Ultrasound and echocardiographic findings obtained in the second and third trimesters of gestation in fetuses with normal karyotype and increased nuchal translucency.

INTRODUCTION: Numerous papers have proven that an increased nuchal translucency is connected with a raised risk of chromosomal aberrations, but few analyses are related to the further state of fetuses with a normal karyotype. THE AIM OF THE STUDY: The aim of the study was to estimate the risk of cardiac defects and other developmental disorders in fetuses with increased nuchal translucency and normal findings of a standard cytogenetic examination.
METHODS: The authors carried out a retrospective analysis of 5183 examinations of 3376 patients who reported to the Department of Diagnosis and Prophylaxis of Congenital Malformations in the Polish Mother's Memorial Hospital in Łódź in the period from January 2008 to March 2011 for prenatal ultrasound and echocardiographic examinations. The authors analyzed the results of the examinations performed in the second and third trimesters of gestation in fetuses with an increased nuchal translucency of ≥3 mm in the first trimester and with a normal karyotype.
RESULTS: Fifty-seven patients (1.7% of the examined group) fulfilled the criteria necessary to be included in the study. In 31 pregnant women (54%) structural defects or anomalies of the fetus were found. Cardiac anomalies were detected in 17 fetuses (29.8%). The authors detected various types of cardiac defects such as tetralogy of Fallot, ventricular septal defect, atrioventricular septal defect, transposition of the great arteries and hypoplastic left heart syndrome.
CONCLUSIONS: In more than half of the fetuses with an increased nuchal translucency (NT ≥ 3 mm) and a normal karyotype, developmental defects of various organs appeared in the further course of pregnancy: mainly heart defects that were either isolated, or accompanied other anomalies.

Introduction

A nuchal translucency (NT) is a transient edema of the subcutaneous tissue in the area of the fetal nucha and occurs in the first trimester of gestation(. It is evaluated between the beginning of the 11th and the end of the 13th weeks of pregnancy (crown-rump length, CRL – 45–84 mm). After the 14th week of gestation, an edema of the nuchal region is called a thickening of the nuchal fold. The term nuchal translucency is used irrespective of whether or not septations are present and whether the edema is limited solely to the nuchal region or extends along the entire body of the fetus(.

The nuchal translucency (which occurs in every fetus) increases with gestational age and crown-rump length and in order to obtain an adequate interpretation, it should be assessed with the use of a growth chart(.

In normal fetuses, the fluid accumulated in the nuchal translucency undergoes absorption after the 14th week of pregnancy. In some fetuses, however, it may persist as a thickening of the nuchal fold, nuchal cystic hygroma or generalized edema(.

An increased nuchal translucency is related to a raised risk of chromosomal aberrations. Therefore, amniocentesis is recommended to each pregnant woman after the detection of an increased NT. An abnormal karyotype is observed in 1/3 of the fetuses with an increased nuchal translucency( – the most commonly diagnosed syndromes being Down, Edwards, Patau or Turner(.

According to some authors, the risk that in subsequent weeks of gestation, fetuses with an increased NT and a normal karyotype will develop various anomalies, such as isolated and multiple defects or genetic syndromes, is elevated. However, according to other studies, the subsequent development of these fetuses is frequently not anomalous(.

The aim of this study was to estimate the risk of cardiac defects and other developmental disorders in fetuses with an increased nuchal translucency and normal karyotype.

Methods

The authors carried out retrospective analyses of 5183 examinations performed in 3376 patients who, in order to perform prenatal ultrasound (US) and echocardiographic examination, reported to the Department of Diagnosis and Prophylaxis of Congenital Malformations in the Polish Mother's Memorial Hospital in Łódź in the period from January 2008 to March 2011.

The established criteria for the enrolment of patients to the study were as follows:

single pregnancy;

nuchal translucency ≥3 mm;

normal fetal karyotype (evaluated on the basis of invasive prenatal tests).

In most cases, ultrasound scanning with the analysis of the NT in the first trimester was performed in a different center. Only documented US examinations from the first trimester (photographs or digital documentation), after being verified by physicians with the Fetal Medicine Foundation Certificate, were used in further analysis.

