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Nuchal Translucency

 

 

Normal nuchal translucency. The outer measurement of the skin (yellow arrow) should be distinguished from the amnion (red arrows)
Prominent but normal nuchal translucency (arrow) measuring 2.4 mm. Nl chromosomes
Markedly increased nuchal translucency (arrow) bulging the fetal skin (Trisomy 21)

Findings:

Three patients with sonograms demonstrating the nuchal translucency. In the first case on the left the normal nuchal translucency measured from the inner aspect of the skin (yellow arrow) is well seen and is normal. The skin should be distinguished from the amniotic membrane (red arrows). In the middle image the nuchal translucency is prominent but measured normal. The case on the right demonstrates an increased nuchal translucency. Note the outer bulge of the fetal skin.

Discussion:

In the past decade there have been over 1,000 reports documenting methods which attempt to diagnose chromosomal abnormalities (commonly trisomy 21) non-invasively, utilizing either maternal serum or sonography. The first major sonographic observations were made by Benacerraf et al in the 1980's at which time excess soft tissue in the nuchal area of fetus was commonly seen in fetuses with trisomy 21. This observation was initially applied to fetuses in the second trimester of pregnancy. In 1989 Bronshtein et al and subsequently others noted an association of "increased fluid at the back of the fetal neck" in the first trimester of pregnancy and fetal aneuploidy. In the early 1990's Nicolaides and his coworkers began an intensive evaluation of this finding with large well-controlled multicenter studies. While this sign is presently termed "nuchal translucency" or NT, it has also been referred to as a nuchal fold, simple hygroma and non-loculated cystic hygroma. The actual anatomic structure being referred to is likely the normal integument at the back of the neck which either may become edematous or in some cases fluid filled with dilated lymphatic sacs due to altered normal embryological connections. The literature is sometimes confusing. All fetuses have a "nuchal translucency" (as will be described below) representing normal integument, however in some cases this area may be abnormally increased in thickness. While an abnormal nuchal area should be referred to as "increased nuchal translucency" some reports use the term nuchal translucency to imply that it is abnormally increased. The term "nuchal thickening and nuchal fold" are commonly used to indicate thickening seen in the second trimester.

Illustration demonstrating an increased nuchal translucency in an embryo in the first trimester.

Adapted from: van Vugt JMG, van Zalen-Sprock RM, Kostense PJ. First-trimester nuchal translucency: a risk analysis on fetal chromosome abnormality. Radiology 200:537-540, 1996

Pathophysiology

A recent review by Nicolaides et al summarized the most likely etiologies of increased nuchal translucency. These include: cardiac failure in association with abnormalities of the heart and great vessels; venous congestion of the head and neck due to constriction or compression from amniotic bands, congenital diaphragmatic hernia or narrow chest seen in skeletal dysplasia; altered composition of the extracellular matrix; abnormal or delayed development of the lymphatic system; failure of lymphatic drainage due to impaired fetal movements such as in various neuromuscular disorders; fetal anemia or hypoproteinemia and congenital infection.

Increased Nuchal Translucency and Chromosomal Abnormalities

In the early 1990's a number of reports documented an association between increased nuchal translucency and chromosomal defects. These studies were often in "high risk" groups. The mean prevalence of chromosomal defects in fetuses with this finding was 27%, however with a wide range varying from 12% to 88%. The disparity in prevalence rates was likely due to a combination of either differing maternal ages or differing criteria for abnormal nuchal translucency. The readers are referred to an excellent review of the studies evaluating nuchal translucency by Chitty and Pandya in 1997. Nicolaides et al in 1994 reported a series of 1273 pregnancies in which a nuchal translucency >= 2.5 mm was seen in 84% of fetuses with trisomy 21 and 4.5% of normal fetuses. In Chitty and Pandya's review of the literature they found that the average sensitivity for the detection of trisomy 21 in similar studies was 77% and 67% for all karyotypic abnormalities. The sensitivities ranged from 0% to 88% and the false positive rate ranged from 2.7% to 9.9%. Studies by Nicolaides et al and Pandya et al revealed that the prevalence of trisomies increased with increasing maternal age as well as increasing nuchal translucency thickness. A study by Pandya et al in 1995 found that the observed number of trisomies in fetuses with a nuchal translucency of 3 mm, 4 mm 5 mm and >= 6 mm was approximately 3 times, 18 times, 28 times and 36 times the respective numbers expected on the basis for maternal age.

