Pregnancy outcome and infant follow-up of fetuses with abnormally increased first trimester nuchal translucency

Ron Maymon1,3, Eric Jauniaux2, Ofir Cohen1, Eli Dreazen1, Zwi Weinraub1 and Arie Herman1

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


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The numbers of fetuses with an abnormal increased first trimester nuchal translucency (NT) but a confirmed normal anatomy and karyotyping is relatively small and therefore a challenge for prenatal counselling. The aim of the current study was to assess the long-term pregnancy outcome and infancy prognosis of 78 fetuses with NT > 95th centile of the normal range for crown–rump length (CRL). The most common abnormalities in this group were aneuploidy, which affected 32 of the fetuses followed by four and three cases which were miscarried or had cardiac defects respectively. The remaining euploid fetuses with normal detailed scans were followed throughout their infancy (mean 24 months; range 12–36 months). Post-natally, except for a correctable case of ventricular septal defect and a case of posterior urethral valve, no other abnormalities were detected. After excluding all aneuploid cases and using the maternal age as a second variable, an uncomplicated pregnancy outcome could be anticipated in 17 cases (100%) when the maternal age was <30 years and NT between 95th centile and 5 mm. However, the chance of a normal outcome dropped to 50% in four cases with maternal age >=30 years and NT >=5 mm (Fisher's exact test; P = 0.02). These findings suggest that the long-term prognosis of the euploid fetuses with large NT (<5 mm) is reassuring in younger women.

Key words: fetal karyotype/fetal outcome/neonatal outcome/nuchal translucency/ultrasound


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Skin elevation in the posterior and lateral neck region of aborted human fetuses was first reported in the 19th century (Steinwirker, 1872Go). The advancement of ultrasonographic techniques has made earlier detection of such nuchal findings feasible; they appear as hypo-echogenic areas beneath the skin and outside the tissue covering the cervical vertebral column (Szabo and Gellen, 1990Go). Increased thickness of this ultrasonographic feature, later defined as nuchal translucency (NT), has been reported in very large series in association with chromosomal abnormalities (Pandya et al., 1995a; Snijders et al., 1996Go, 1998Go; Taipale et al., 1997Go), cardiac and other structural defects (Snijders et al., 1996Go; Iskaros et al., 1997Go; Souka et al., 1998Go; Hyett et al., 1999Go; Matias et al., 1999Go), as well as an increased risk of either spontaneous abortion or premature delivery (Fukada et al., 1997Go; Iskaros et al., 1997Go; Reynders et al., 1997Go; Pajkrt et al., 1999Go).

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., 1997Go; Brady et al., 1998Go; Souka et al., 1998Go; Nicolaides et al., 1999Go).

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., 1998Go; Brady et al., 1998Go; Van Vugt et al., 1998Go; Adekunle et al., 1999Go; Nicolaides et al., 1999Go). 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, 1997Go).

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.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The study was carried out in two fetal medicine units: at Assaf Harofe Medical Center, Zrifin, Israel and University College London Hospital (UCL), London, UK. Pregnant patients with abnormally increased NT were referred. The gestational ages were calculated from the last menstrual period and thereafter confirmed by the crown–rump length (CRL) (Robinson et al., 1975). Only singleton fetuses with CRL of 38–84 mm were included in the study.

In all cases, both transabdominal and transvaginal examination (Aloka 650 CL, Japan; HDI 3000; Advanced Technology Laboratories, Seattle, WA, USA) with variable focus 3.5–5 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 83–84 mm; Herman et al., 2000), in which the callipers were placed `on–on' 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., 1998Go). 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.


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The study comprised 78 fetuses with NT >=95th centile for which complete information was available and none of them was lost for follow-up. Fifty seven cases were from Assaf Harofe and the rest from UCL. The mean maternal age was 31 ± 5 years, the mean CRL was 62 ± 11 mm, corresponding to a mean gestational age of 12 weeks ± 10 days. The mean NT was 5.4 ± 3.1 mm, range 2.6–25 mm. Out of the 78 cases there were 4 (5%) miscarriages. Although all patients were offered prenatal fetal karyotyping, in seven cases this information was not available; three patients had a miscarriage and karyotype was not performed. The other four, who declined prenatal karyotyping, delivered live newborns, which were assessed and found to be normal.