In the Department of Diagnosis and Prophylaxis of Congenital Malformations in the Polish Mother's Memorial Hospital in Łódź, at least one US + ECHO examination was performed in each pregnant patient above the 20th week of gestation. The examinations were performed by means of the following US scanners: GE Voluson 730 Expert and ATL HDI 5000. The patients’ personal details were encoded and included in the calculation chart preserving the physician-patient privilege of confidentiality. Fetal anomalies were diagnosed in a single scan, but also analyzed during check-up examinations.

The statistical analysis was performed by means of R program, version 2.13.1 (The R Foundation for Statistical Computing, www.r-project.org). The assumed statistical significance level was p < 0.05.

Results

Fifty-seven patients (1.7% of the examined group) fulfilled the necessary criteria and were included in the study. In 31 patients (54%), structural defects or anomalies of the fetus were found. The median for the nuchal translucency in this group was 4.6 mm, with the mean value of 4.72 mm (range between 3.0 and 9.4 mm). The types of detected anomalies (both cardiac and extracardiac) in the examined group are presented in table 1.

Tab. 1

Types of detected anomalies in 31 fetuses with increased nuchal translucency (median for NT 4.6 mm) and normal karyotype

No.	Year of examination	Weeks of gestation	NT [mm]	Cardiologic diagnosis	Extracardiac defects and anomalies
1	2009	13	3,6	Normal heart anatomy	Bilateral pyelectasis
2	2009	13	4,7	Normal heart anatomy + cardiac hypertrophy	Non-immune hydrops fetalis, ascites, pleural effusion, nuchal cystic hygroma
3	2009	11	5,4	Tetralogy of Fallot	Thymic hypoplasia, congenital talipes equinovarus
4	2009	12	3,7	Single ventricle with parallel origin of the great vessels
5	2009	12	3	Pulmonary atresia, ventricular septal defect
6	2009	13	5	Pulmonary stenosis, corrected transposition of the great arteries, ventricular septal defect, complete heart block
7	2009	12	7	Ventricular septal defect	Scoliosis, anhydramnios, nuchal cystic hygroma
8	2009	13	3,2	Hypoplasia of the right ventricle, double, parallel origin of the vessels from the left ventricle, ventricular septal defect	Single umbilical artery
9	2009	13	6,6	Pulmonary valve regurgitation	Gastrointestinal tract duplication
10	2009	12	9,4	Hypoplastic left heart syndrome	Unilateral pyelectasis, hydrocele testis
11	2009	13	3,6	Normal heart anatomy	Choroid plexus cysts
12	2010	12	3,1	Transposition of the great arteries, ventricular septal defect, cardiac hypertrophy
13	2010	12	4,6	Normal heart anatomy	Diaphragmatic hernia, polyhydramnios
14	2010	11	4,6	Normal heart anatomy + cardiac hypertrophy, cardiomegaly
15	2010	12	4,5	Normal heart anatomy	Unilateral pyelectasis, hydronephrosis
16	2010	12	4,8	Atrioventricular septal defect
17	2010	12	4	Left isomerism, totally anomalous pulmonary venous drainage, atrioventricular septal defect, cardiomegaly, complete heart block	Shortened long bones, polyhydramnios, subcutaneous edema, ascites
18	2010	13	3,8	Normal heart anatomy + pericardial effusion, cardiac hypertrophy
19	2010	13	7	Normal heart anatomy + tricuspid regurgitation	Non-immune hydrops fetalis, ascites, pleural effusion, pulmonary hypoplasia, polyhydramnios
20	2010	11	4,6	Subaortic ventricular septal defect with an overriding aorta, cardiomegaly	Hypotelorism, cerebellar hypoplasia, auricle anomaly, esophageal atresia with tracheoesophageal fistula, polyhydramnios
21	2010	11	5	Normal heart anatomy + tricuspid regurgitation	Bilateral pyelectasis
22	2010	13	3,2	Normal heart anatomy	Pulmonary lesion/sequestration, pulmonary hypoplasia, renal hypoplasia
23	2010	12	5,5	Left isomerism, atrioventricular septal defect, “mild” coarctation of the aorta, sinus bradycardia
24	2010	12	8,7	Normal heart anatomy + cardiac hypertrophy
25	2010	12	5,1	Mitral atresia, ventricular septal defect	Single umbilical artery, shortened long bones, upper extremity deformation, hypotelorism
26	2011	12	3,6	Ectopia cordis, atrioventricular septal defect, double outlet right ventricle
27	2011	12	3,5	Tricuspid atresia, single ventricle, pulmonary atresia, parallel origin of the great vessels, aortopulmonary collateral vessels, right-sided aortic arch, accessory left superior vena cava	Polyhydramnios
28	2011	12	3,3	Normal heart anatomy	Single umbilical artery
29	2008	11	5,4	Tetralogy of Fallot	Polyhydramnios
30	2008	14	3,3	Normal heart anatomy	Gastroschisis
31	2008	12	3,6	Hypoplastic left heart syndrome, aortic arch hypoplasia/interrupted aortic arch