Summary of Studies Reporting the Use of Nuchal Translucency Measurement in the Screening for Aneuploidy

Selected Populations
Gestational Age (wks)
Nuchal Thickness
Sensitivity (All aneupl.)
Sensitivity Trisomy 21
False + Rate

Nicolaides et al (1994)

10-13
>/= 3 mm
72%
84%
4.4%

Szabo et al (1995)

9-12
>/= 3 mm
92%
88%
2.6%

Comas et al (1995)

9-13
>/= 3 mm
47%
57%
9.9%

Brambati et al (1995)

8-15
>/= 3 mm
30%

3.2%

Pandya et al (1995)

10-14
>/= 2.5 mm
77%
77%
6.9%

Kornman et al (1996)

>/=13
>/= 3 mm
0%
0
2.7%

Snijders et al (1996)

10-14
> 95%
87%
86
6.0%
Mean Selected Populations

67%
77%
6.0%
Routine Screening Populations
Gestational Age (wks)
Nuchal Thickness
Sensitivity (All aneupl.)
Sensitivity Trisomy 21
False + Rate

Bewley et al (1995)

8-14
>/= 3 mm
40%
33%
6.0%

Szabo et al (1995)

9-12
>/= 3 mm
100%
100%
0.9%

Hafner et al (1995)

10-13
>/=2.5 mm
73%
50%
0.9%

Kornman et al (1996)

>/=13
>/= 3 mm
67%
67%
4.8%

Pandya et al (1995)

10-13
>/= 2.5 mm
76%
75%
3.4%

Bower et al (1995)

8-13
>/= 3 mm
53%
45%
6.3%
Mean Routine Screening

70%
62%
4.0%

Adapted from Chitty LS, Pandya PP. Ultrasound screening for fetal abnormalities in the first trimester. Prenatal Diagnosis 17:13:1269-1281, 1997

The nuchal translucency is defined as the maximum thickness of the subcutaneous translucency between the skin and soft tissue overlying the cervical spine.

Measurement Criteria

In a recent review, Nicolaides et al described the measurement criteria necessary to achieve uniformity of this measurement

1. All sonographers performing fetal scans should be appropriately trained and their results subjected to rigorous audit. The Fetal Medicine Foundation, under the auspices of the International Society of Ultrasound in Obstetrics and Gynecology, has introduced a Certificate of Competence in the 11- 14-week scan, which is awarded to those sonographers who can perform the scan to a high standard and can demonstrate a good knowledge of the diagnostic features and management of the conditions identified by this scan.

2. The ultrasound equipment must be good quality, it should have a video-loop function and the calipers should be able to provide measurements to one decimal point.

3. NT can be measured successfully by transabdominal ultrasound examination in about 95% of cases; in the others, it is necessary to perform transvaginal sonography.

4. The ability to measure NT and obtain reproducible results improves with training; good results are achieved after 80 and 100 scans for the transabdominal and the transvaginal routes, respectively (Braithwaite et al., 1996). The intra-observer and inter-observer differences in measurements are less than 0.5 mm in 95% of cases (Pandya et al., 1995).

5. The minimum fetal CRL should be 45 mm and the maximum 84 mm. The optimal gestational age for measurement of fetal NT is 11 to 13 weeks.

6. Fetal NT increases with CRL and therefore it is essential to take gestation into account when determining whether a given translucency thickness is increased (Snijders et al., 1998).

