Objective
We sought to assess blood flow in relation to jugular lymphatic distension in fetuses with increased and normal nuchal translucency (NT).
Study Design
In all, 72 fetuses with normal NT and 71 fetuses with NT >95th percentile were evaluated. NT size, jugular lymphatic sacs (JLS), jugular vein and ductus venosus pulsatility index for veins (PIV), and intracardiac velocities were measured.
Results
JLS were visualized in 22/72 fetuses with normal and in 55/71 fetuses with increased NT. Jugular vein and ductus venosus PIV was higher in fetuses with increased NT compared to normal NT ( P < .01). Visibility of JLS was associated with a higher ductus venous PIV ( P < .05), but not with a higher jugular vein PIV. Larger NT and larger JLS volumes were associated with higher jugular vein and ductus venosus PIV ( P < .05).
Conclusion
This study shows a relation among increased NT, jugular lymphatic distension, and altered blood flow in jugular vein and ductus venosus.
The ultrasonographic measurement of the nuchal translucency (NT) in the first trimester of pregnancy is a widely used screening method to identify chromosomal abnormalities in human fetuses. Increased NT is also associated with structural anomalies such as cardiac defects and several genetic syndromes. Recent studies implicate a disturbed lymphatic development as a likely explanation for the pathophysiology of increased NT. First-trimester fetuses with increased NT morphologically show nuchal edema, accompanied by distended jugular lymphatic sacs (JLS). Ultrasound studies of first-trimester fetuses show a similar association between increased NT and the presence of enlarged JLS.
Also, altered ductus venosus flow velocities have been described in fetuses with increased NT. These altered flow velocities and the frequently found cardiovascular malformations have led to cardiac failure as a possible explanation for increased NT. However, other signs of cardiac decompensation are rarely seen in fetuses with enlarged NT.
So far, no study has been performed to investigate if there is a relation between the jugular lymphatic development and hemodynamics in fetuses with increased NT. In this study, we prospectively assessed first-trimester fetuses with normal and increased NT to evaluate presence and volumes of the JLS. The carotid artery, jugular vein, ductus venosus, intracardiac velocities, and flow across the tricuspid valve were evaluated using Doppler flow to assess a possible relation between disturbed jugular lymphatic development and altered hemodynamics of fetuses with increased NT.
Materials and Methods
Women referred to our hospital for tertiary care because of an increased NT, and women attending our hospital for first-trimester screening, were asked to participate in the study. A total of 144 singleton pregnancies were examined. In all, 71 fetuses had an increased NT and 73 fetuses had a normal NT. An increased NT was defined as a NT >95th percentile. All patients received written information and gave informed consent. The medical ethical committee of the Vrije Universiteit University Medical Center approved the study.
Gestational age was calculated based on the reported last menstrual period and adjusted according to crown-rump length if appropriate. Ultrasound examination was performed weekly from the initial scan between 11-13 +6 weeks of gestational age until 17 weeks of gestation by 1 experienced ultrasonographer (Y.M.d.M.). The number of examinations differed because of different gestational ages at the initial scan and patients’ cooperation ( Table 1 ). During each ultrasound examination, the NT was measured using a transabdominal probe (4-8 MHz; Voluson 730 Expert series or Voluson E8; GE Medical Systems Kretz Ultrasound, Zipf, Austria) according to the guidelines of the Fetal Medical Foundation.
| Examinations, n | Fetuses with normal NT (n = 72) | Fetuses with increased NT (n = 71) |
|---|---|---|
| 1 | – | 28 |
| 2 | 10 | 19 |
| 3 | 49 | 20 |
| 4 | 13 | 5 |
The anterolateral region of the neck was examined both transvaginally and transabdominally for the presence of JLS, which appear as spheroid translucencies. If present, the volume of the JLS was calculated using the formula of a spheroid: length × height × width × π/6. Doppler measurements of the carotid artery, jugular vein, and ductus venosus were performed as described previously. Care was taken to keep the interrogation angle as low as possible and always <60 degrees. Flow velocity waveforms of the 3 vessels were used to analyze the peak systolic (S), diastolic, atrial contraction (a-V [for jugular vein and ductus venosus]) and time-average velocity (TAV). The pulsatility index (PI) was calculated (carotid artery: PI = S – diastolic/TAV; jugular vein and ductus venosus: pulsatility index for veins (PIV) = S – aV/TAV).