In the case of 40 fetuses, a normal cardiac structure was observed (with or without functional changes) and 17 fetuses (29.8% of the examined group) presented cardiac defects. The median for the nuchal translucency measurement in the group with cardiac defects constituted 4.6 mm, with the mean value of 4.7 mm (range between 3.0 and 9.4 mm). In 7 fetuses with normal anatomic structure, the following functional changes were found: cardiac hypertrophy (n = 4), tricuspid insufficiency (n = 2) and pulmonary valve insufficiency (n = 1). Additionally, one of the fetuses with cardiac hypertrophy was diagnosed with cardiomegaly and another, with pericardial effusion. The discussed functional changes are transient in fetuses, in contrast with the persistent hypertrophy that often occurs in pediatric or adult cardiology.

Extracardiac anomalies (both in fetuses with cardiac defects and with normal cardiac anatomy) were found in 20 fetuses (35%).

Twenty-six fetuses (45.6%) presented normal development, correct heart structure and no extracardiac anomalies. The median for the nuchal translucency in this group was 3.6 mm, with a mean value of 3.88 mm (range between 3.0 and 5.3 mm).

The comparison of the median and quartile for the NT measurement in fetuses without accompanying defects and in those with detected structural abnormalities or other anomalies, is presented in fig. 2 (Mann-Whitney U test, p < 0.04).

Fig. 2

Comparison of the median and quartile for NT measurement in fetuses without accompanying defects (n = 26) and in those with detected structural defects or other anomalies (n = 31) (Mann-Whitney U test, p < 0.04)

Results of echocardiographic fetal examinations

Discussion

The conducted analysis shows that more than a half of fetuses (54%) with an increased NT in the first trimester and with a normal karyotype developed a structural defect and/or functional anomaly, as revealed in the ultrasound/ echocardiographic examination performed several weeks later. In a similar study conducted among the Spanish population on the basis of 171 fetuses with a normal karyotype and an increased NT, an unfavorable course of pregnancy was observed in 37% of the subjects. Structural abnormalities were diagnosed in 21.6% of the examined fetuses. The most common abnormalities, seen in 13.5% of all fetuses, were cardiac defects(.

In the examined population, structural heart defects were detected in 17 fetuses (29.8%); the median for the NT in this group constituted 4.6 mm. Most of the cardiac defects were complex and consisted of numerous anomalies. When examining the cardiac structure, prenatal echocardiography encompasses the assessment of the atria, atrioventricular valves, fetal ventricles, ventriculoarterial connections, location of the aortic arch, fetal mediastinum and pulmonary and systemic venous drainage. The indicators of circulatory system sufficiency and functional changes are assessed separately(. In the analyzed material, the majority of cardiac defects were severe and complex.

Previous studies estimate the incidence of structural cardiac defects in fetuses with an increased NT and a normal karyotype to be approximately 4.9–7%(. However, these results concern the general population. It needs to be added that our center is a cardiologic reference center where screening tests are not performed and this constitutes its specific character. It focuses on various pathologies and therefore, has greater experience, much greater than the centers which perform screening tests.

The analysis of echocardiographic examinations of fetuses with a normal karyotype, which was performed in two reference centers in Great Britain (with the structure similar to our center), gave similar results to the ones quoted in this paper. The analysis followed that an increased NT occurred in nearly a half of the fetuses with a congenital heart defect (47%)(.