7. A good sagittal section of the fetus, as for measurement of fetal CRL, should be obtained and the NT should be measured with the fetus in the neutral position. When the fetal neck is hyperextended the measurement can be increased by 0.6 mm and when the neck is flexed, the measurement can be decreased by 0.4 mm (Whitlow et al., 1998)

8. The magnification should be such that each increment in the distance between calipers should be only 0.1 mm. A study, in which rat heart ventricles were measured initially by ultrasound and then by dissection, has demonstrated that ultrasound measurements can be accurate to the nearest 0.1-0.2 mm (Braithwaite et al., 1996

9. Care must be taken to distinguish between fetal skin and amnion because, at this gestation, both structures appear as thin membranes (Nicolaides et al., 1992). This is achieved by waiting for spontaneous fetal movement away from the amniotic membrane; alternatively, the fetus is bounced off the amnion by asking the mother to cough and/or tapping the maternal abdomen.

10. The maximum thickness of the subcutaneous translucency between the skin and the soft tissue overlying the cervical spine should be measured.During the scan, more than one measurement must be taken and the maximum one should be recorded.

11. The umbilical cord may be around the fetal neck in 5-10% of cases and this finding may produce a falsely increased NT, adding about 0.8 mm to the measurement (Schaefer et al., 1998).

12. In such cases, the measurements of NT above and below the cord are different and, in the calculation of risk, it is more appropriate to use the smaller measurement.

 

Measurement of the nuchal translucency. The sonolucency is measured and should not include the skin or moderately echogenic soft tissues.

In this case, while it is possible that the line depicted by the arrow represents the skin, it could also represent the amnion. Another image where these two structures can be distinguished should be selected.

A major concern of Nicolaides and his coworkers and other investigators concerned the reproducibility of this finding. A study by Roberts et al in 1995 reported poor reproducibility of the fetal nuchal translucency measurement thickness. In their study they used a cutoff of 3 mm to identify low and high risk groups. By repeating the measurement with either the same or a different sonographer, 17.5% and 18.8% of the nuchal translucency measurements would have been reclassified as normal or abnormal respectively. Most investigators have not found similar poor results in the reproducibility of this measurement. A study of 200 patients by Pandya et al with two to four sonographers found that the the intraobserver and interobserver repeatability was less than 0.54 mm and 0.62 mm, respectively. The authors analysis revealed that a significant factor in the variation of the measurements was the placement of the calipers rather than the generation of the image. Some authors have reported high failure rates (42%) in obtaining the correct image for measurement of the nuchal translucency. The most likely explanation for this is attempting measurements at very early gestational ages (< 10 weeks.). A recent article examined the issue of the importance of measurement error as well as evaluating the issue of ascertainment bias when evaluating the utility of clinical tests. The authors presented a review and analysis to evaluate the effect of verification bias on the accuracy of first-trimester nuchal translucency measurement for Down syndrome detection. Verification or ascertainment bias occurs when the selection for verification of the diagnosis depends on the results of the test under study. Fetuses with an increased nuchal translucency thickness were more likely to undergo fetal karyotyping than fetuses with a normal nuchal translucency in some studies. This implies that Down syndrome fetuses with an increased nuchal translucency thickness almost always were detected, whereas the false-negatives, ie Down syndrome fetuses with a normal nuchal translucency thickness, had about a 50% chance of being missed due to fetal loss. They used MEDLINE and EMBASE to identify all papers relating the results of nuchal translucency measurement to fetal karyotype. The detected studies were scored for verification bias. Fifteen studies without and ten with verification bias were included. The sensitivity and specificity were calculated for each study. For studies with verification bias, adjusted estimates of the sensitivity were calculated assuming a fetal loss rate for Down syndrome pregnancies of 48%. The sample size weighted sensitivity was 55% in studies without and 77% in those with verification bias, for specificities of 96% and 97%, respectively. After adjustment for verification bias, the sample size weighted sensitivity changed from 77% to 63%. Studies with verification bias reported higher sensitivities, but also slightly higher specificities of nuchal translucency measurement than studies without verification bias. The difference in sensitivity is greater than could be explained by verification bias. They postulated that the experience of the sonographer might be an explanation for the differences.

