1 Department of Obstetrics and Gynecology, Assaf Harofe Medical Center, Zerifin, Israel and 2 Academic Department of Obstetrics and Gynaecology, Royal Free and University College, London, UK
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Abstract |
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Key words: fetal karyotype/fetal outcome/neonatal outcome/nuchal translucency/ultrasound
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Introduction |
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Additionally, several reports have also demonstrated a link between increased NT and a wide range of genetic syndromes or single gene disorders, in particular Noonan syndrome (Reynders et al., 1997; Brady et al., 1998
; Souka et al., 1998
; Nicolaides et al., 1999
).
Although a large amount of data has been accumulated concerning these complications, there is still very little information on the long term follow-up of babies after the diagnosis of a large NT during a first trimester scan (Bilardo et al., 1998; Brady et al., 1998
; Van Vugt et al., 1998
; Adekunle et al., 1999
; Nicolaides et al., 1999
). Therefore, even when commonly associated abnormalities have been ruled out, both the parents and their physician will still remain concerned as to the significance of this new ultrasound marker (Whittle, 1997
).
The aim of the current study was to assess pregnancy and long-term infant outcome of those fetuses with abnormally increased first trimester nuchal translucency.
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Materials and methods |
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In all cases, both transabdominal and transvaginal examination (Aloka 650 CL, Japan; HDI 3000; Advanced Technology Laboratories, Seattle, WA, USA) with variable focus 3.55 MHz curvilinear transducer and a transvaginal 5 or 7 MHz transducer were performed. This was done without a time limitation to generate a satisfactory image. All examinations were carried out by experienced sonographers.
Accurate measurement of the maximum NT thickness was obtained in the sagittal section of the fetus as described by Pandya et al. (1995). Only cases with NT 95 centiles thickness of the normal range for various CRL (2 mm at CRL
44 mm to 2.85 mm at CRL 8384 mm; Herman et al., 2000), in which the callipers were placed `onon' the nuchal lines were enrolled in this study. The images were subject to regular internal audit to check standardization and distribution of measurement (Herman et al., 1998
). Before the examination, the pregnant women were given an explanation on the nature and implications of the test and upon its completion they were counselled on the potential risks and further recommendations. Genetic counselling, fetal karyotyping, mid-gestation detailed anomaly and fetal echocardiography scans were advised. Following the NT measurement, each patient was referred to her obstetrician for further prenatal care. The maternal age at measurement, karyotype results and pregnancy outcome were recorded prospectively on a computer database.
Fetal outcomes were subdivided into miscarriage, intrauterine fetal death, neonatal death or alive and well. Any disorder or abnormalities were recorded specifically.
The details concerning pregnancy and delivery outcome, karyotype results and neonatal follow-up of all the liveborn infants and their medical history since birth were obtained from the parents by a telephone interview and when necessary their medical records were requested from the respective departments.
Statistical analysis
Standardized kurtosis showed that the data derived from a normal distribution and are thus expressed as mean ± standard deviation (SD). Frequencies are given in percentage. The prediction of an uncomplicated pregnancy outcome in this very high risk group was based both on the NT values, which were transformed using natural logarithms and the maternal age. A stepwise logistic regression model was fitted to the data. After excluding all cases with chromosomal aneuploidy and those cases for which this information was not available the remaining cases were further sub-divided according to pregnancy outcome. The difference between cases with complicated versus uncomplicated pregnancy outcome were compared using Fisher's exact test. P values < 0.05 were considered statistically significant.
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Results |
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There were 32 (41%) aneuploid fetuses. Their mean maternal age was 33 ± 5 years. The other corresponding data are presented in Table I. One woman had two consecutive Down's syndrome fetuses, both of which were picked up because of an enlarged NT (Figure 1
). Three women in this group chose to continue with their pregnancy, but the pregnancy resulted in either intrauterine or intra-partum fetal death.
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where P is the probability of having an uncomplicated pregnancy outcome. Abnormalities and complications were defined as: aneuploidy; miscarriage; and severe cardiac anomalies. The odds ratio of the ln(NT) measurements was 0.03 [95% confidence interval (CI) 0.0060.156 (P < 0.001)]; the odds ratio of the maternal age was 0.79 [95% CI 0.6830.914 (P = 0.002)].
When we use the cut-off point of (P) 0.5, a normal pregnancy outcome could be anticipated with a sensitivity, specificity, positive and negative predictive values of 75, 83, 79 and 80% respectively.