The observations made so far indicate that the risk of a cardiac defect in a fetus increases together with the thickness of the NT(. In the case of a NT that is equal or lower than 3.5 mm, septal defects occur more frequently (such as atrioventricular septal defect or ventricular septal defect)(. From the point of view of prenatal cardiology, the ostium secundum type of atrial septal defect does not occur in fetuses: maintaining the correct flow at this level determines the appropriate fetal development. However, when the NT exceeds 3.5 mm, the connection between the type of detected cardiac defects and the NT value is no longer observed(. The study discussed herein does not show a single dominant cardiac defect in fetuses with an increased NT and a normal karyotype.

According to our data, the fetuses with an increased NT are burdened with much greater risk of developing cardiac defects irrespective of their karyotypes. Therefore, echocardiographic examination performed in a reference center should be conducted in each fetus with an increased NT. At present, the first cardiac examination in a fetus may be performed in the first trimester of gestation(. The sensitivity and specificity of such an examination depend on the experience of the center which performs the test as well as on the examined population(. The sensitivity and specificity of echocardiographic examination in the first trimester were calculated on the basis of ten studies (which encompass 1243 examinations altogether) and constitute 85% and 99% respectively(. However, the role of echocardiography in the 20th week of pregnancy should also be emphasized. The examination conducted in this period of gestation is characterized by a high sensitivity value of up to 95%(. What is more, some cardiac defects may reveal themselves in the second or even the third trimester of pregnancy. Therefore, an examination in the first trimester may not replace the one conducted in the 18th–20th weeks of gestation.

In the conducted examination, extracardiac defects were observed in 20 fetuses (35%). Above, numerous extracardiac anomalies were mentioned that are connected with an increased NT such as: body stalk anomaly, diaphragmatic hernia, umbilical hernia, megacystis, skeletal system defects, hydrops fetalis as well as numerous syndromes of congenital defects(.

In the analyzed group, diaphragmatic hernia occurred in only one case. One fetus presented with esophageal atresia with tracheoesophageal fistula, polyhydroamniosis, auricle anomaly, cerebellar hypoplasia and hypotelorism as well as a cardiac anomaly namely, ventricular septal defect. In single fetuses, gastroschisis, hydronephrosis and pulmonary hypoplasia were observed incidentally. Moreover, 4 fetuses demonstrated increased renal pelves (defined as an anteroposterior dimension of the renal pelvis equal to 5–10 mm). Finally, in 2 fetuses, non-immune edema with the pleural and peritoneal effusion was observed.

All analyzed fetuses had a normal karyotype, which, however, does not exclude genetic syndromes that may be accompanied by an increased NT. Some fetuses from the analyzed group presented cardiac and extracardiac abnormalities which might have been suggestive of DiGeorge syndrome. Such anomalies include conotruncal heart malformations: tetralogy of Fallot, persistent truncus arteriosus, transposition of the great arteries, double outlet right ventricle, tetralogy of Fallot with pulmonary atresia or interrupted aortic arch. The extracardiac defects encompassed: thymic hypoplasia, cleft lip/palate as well as defects of the kidneys, extremities and neural tube(.

In the conducted analysis the cut-off point of the NT value was ≥3 mm. The NT increases together with the CRL. The 95th percentile at the beginning of the 11th week constitutes 2.2 mm and at the end of the 13th week – 2.8 mm. The 99th percentile does not undergo significant changes with the CRL and constitutes 3.5 mm(. In the study of Orvos et al., the assumed cut-off point for NT ≥ 3 allowed more than half of fetal cardiac defects to be diagnosed(. The cut-off point used by Nicolaides et al. also constituted NT ≥ 3 mm(.

To conclude, an increased NT in fetuses with a normal karyotype may result from the presence of accompanying defects, mainly involving the heart.

A statistical analysis comparing the values of the nuchal translucency in particular subgroups of developmental defects would be an interesting study. Nevertheless, due to a small number of subjects in the subgroups, the statistical analysis would not provide reliable results. Therefore, such an analysis was not performed.

A comparison of the incidence of developmental defects with the frequency of their occurrence in fetuses with a normal nuchal translucency and a normal karyotype would undoubtedly constitute another valuable study. Unfortunately, in the majority of cases, there are no clinical indications for invasive cytogenetic examinations in fetuses with a correct NT.

Conclusions

The fetuses with an increased nuchal translucency (NT ≥ 3 mm) and a normal karyotype should be included in the high-risk pregnancy group, where it is necessary to perform detailed echocardiographic examinations in subsequent weeks of gestation in order to confirm a correct cardiac structure or detect its defect.