One of the controversies in the use of the nuchal translucency measurement is at what gestational age is it most appropriate to make this measurement. Two studies by Pajkrt et al evaluated this question. In an initial study in 1995 in 771 normal fetuses the median nuchal translucency increased from 0.7 mm at 10 weeks gestation to 1.5 mm at 13 weeks gestation. In a recent study, also evaluating normal fetuses, they found that the nuchal translucency measurement reached its maximum at approximately 91 days gestation, after which a progressive decrease occurred. In this study, at 77 days (11 weeks) gestation, 97% of the fetuses had visible nuchal translucencies. They concluded that because all fetuses in their study developed a measurable nuchal translucency at 86 days (12 weeks), if an initial measurement is 0 mm then it should be repeated at 12 weeks. On the other hand, if a nuchal translucency could not be measured from 12 weeks onward, it may be that the "waning phase" of nuchal prominence may have already begun. Other authors (Brambati et al, Roberts et al) have also found that not accounting for gestational age may be inappropriate and that a single measurement may not be applicable across all gestational ages. Roberts et al reported that 1% of pregnancies at 8 weeks gestation had nuchal translucencies >/= 2.5 mm. This increased to over 20% at 13 weeks gestation. A recent editorial by Malone et al readdressed the issue of gestational age and nuchal translucency cutoff. As they stated: "It is well recognized that nuchal translucency normally increases with gestational age. Use of a single cutoff to define increased nuchal translucency is therefore inappropriate. For example, use of a 2.5-mm cutoff may be associated with a 1.3% false-positive rate when screening occurs at 10 weeks' gestation, whereas at 13 weeks' gestation a 2.5-mm cutoff may be associated with a false-positive rate as high as 13%. The approach of the Fetal Medicine Foundation investigators has been to use the 95th percentile nuchal translucency value according to fetal crown-rump length, which adjusts for this effect of gestational age. The 95th percentile nuchal translucency values used by the Fetal Medicine Foundation are 2.2 mm at 10 weeks' gestation and 2.8 mm at 14 weeks' gestation. There is also some evidence to suggest that, as with current second-trimester serum screening, use of multiples of the median may be associated with a lower false-positive rate than use of 95th percentile values while maintaining a high detection rate."

Association of Increased Nuchal Translucency and Other Abnormalities

There have been numerous reports suggesting that the finding of an increased nuchal translucency may be a marker for a wide variety of abnormalities such as: cardiac malformations, anencephaly, omphalocele and others. Pathological studies reported by Hyett et al found that of fetuses terminated due to an increased nuchal translucency and other abnormalities, 19 of 21 cases had an abnormality of the heart or great vessels. Cardiac abnormalities such as septal defects and narrowing of the aortic isthmus have been commonly found, particularly in those patients with trisomy 21.

A recent study by Souka et al, as part of their continuing study of nuchal translucency screening in the 1st trimester, reported their analysis of the prevalence of fetal abnormalities and genetic syndromes in more than 4000 chromosomally normal pregnancies with increased nuchal translucency. The patients were scanned between 10-14 weeks gestation and those patients were identified with nuchal translucency above the 95th centile and either a normal karyotype or birth of a child with no features to suggest a chromosomal abnormality. Patients were, for the most part, scanned transabdominally using criteria previously reported. From their database they found 4116 singleton, chromosomally normal pregnancies with nuchal translucency thickness above the 95th centile for crown-rump length. (Nuchal translucency normally increases with crown-rump length and the 95th centile is 2.2 mm for a crown-rump length of 38 mm and 2.8 mm for a crown-rump length of 84 mm. There were 3885 live births of infants who survived the neonatal period, 38 neonatal deaths, 74 spontaneous abortions and 77 terminations. The authors did a literature search of similar studies and found 16 reports. Combining the additional data there were a total of 416 fetuses, of which 68 (16%) had defects. In the present study there were 141 fetuses with fetal abnormalities and/or genetic syndromes. The abnormalities were quite varied and they comment on the more major ones in their report. Their analysis is that the observed prevalence for some of the abnormalities such as anencephaly, holoprosencephaly, microcephaly, facial cleft, gastroschisis, renal abnormalities, bowel obstruction and spina bifida, may not be different from that in the general population. However, the prevalence of major cardiac defects, diaphragmatic hernia, omphalocele, body stalk anomaly and fetal akinesia deformation sequence appear to be significantly higher than in the general population.