After excluding all aneuploid cases and those for which this information was not available, there were 42 euploid cases for follow-up. This group of fetuses was further subdivided according to the NT measurement (above or below 5 mm). It was found that 29 (91%) out of 32 fetuses with NT <5 mm had an uncomplicated pregnancy outcome, but dropping to 60% in cases for which the NT >5 mm (2; P = 0.023).
When the maternal age was analysed at a threshold level of 30 years as a second variable, it was found that all women younger than 30 years who had a fetus with NT <5 mm had a normal pregnancy outcome. This was found to be significantly improved outcome compared with all the other cases (Table II).
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Discussion |
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The presence of a fluid collection behind the neck of the first trimester fetus occurs partly because of its tendency, at this stage of development, to lie on its back and partly because of the laxity of the fetal skin at the level of the neck (Berger, 1999). During early fetal life, the lymphatic vessels drain into two large sacs in the nuchal area, which are directly connected to the jugular vein system. At this stage the fetal lymphatic system is developing and the peripheral resistance of the placenta is high. As a result, there is a brief opportunity between 1014 weeks of gestation to detect abnormal fluid collection of the fetal neck by ultrasound. After 14 weeks, the lymphatic system is likely to have developed sufficiently to drain away any excess fluid and changes to the placental circulation will result in a drop in peripheral resistance. Thus after this time many abnormalities causing fluid accumulation may seem to correct themselves and thus can go undetected by measuring NT (Pandya et al., 1995
; Snijders et al., 1996
, 1998
; Nicolaides et al., 1999
). Increased fluid accumulation has been reported in fetuses with Turner's syndrome, and includes cystic hygroma, which characteristically contains fluid-filled lymphatic cavities (Chervenak, 1983). The aetiology of this formation is believed to be caused by abnormal lymphatic development or local lymphatic vessel aplasia interrupting their drainage into the jugular lymph systems (Chervenak et al., 1983
; Brand-Saberi et al., 1994
). Recently, it has been shown by immunohistochemistry technique that specifically in Turner's syndrome the lymphatic vessels in the upper dermis are hypoplastic (von Kaisenberg et al., 1999
). Thus the fluid is then collected in the posterior neck fold, causing the ultrasonographic appearance of a septated or non-septated nuchal cystic hygroma. As the pregnancy continues, this collection may resolve and a thick nuchal fold ensues (Chervenak et al., 1983
).
In trisomy 21, the interstitial fluid has been found to be bound to collagen subtype VI (Brand-Saberi et al., 1994; Berger, 1999
). Chromosome 21 contains the gene that codes for type VI collagen. In trisomy 21 one subunit of this can be over-expressed, resulting in connective tissue that has a more elastic composition, leading to a swelling of the fetal derma, including the nuchal and leg skin (Brand-Saberi et al., 1994
; Berger, 1999
). Another feature more commonly occurring in trisomy 21 fetuses is the alteration in fetal haemodynamics due to early heart failure, secondary to cardiac and/or great artery abnormalities (Hyett et al., 1997a
, b
; Montenegro et al., 1997
; Nicolaides et al., 1999
) either alone or in combination with an increase in mRNA expression of atrial natriuretic peptide and brain natriuretic peptide in trisomic fetuses (Hyett et al., 1996
).
Beside a great variety of structural and genetic anomalies, euploid fetuses with increased NT have mainly been reported to be at risk of cardiac defects (Bilardo et al., 1998; Souka et al., 1998
; Hyett et al., 1999
). In this respect, it has recently been reported that detecting an abnormal ductus venosus blood flow in euploid fetuses with increased NT identifies those with underlying major cardiac defects (Matias et al., 1999
). Some authors (Pajkrt et al., 1999
) have hypothesized that the majority of spontaneously aborted fetuses may have a cardiac defect as well, in which the same insult causing excessive fluid accumulation in the nuchal region may be responsible for fetal demise. This theory should be further confirmed by detailed pathological examination.
The `transient appearance' of increased NT and even fetal hydrops has been occasionally documented both in normal and abnormal cases (Pajkrt et al., 1995; Fukada et al., 1997
; Huisman and Bilardo, 1997
; Iskaros et al., 1997
). In this respect, we have described two cases in which nuchal cord was proposed to cause temporary neck congestion (Maymon et al., 1999
).
The explanation which has been suggested is the correction of the haemodynamic disturbances occurring later in gestation (Hyett et al., 1997b; Huisman and Bilardo, 1997
).
