first trimester that confers a special risk status independent of the NT thickness.
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© 2006 The American College of Obstetricians and Gynecologists
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