With cardiac defects, the prevalence of cardiac abnormalities increased significantly with increasing nuchal translucency thickness from 4 per 1000 in the group of nuchal translucency from the 95th centile to a measurement of 3.4 mm to 169 per 1000 for nuchal translucency thickness of greater than or equal to 6.5 mm. In a prospective study Zosmer et al evaluated 398 euploid fetuses with NT measurements of greater than the 99th percentile. The prevalence of major cardiac defects was at least 10 times higher than the prevalence noted in the general population. As in the study by Hyett et al,36 the prevalence was directly related to the degree of NT. Congenital diaphragmatic hernia has a prevalence of approximately one in 4000. In this study the prevalence was 8 in 4116 patients, suggesting an association increased nuchal translucency and CDH. There authors have previously reported on the possibility that those fetuses with CDH and nuchal translucency have a worse prognosis than those who do not. In both omphalocele and body stalk anomaly the prevalence of these conditions is increased dramatically when the nuchal translucency is increased.

The authors appropriately caution that increased nuchal translucency is not an abnormality itself and that once an chromosomal abnormality is excluded approximately 90% of pregnancies with nuchal translucencies below 4.5 mm result in healthy live births. The wide variety of conditions associated with increased nuchal translucency suggest the pathophysiology may be due to a variety of mechanisms. They list the following possible mechanisms: 1) Cardiac failure in association with abnormalities of the heart and great vessels, 2)Venous congestion in the head and neck in association with constriction of the fetal body in amnion rupture sequence, or superior mediastinal compression found in diaphragmatic hernia or the narrow chest in skeletal dysplasia, 3) Failure of lymphatic drainage due to impaired fetal movements in various neuromuscular disorders, 4) Abnormal or delayed development of the lymphatic system, and 5) Altered composition of the subcutaneous connective tissue.

One should be aware that there is a potential "downside" to identifying fetuses using nuchal translucency measurements or other non-invasive techniques. Several studies have demonstrated an increased miscarriage rate in pregnancies with an increased nuchal translucency. In one series the fetal death rate was as high as 23.5% when the nuchal translucency was > 7 mm. Thus early screening programs will identify a number of fetuses that would likely have died or miscarried spontaneously at a slightly later time. Fetuses identified as abnormal at an early gestational age are likely to have early invasive testing, which has a slightly higher loss rate. In addition, the patient would likely be labeled as being at increased risk for aneuploidy in subsequent pregnancies (resulting in subsequent invasive testing), which would not have been true if they had aborted spontaneously.

Increased Nuchal Translucency and Other Biochemical Markers

In the excellent review of the subject of nuchal translucency screening in the first trimester by Souter and Nyberg they discuss the role of biochemical screening. As they state: Among the common analytes used during the second trimester, the most useful during the first trimester was found to be human chorionic gonadotropin (hCG) in the form of free Beta-hCG. The association of elevated free Beta-hCG and fetal Down syndrome during the first trimester was established in 1992. About the same time, Brambati and colleagues made the association between low levels of pregnancy-associated plasma protein A (PAPP-A) with trisomy 21. These observations were quickly confirmed by others. The combination of free Beta-hCG, PAPP-A, and maternal age yields detection rates in the first trimester that are similar to those of second-trimester screening with 2 biochemical markers. The detection rates for trisomy 21 are approximately 60% together with maternal age at a 5% false-positive level.

Fortuitously biochemical markers are largely independent of sonographic markers so that the combination of NT with first-trimester bio-chemical markers is more effective than either alone. Even mild degrees of increased NT may be significant when combined with biochemistry and maternal age, and this improves detection rates . Combining 2 serum markers (PAPP-A and free Beta-hCG) with NT results in a detection rate of approximately 85%, for a 5% false-positive rate. Combining NT with biochemical markers also increases the detection rates for other aneuploidies.

