Fetal cardiac function between 11 and 35 weeks' gestation and nuchal translucency thickness

Authors

  • S. A. B. Clur,

    Corresponding author
    1. Department of Paediatric Cardiology of the Emma Children's Hospital, Academic Medical Centre, Amsterdam, The Netherlands
    2. The Centre for Congenital Heart Anomalies Amsterdam-Leiden, The Netherlands
    • Department of Paediatric Cardiology, Emma Children's Hospital, Academic Medical Centre, Meibergdreef 9, PO Box 2244, 1100 DD, Amsterdam, The Netherlands
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  • K. Oude Rengerink,

    1. Department of Obstetrics and Gynaecology, Fetal Medicine Unit, Academic Medical Centre, Amsterdam, The Netherlands
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  • B. W. J. Mol,

    1. Department of Obstetrics and Gynaecology, Fetal Medicine Unit, Academic Medical Centre, Amsterdam, The Netherlands
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  • J. Ottenkamp,

    1. Department of Paediatric Cardiology of the Emma Children's Hospital, Academic Medical Centre, Amsterdam, The Netherlands
    2. The Centre for Congenital Heart Anomalies Amsterdam-Leiden, The Netherlands
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  • C. M. Bilardo

    1. Department of Obstetrics and Gynaecology, Fetal Medicine Unit, Academic Medical Centre, Amsterdam, The Netherlands
    2. Department of Obstetrics and Gynecology, University Medical Centre Groningen, Groningen, The Netherlands
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Errata

This article is corrected by:

  1. Errata: Erratum Volume 38, Issue 4, 486, Article first published online: 20 September 2011

Abstract

Objectives

The pathophysiological background of an increased nuchal translucency (NT) is still poorly understood. Cardiac dysfunction has been proposed as a cause. The aim of this study was to determine if, in fetuses with normal hearts, the NT thickness is related to cardiac function throughout gestation.

Methods

The NT was measured in 191 karyotypically/phenotypically normal fetuses with structurally normal hearts and was increased (≥ 95th centile) in 104. All fetuses had been referred for fetal echocardiography and were prospectively included between October 1 2003 and April 1 2009. Three-hundred and ten echocardiograms were performed between 11 and 35 weeks' gestation. The E- and A-wave velocity, E/A velocity ratio, E/time velocity integral (TVI) ratio over the atrioventricular (AV) valves, myocardial performance index, acceleration time (AT) and peak velocity over the semilunar valves, stroke volume (SV) and cardiac output (CO) as well as the ductus venosus pulsatility index for veins at 11–14 weeks' gestation (DV-PIV), were measured. A multilevel analysis was performed using the NT multiples of the median (MoM) as a continuous variable.

Results

AV-E- and A-wave velocities, E/A velocity ratios, semilunar valve peak velocity, SV, CO and aortic valve (AoV) AT increased significantly with advancing gestation. At 11–14 weeks' gestation, the AoV-AT, tricuspid valve (TV)-E/A, TV-E/TVI ratios and DV-PIV increased, and the pulmonary valve (PV) AT decreased, with increasing NT-MoMs. After midgestation, the PV-AT increased and the AoV-AT, TV-E/A and TV-E/TVI ratios decreased with increasing NT-MoMs.

Conclusions

NT thickness is related to right ventricular diastolic function and semilunar valve AT. Our findings suggest improved first-trimester, but later reduced, right ventricular relaxation and discordant ventricular afterload in fetuses with an increased NT. Copyright © 2011 ISUOG. Published by John Wiley & Sons, Ltd.

Introduction

Nuchal translucency (NT) defines the transient nuchal fluid accumulation seen in fetuses at 11–14 weeks' gestation1, 2. In the presence of a normal karyotype, an enlarged NT is associated with a variety of structural and genetic disorders, congenital heart defects (CHDs) being the most common3–11. A single pathophysiological denominator explaining the complete spectrum of malformations seen, the cause of the fluid accumulation and its transient nature remains to be found. Much emphasis has been placed on possible cardiac failure as the cause of the increased nuchal fluid, based on the frequent association between increased nuchal fluid and abnormal DV flow12, 13. Cardiac failure has been thought to be caused by intrinsic myocardial dysfunction or altered fetal hemodynamics secondary to the CHD itself12, 13. Besides edema from venous congestion, over-perfusion of the head, supported by the finding of narrowing of the aortic isthmus and widening of the ascending aorta14, has been considered as one of the mechanisms leading to nuchal fluid accumulation.

The few studies on cardiac function and increased NT have given contradictory results. In second-trimester fetuses, with and without first-trimester NT enlargement, no significant difference in the ejection fraction measured at midgestation was found in one study15, whereas another study found reduced diastolic function of both ventricles, but no systolic dysfunction16. A study on first-trimester fetuses showed a significant relationship between atrioventricular valve (AV) flow velocities and NT thickness in normal fetuses17, whereas others18, 19, found no differences in myocardial performance index (MPI) and E/A velocity ratio across the AV valves, among normal fetuses, fetuses with CHDs and fetuses with an increased NT and normal chromosomes. Cardiac function in fetuses with normal hearts and increased or normal NT has been studied in either the first trimester or the second trimester, but never throughout gestation. The aim of this study was to investigate if NT thickness is related to cardiac function parameters at any point in gestation.