Our data validate previous reports (Bilardo et al., 1998; Adekunle et al., 1999
) that the overall chance of a healthy baby in the total group of enlarged NT, after exclusion of chromosomal aneuploidies, is ~60%. Only three other studies (Van Vugt, 1998; Brady et al., 1998
; Adekunle et al., 1999
) have examined long term infant outcomes in such pregnancies. While two of them have found a similar prevalence of neuro-developmental delay (35.6%) (Van Vugt, 1998; Adekunle et al., 1999
), their findings were not confirmed by Brady et al. (1998), who reported no delay in achievement of developmental milestones among fetuses with enlarged NT in comparison to normal controls. In agreement with Van Vugt (1998) data, the present study demonstrates that euploid fetuses with increased NT and with no other additional anomalies by follow-up scans have a very good prognosis both for term delivery and normal early childhood. Similarly, we did not find any increased risk of severe early childhood diseases or developmental disorders.
As to genetic syndromes and single gene disorder, which are usually found in less than one in 10 000 pregnancies, they are too sporadic for definite conclusion to be drawn (Souka et al., 1998). However, the association of enlarged NT and those genetic abnormalities may be of clinical value for a couple at high risk for a specific inherited genetic syndrome in which definitive prenatal diagnosis is not yet available (Bilardo et al., 1998
).
It is accepted that when isolated increased NT is diagnosed, counselling for the parents is needed. At this stage, by using the logistic regression model currently presented in which data concerning NT measurement and maternal age are used, the probability of having an uncomplicated pregnancy outcome could be calculated. However, if a complete fetal investigation, including karyotyping and detailed scans, shows no obvious abnormalities this counselling becomes even more challenging. Even at this stage, the background maternal age should be further taken into account as well as the presence of any other risk factors such as family history. A favourable prognosis was found in euploid fetuses with NT <5 mm and maternal age <30 years, but decreasing when those parameters exceeded this threshold level.
These issues need to be further explored and more data should be collected as screening recommendations are developed, especially in the areas of ultrasonographic markers like increased NT on prenatal scan.
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Notes |
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References |
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Berger, A. (1999) Science commentary: what is fetal nuchal translucency? Brit. Med. J., 318, 85.[ISI][Medline]
Brady, A.F., Pandya, P.P., Yuksel, B. et al. (1998) Outcome of chromosomally normal livebirth with increased fetal nuchal translucency at 1014 weeks' gestation. J. Med. Genet., 35, 222224.[Abstract]
Brand-Saberi, B., Floel, W., Christ, B. et al. (1994) Alterations of fetal extracellular matrix in nuchal oedema of Down's syndrome. Ann. Anat., 176, 539547.[ISI]
Bilardo, C.M., Pajkrt, E., de Graaff, I.M. et al. (1998) Outcome of fetuses with enlarged nuchal translucency and normal karyotype. Ultrasound Obstet. Gynecol., 11, 401406.[ISI][Medline]
Chervenak, F.A., Isaacson, B., Blakemore, K.J. et al. (1983) Fatal cystic hygroma. N. Engl. J. Med., 309, 822825.[Abstract]
Fukada, Y., Yasumizu, T., Takizawa, M. et al. (1997) The prognosis of fetuses with transient nuchal translucency in first and early second trimester. Acta Obstet. Gynecol. Scand., 76, 913916.[ISI][Medline]
Herman, A., Maymon, R., Dreazen, E. et al. (1998) Nuchal translucency audit: a novel image screening method. Ultrasound Obstet. Gynecol., 12, 398403.[ISI][Medline]
Herman, A., Dreazen, E., Samandarov, A. et al. (2000) On-to-on versus on-to-out nuchal translucency measurements. Ultrasound Obstet. Gynecol., 15, 126130.[ISI][Medline]
Huisman, T.W.A. and Bilardo, E.M. (1997) Transient increase in nuchal translucency thickness and reversed and diastolic ductus venosus flow in fetus with trisomy 18. Ultrasound Obstet. Gynecol., 10, 398399.
Hyett, J.A., Brizot, M.L., von Kaisenberg, C.S. et al. (1996) Cardiac gene expression of atrial natriuretic peptide and brain natriuretic peptide in trisomic fetuses. Obstet. Gynecol., 87, 506510.
Hyett, J.A., Moscaso, G. and Nicolaides, K.H. (1997a) Abnormalities of the heart and great arteries in first trimester chromosomally abnormal fetuses. Am. J. Med. Genet., 69, 207216.[ISI][Medline]
Hyett, J.A., Perdu, M., Sharland, G.K. et al. (1997b) Increased nuchal translucency at 1014 weeks of gestation as a marker for major cardiac defects. Ultrasound Obstet. Gynecol., 10, 242246.[ISI][Medline]
Hyett, J.A., Perdu, M., Sharland, G.K. et al. (1999) Using fetal nuchal translucency to screen for major congenital cardiac defects at 1014 weeks of gestation: population breed cohort study. Brit. Med. J., 318, 8185.