Urinary Beta-core Fragment

 

In the past two years a new biochemical marker for aneuploidy has been detected, the Beta-core fragment. A number of studies have reported high detection rates of Down syndrome using the elevated Beta-core fragment levels in the maternal urine (72%-100%). In a recent study by Bahado-Singh et al utilizing elevated Beta-core fragment in the urine and ultrasonography the sensitivity was 77.8% and a false positive rate of 4.1%. With an abnormal prenatal screen the odds ratio was 82.8 for having a Down syndrome fetus.In this paper the authors nicely review the metabolism of hCG. "Beta-core fragment is a stable end product of hCG metabolism. The degradation of hCG is thought to involve the enzymatic cleavage of an amino acid sequence from the Beta-subunit by a macrophage enzyme. The so-called nicking of the Beta-subunit results in its dissociation into alpha-subunit and nicked free Beta-subunit. The nicked free Beta-subunit is subsequently metabolized to the Beta-core fragment in the maternal kidneys and ultimately accumulates in the fetal urine." While more studies are needed to confirm this work it is likely to be a useful addition to other serum and urine analytes.

As nuchal thickening changes with gestational age, one investigator, Nicolaides et al, suggests using an algorithm combining nuchal translucency, crown-rump length (CRL), maternal age, and previous history of Down syndrome to provide the most accurate risk assessment data.

References:

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Comas, C., Martinez, J.M., Ojuel, J., Casals, E., Puerto, B., Borrell, A., Fortuny, A. First-trimester nuchal edema as a marker of aneuploidy, Ultrasound Obstet. Gynecol., 5, 26-29, 1995

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Pandya, P.P., Goldberg, H., Walton, B., Riddle, A., Shelley, S., Snijders, R.J.M., Nicolaides, K.H. The implementation of Ist trimester scanning at 10-13 weeks' gestation and the measurement of fetal nuchal translucency thickness in two maternity units, Ultrasound Obstet. Gynecol., 5, 20-25, 1995a

Pandya, P.P., Kondylios, A., Hilbert, L., Snijders, R.J.M., Nicolaides, K.H. Chromosomal defects and outcome in 1,015 fetuses with increased nuchal translucency, Ultrasound Obstet. Gynecol, 5, 15-19, 1995b

Pandya, P.P., Altman, D.G., Brizot, M.L., Pettersen, H., Nicolaides, K.H. Repeatability of measurement of fetal nuchal translucency thickness, Ultrasound Obstet. Gynecol., 5, 334-337, 1995c

Pandya, P.P., Snijders, R.J.M., Johnson, S.P., Brizot de Lourdes, M., Nicolaides, K.H. Screening for fetal trisomies by maternal age and fetal nuchal translucency thickness at 10-14 weeks of gestation, Br. J. Obstet. Gynaecol., 102, 957-962, 1995d

Roberts, L.J., Bewley, S., Mackinson, A.M., Rodeck, C.H. First trimester fetal nuchal translucency: problems with screening the general population 1, Br. I Obstet. Gynaecol., 102, 381-385, 1995

Schulte-Vallentin, M., Schindler, H. Nonechogenic nuchal oedema as a marker in trisomy 21 screening, Lancet, 339, 1053, 1992

Shulman, L.P., Emerson, D.S., Felker, R.E., Phillips, O.P., Simpson, J.L., Elias, S. High frequency of cytogenetic abnormalities in fetuses with cystic hygroma diagnosed in the first trimester, Obstet. Gynecol., 80, 80-81, 1992

Snijders, R.J.M., Sebire, N.J., Nicolaides, K.H. Maternal age and gestational age specific risk for chromosomal defects, Fetal Diagn. Ther 10, 356-367, 1995a

Snijders, R.J.M., Johnson, S., Sebire, N.J., Noble, P.L., Nicolaides, K.H. First-trimester ultrasound screening for chromosomal defects, Ultrasound Obstet. Gynecol., 7, 216-226, 1996