Flow velocity waveforms were recorded across the mitral and tricuspid valves as described previously. Adjustment was made for the insonation angle, which never exceeded 30 degrees. Peak flow velocities in early diastole (E) and late diastole with atrial contraction (A) were measured and the E/A ratio was calculated. The presence or absence of tricuspid regurgitation was determined by pulsed wave Doppler as described previously. Digital images of each examination were stored.
Karyotyping was performed by chorion villus sampling or amniocentesis. In case of termination of the pregnancy, suction aspiration was performed or labor was induced. Postmortem morphological examination was carried out if the patients approved. The fetus or aspiration tissue was fixed in formalin 4%. Subsequently, postmortem evaluation of the whole fetus or the fetal heart (in case of suction aspiration) was carried out using a dissection microscope. A sequential segmental analysis of the heart was performed by an experienced cardiac morphologist. The neck region was analyzed by microscopic examination of paraffin-embedded serial sections, stained with the lymphatic marker lymphatic vessel endothelial hyaluron receptor-1. The size and morphology of the JLS were compared with those of euploid fetuses with normal nuchal skin (n = 4).
In ongoing pregnancies, a second-trimester ultrasound examination was performed in all cases. After delivery, the parents completed questionnaires concerning newborn health.
Statistical analysis
Doppler measurements of fetuses with and without visualized JLS were compared. Also, Doppler measurements of fetuses with normal and increased NT, with respect to the presence of a cardiac defect, were compared.
Data were studied using general estimating equations analysis (SPSS, version 15.0; SPSS Inc, Chicago, IL). This method takes into account that the same patients are repeatedly measured, which indicates that missing observations are allowed. Furthermore, general estimating equations analysis is capable of dealing with irregularly spaced time intervals. Variables indicating JLS not visible/JLS visible, normal NT/increased NT, normal NT/increased NT without cardiac defect, increased NT without cardiac defect/increased NT with cardiac defect were used to create groups. It was analyzed whether Doppler flow measurements of the compared groups differed significantly in relation to advancing of gestational age. If necessary, a log transformation was used to account for nonnormality of the data.
GEE analysis was also used to assess a possible relationship between Doppler flow measurements and JLS volume, and between Doppler flow measurements and NT-size (correlation coefficient). The statistical significance level was set on P = .05.
Results
In the group of the 73 fetuses with normal NT, 1 patient was excluded from further analysis because of an intrauterine fetal death due to fetal growth restriction. Postmortem examination revealed no abnormalities. Follow-up was complete and in all 72 cases healthy infants were born.
The characteristics of the included 143 fetuses are listed in Table 2 . Invasive tests were offered in case of increased NT, but refused in 1 case. In this case, a healthy neonate without dysmorphic features was born and was considered to have a normal karyotype. A normal karyotype was found in 46 of the 71 fetuses with increased NT (65%); 25 fetuses were aneuploid (35%). Follow-up was known in all cases. Figure 1 shows the disposition of the fetuses included in the study.
| Characteristics | Normal NT (n = 72) | Increased NT (n = 71) | ||
|---|---|---|---|---|
| Mean (SD) | Range | Mean (SD) | Range | |
| Maternal age, y | 34.4 (3.7) | 26–41 | 33.8 (4.5) | 21–44 |
| Gestational age, wk a | 11 +4 (0 +3 ) | 11 +0 –13 +2 | 12 +3 (0 +5 ) | 11 +0 –13 +6 |
| NT, mm a | 1.2 (0.4) | 0.7–2.2 | 4.8 (2.4) | 2.4–14.0 |
| Crown-rump length, mm a | 54.0 (5.9) | 41.9–72.5 | 64.1 (10.8) | 44.7–89.4 |
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