Iskaros, J., Jauniaux, E. and Rodeck, C. (1997) Outcome of nonimmune hydrops fetalis diagnosed during the first half of pregnancy. Obstet. Gynecol., 90, 321325.
Mascoso, G. (1995) Fetal nuchal translucency: a need to understand the physiological basis. Ultrasound Obstet. Gynecol., 5, 68.[ISI][Medline]
Matias, A., Huggon, I., Areias, J.C. et al. (1999) Cardiac defects in chromosomally normal fetuses with abnormal ductus venosus blood flow at 1014 weeks. Ultrasound Obstet. Gynecol., 14, 307310.[ISI][Medline]
Maymon, R., Herman, A., Dreazen, E. et al. (1999) Can nuchal cord cause transient increased nuchal translucency thickness? Hum. Reprod., 14, 556559.
Montenegro, N., Matias, A., Areias, J.C. et al. (1997) Increased fetal nuchal translucency: possible involvement of early cardiac failure. Ultrasound Obstet. Gynecol., 10, 265268.[ISI][Medline]
Nicolaides, K.H., Sebire, N.J. and Snijders, R.J.M. (1999) The 1114 week scan: the diagnosis of fetal abnormalities. Parthenon, New York.
Pajkrt, E., Bilarder, C.M., Vanlith, J.M. et al. (1995) Nuchal translucency measurement in normal fetuses. Obstet. Gynecol., 86, 994997.
Pajkrt, E., Mol, B.W.J., Bleker, O.P. et al. (1999) Pregnancy outcome and nuchal translucency measurements in fetuses with normal karyotype. Prenat. Diagn. 19, 11041108.[ISI][Medline]
Pandya, P.P., Snijders, R.J.M., Johnson, S.J. et al. (1995) Screening for fetal trisomies by maternal age and fetal nuchal translucency thickness at 10 to 14 weeks of gestation. Br. J. Obstet. Gynaecol., 102, 957962.[ISI][Medline]
Reynders, C.S., Pauker, S.P. and Benacerraf, B.R. (1997) First trimester isolated fetal nuchal lucency: significance and outcome. J. Ultrasound Med., 16, 101105.[Abstract]
Robinson, H.P. and Fleming, J.E.E. (1975) A critical evaluation of sonar crown-rump length measurements. Br. J. Obstet. Gynaecol., 82, 702710.[ISI][Medline]
Snijders, R.J.M., Johnson, S., Sebire, N.J. et al. (1996) First trimester ultrasound screening for chromosomal defects. Ultrasound Obstet. Gynecol., 7, 216266.[ISI][Medline]
Snijders, R.J.M., Noble, P.L., Sebire, N.J. et al. (1998) UK multicentre project on assessment of risk of trisomy 21 by maternal age and nuchal translucency thickness at 1014 weeks of gestation. Lancet, 352, 343346.[ISI][Medline]
Souka, A.P., Snijders, R.J.M., Novakov, A. et al. (1998) Defects and syndrome in chromosomally normal fetuses with increased nuchal translucency thickness at 1014 weeks gestation. Ultrasound Obstet. Gynecol., 11, 391400.[ISI][Medline]
Steinwirker, J. (1872) Elephantiosis congenita cystica. Inaugural dissertation. Halle, Germany.
Szabo, J. and Gellen, J. (1990) Nuchal fluid accumulation in trisomy 21 detected by vaginosonography in first trimester. Lancet, 336, 1133.
Taipale, P., Hiilesmaa, V., Salonen, R. et al. (1997) Increased nuchal translucency as a matter for fetal chromosomal defects. N. Engl. J. Med., 337, 16541658.
Van Vugt, J.M.G., Tinnemans, B.W.S. and Van Zalen-Sprock, R.M. (1998) Outcome and early childhood follow-up of chromosomally normal fetuses with increased nuchal translucency at 1014 weeks' gestation. Ultrasound Obstet. Gynecol., 11, 407409.[ISI][Medline]
Von Kaisenberg, C.S., Nicolaides, K.H. and Brand-Saberi, B. (1999) Lymphatic vessel hypoplastic in fetuses with Turner's syndrome. Hum. Reprod., 14, 823826.
Whittle, M. (1997) Ultrasonographic `soft markers' of fetal chromosomal defects. Detecting them may do more harm than good. Editorial. Brit. Med. J., 134, 918.
Submitted on February 16, 2000; accepted on June 2, 2000.