There were 32 (41%) aneuploid fetuses. Their mean maternal age was 33 ± 5 years. The other corresponding data are presented in Table IGo. One woman had two consecutive Down's syndrome fetuses, both of which were picked up because of an enlarged NT (Figure 1Go). 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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Table I. Karyotype information and pregnancy outcome of 32 aneuploid fetuses
 


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Figure 1. Transvaginal ultrasound of two consecutive trisomy 21 fetuses (A and B) in the same patient. Notice images were performed in a mid-sagittal section and the arrowheads point to the hypo-echogenic nuchal translucency area.

 
The mean maternal age in the remaining 42 euploid fetuses was 29 ± 4 years [significantly younger than the previous group (t-test, P < 0.005)]. Among them there were three cases in which the enlarged NT resolved spontaneously within 2 weeks. Those pregnancies had a normal outcome and two of them were previously reported (Maymon et al., 1999Go). Two fetuses had severe cardiac malformation and termination of pregnancy was carried out. Post-natally one case was found to have cardiac anomaly of ventricular septal defect and in another a urologic anomaly of a posterior urethral valve. Both were successfully corrected. Long-term follow-up (mean 24; range 12–36 months) was available for all 36 infants who were born alive and had an uneventful pregnancy and delivery outcome (Figure 2Go). In this subgroup, no other genetic or anatomical abnormalities were detected. Their motor and mental developmental was apparently normal.



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Figure 2. Transabdominal mid-sagittal scan of a euploid normal fetus with 6.6 mm nuchal translucency (arrowheads). This case had both an uneventful pregnancy outcome, and normal long-term infant follow-up.

 
Using a logistic regression model, the probability of a normal pregnancy outcome (dependent variable) and the maternal age and ln(NT) (independent variables) was calculated using the following equation:


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) 0.006–0.156 (P < 0.001)]; the odds ratio of the maternal age was 0.79 [95% CI 0.683–0.914 (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 ({chi}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 IIGo).


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Table II. Pregnancy and infant outcome of 42 euploid cases, based on maternal age (above/below 30 years) and nuchal translucency (NT) measurement (above/below 5 mm)
 

    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The current study confirms previous reports indicating that among fetuses with enlarged NT, the most common abnormality is aneuploidy (Snijders et al., 1996Go, 1998Go; Taipale et al., 1997Go) contributing to 40% of the cases in the present report. In euploid fetuses, the most common anatomical defect associated with a large NT is cardiac anomaly (Souka et al., 1998Go; Nicolaides et al., 1999Go), which was currently found in three fetuses (7%). The 5% spontaneous fetal loss rate found in this high risk group is in agreement with other reports (Bilardo et al., 1998Go; Pajkrt et al., 1999Go) being almost double the 2% rate observed in the unselected population at 10–14 weeks gestation (Mascoso, 1995Go; Pajkrt et al., 1999Go).

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, 1999Go). 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 10–14 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., 1995Go; Snijders et al., 1996Go, 1998Go; Nicolaides et al., 1999Go). 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., 1983Go; Brand-Saberi et al., 1994Go). 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., 1999Go). 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., 1983Go).

In trisomy 21, the interstitial fluid has been found to be bound to collagen subtype VI (Brand-Saberi et al., 1994Go; Berger, 1999Go). 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., 1994Go; Berger, 1999Go). 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., 1997aGo, bGo; Montenegro et al., 1997Go; Nicolaides et al., 1999Go) 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., 1996Go).

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., 1998Go; Souka et al., 1998Go; Hyett et al., 1999Go). 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., 1999Go). Some authors (Pajkrt et al., 1999Go) 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., 1995Go; Fukada et al., 1997Go; Huisman and Bilardo, 1997Go; Iskaros et al., 1997Go). In this respect, we have described two cases in which nuchal cord was proposed to cause temporary neck congestion (Maymon et al., 1999Go).

The explanation which has been suggested is the correction of the haemodynamic disturbances occurring later in gestation (Hyett et al., 1997bGo; Huisman and Bilardo, 1997Go).

Our data validate previous reports (Bilardo et al., 1998Go; Adekunle et al., 1999Go) 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., 1998Go; Adekunle et al., 1999Go) have examined long term infant outcomes in such pregnancies. While two of them have found a similar prevalence of neuro-developmental delay (3–5.6%) (Van Vugt, 1998; Adekunle et al., 1999Go), 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., 1998Go). 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., 1998Go).

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.


    Notes
 
3 To whom correspondence should be addressed at: Department of Obstetrics and Gynecology, Assaf Harofe Medical Center, Zerifin 70300 (affiliated with Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv), Israel.E-mail: intposgr{at}post.tau.ac.il Back


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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
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Submitted on February 16, 2000; accepted on June 2, 2000.





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