Suchet, 1.13,, Van der WesthUizen' N.G., Labatte. M.F Fetal cystic hygromas: further insights into their natural history, Can. Assoc. Radiol 6:420-424, 1992

Szabo, J., Gellen, J. Nuchal fluid accumulation in trisomy-21 detected by vaginosonography in first trimester, Lancet, 336, 1133, 1990

Szabo, J., Gellen, J., Szemere, G. First-trimester ultrasound screening for fetal aneuploides in Women over 35 and under 35 years of age, Ultrasound Obstet. Gynecol., 5, 161-163, 1995

Trauffer, P.M.L., Anderson, C.E., Johnson, A., Heeger, S., Morgan, P., Wapner, R.J. The natural history of euploid pregnancies with first-trimester cystic hygromas, Am. J Obstet. Gynecol., 170, 12791283, 1994

van Vugt JMG, van Zalen-Sprock RM, Kostense PJ. First-trimester nuchal translucency: a risk analysis on fetal chromosome abnormality. Radiology 200:537-540, 1996

van Zalen-Sprock, R.M., van Vugt, J.M.G., van Geijn, H.P. First-trimester diagnosis of cystic hygroma-course and outcome, Am. J Obstet. Gynecol., 167, 94-98, 1992

Ville, Y., Lalondrelle, C., Dournerc, S., Daffos, F., Frydman, R., Oury, J.F., Dumez, Y. First-trimester diagnosis of nuchal anomalies: significance and fetal outcome, Ultrasound Obstet. Gynecol, 2, 314-316, 1992

Wald, N.J., Hackshaw, K. Combining ultrasound and biochemistry in first-trimester screening for Down's syndrome, Prenat. Diagn 17, 821-829, 1997

Wilson, R.D., Venir, N., Farquharson Fetal nuchal fluid-physiological or pathological?-in pregnancies less than 17 menstrual weeks, Prenat. Diagn., 12, 755-763, 1992

Bahado-Singh RO, Deren O, Acuna E, Cermik D, Mahoney MJ, Cole L. A New Screening Protocol Combining Urine Beta-core Fragment and Ultrasonography for Down Syndrome Detection Am J Obstet Gynecol 178:779-82, 1998 Copyright © 1998 by Mosby-Year Book, Inc.

Souka AP, Snijders RJM, Novakov A, Soares W, Nicolaides KH. Defects and Syndromes in Chromosomally Normal Fetuses with Increased Nuchal Translucency Thickness at 10-14 Weeks Gestation Ultrasound Obstet Gynecol 11:391-400, 1998

Mol BWJ, van der Meulen J, Pajkrt E, Bilardo CM, Bossuyt PMM Effect of Study Design on the Association Between Nuchal Translucency Measurement Obstet Gynecol 94:864-9, 1999

Malone FD, Berkowitz RL, Canick JA, D'Alton ME. First trimester screening for aneuploidy: Research or standard of care?. Am J Obstet Gynecol 182:490-6, 2000

Souter VL, Nyberg DA. Sonographic screening for fetal aneuploidy:First Trimester. J Ultrasound Med 20:775-90. 2001

Souka AP, Krampl E, Bakalis S, Heath V, Nicolaides KH. Outcome of pregnancy in chromosomally normal fetuses with increased nuchal translucency in the first trimester Ultrasound Obstet Gynecol 18:9-17, 2001

Hippala A, Eronen M, Taiplale P, Salonen R, Hiilesmaa V. Fetal nuchal translucency and normal chromosomes: a long-term follow-up study. Ultrasound Obstet Gynecol 18:18-22, 2001

Nicolaides KH, Heath V, Cicero S. Increased fetal nuchal translucency at 11-14 weeks. Prenatal Diagn. 22:308-315, 2002

 

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Peter W. Callen, M.D.
Professor of Radiology, Obstetrics, Gynecology and Reproductive Science
University of California Medical Center, San Francisco, California