Methods

Consecutive fetuses with a known NT measurement referred to our Fetal Medicine Unit for echocardiography between October 1 2003 and April 1 2009 were prospectively included. The NT was measured by ultrasonographers accredited by The Fetal Medicine Foundation.

Standard referral indications for echocardiography at our Fetal Medicine Unit for echocardiography are an enlarged NT, suspicion of cardiac pathology or an a priori risk of CHD. Gestational age was determined using the fetal crown–rump length measured between 11 and 14 weeks' gestation. Where indicated, karyotyping was offered by chorionic villus sampling or amniocentesis, depending on the gestational age.

Fetal echocardiography was performed, according to standard recommendations20, using the following equipment: a Philips IU22 (Philips Medical Systems, Bothwell, WA, USA), a General Electric Voluson Expert 730 or a Voluson E8 (both GE Medical Systems, Milwaukee, WI, USA). Examinations were performed by a fetal medicine specialist (C.M.B.; 52% of cases) or a pediatric cardiologist (S.A.C.; 48% of cases). After confirming a structurally normal heart, Doppler flow evaluation was performed using the four-chamber and outflow tract views. Angle correction was applied, as appropriate, up to a maximum of 30°. Care was taken to try to identify valve clicks where relevant and the fastest sweep time was used21–23. Peak E-wave (early ventricular filling) and A-wave (atrial contraction) velocities (cm/s), E/A velocity ratio and time velocity integral (TVI) (cm) over the AVs were measured to assess diastolic function24, 25.

The time between AV inflow (ms), semilunar valve ejection time (ms) and heart rate (HR) were measured and used to calculate the MPI according to the formula of Tei et al.26: (a − b)/b, where a = time between AV inflow and b = the ejection time over the semilunar valve. MPI is a measure of global cardiac function incorporating the isovolumetric contraction time reflecting systolic function and the isovolumetric relaxation time reflecting early diastolic function. As the time intervals for the right ventricle (RV) cannot usually be measured simultaneously, we included measurements of tricuspid valve (TV) inflow and pulmonary valve (PV) outflow with similar heart rates and, where possible, recorded in a sweep from the TV towards the PV.

Systolic function was expressed in terms of peak velocity (m/s) and acceleration time (AT) (ms) over the semilunar valves, stroke volume (mL) and cardiac output (mL/min). The great vessel cross-sectional area (CSA) was calculated using the formula CSA = π(diameter/2)2. Stroke volume (SV) = TVI × CSA and cardiac output (CO) = SV × HR24, 27.

Ductus venosus (DV) flow patterns were recorded by C.M.B., as previously described8. The sample volume was kept as small as possible in order to prevent interference from nearby vessels. The mean DV pulsatility index for the veins (DV-PIV) was calculated and evaluated according to published reference ranges28.

Measurements in addition to those of the routine fetal heart examination extended the examination time by no more than 5–10 min. The mechanical and thermal indices were kept as low as possible (ALARA). All women were informed and consented to participate in the study. In each fetus it was attempted to schedule repeat echocardiograms in each trimester of pregnancy according to the moment of entry into the study.

In interobserver and intraobserver reproducibility studies, the cardiac Doppler profiles were assessed and the cardiac function measurements (peak velocity, AT over the semilunar valves, SV, CO, MPI, peak E- and A-wave velocities, E/A velocity ratio and E/TVI over the AVs) were performed by the two operators blinded to their own and each other's results on cases at variable gestational ages.

Outcome data were collected from hospital notes. The presence of a normal heart was confirmed after birth by a physical examination of the baby, and, where possible, by an echocardiogram. Cases with an abnormal karyotype or an abnormal postnatal phenotype, a structurally abnormal heart, extracardiac abnormalities and cardiac arrhythmias were excluded from the analysis.

Statistical analysis

A linear mixed model (also known as multilevel analysis) was used to analyze the longitudinal relationship between the NT at 11–14 weeks' gestation and cardiac function parameters during gestation. The various parameters of cardiac function were measured repeatedly over time (one to four times per fetus), with irregularly spaced time intervals between the measurements. The linear mixed model uses all available data, irrespective of the number of repeated measurements, and is capable of dealing with irregularly spaced time intervals29. The NT and gestational age were the independent variables. We used the NT expressed in multiples of the median (MoM) to correct for the effect of gestational age on the NT measurement. If the parameters of cardiac function were not normally distributed, a natural or log10 transformation was applied. We checked if a quadratic term improved the model. All analyses were performed using SPSS 17.0 (SPSS Inc., Chicago, IL, USA) and P≤0.05 was considered statistically significant.

Results

One-hundred and ninety one fetuses fulfilled the inclusion criteria. The reasons for referral for fetal echocardiography were: increased NT in 71 (37.2%), an increased risk of aneuploidy based on the combined test in 40 (20.9%), a family history of CHD in 39 (20.4%), an increased risk of a fetal abnormality in 23 (12%), suspicion of a fetal abnormality in 15 (7.9%) and other reasons in three (1.6%). The characteristics of the study population are presented in Table 1.

Table 1. Characteristics of the study population
CharacteristicsValue
  1. Data presented as n (%) or n, except where indicated otherwise. DV-PIV, ductus venosus pulsatility index for veins.

Nuchal translucency (n = 191) 
 Median (range) (mm)2.8 (0.5–14)
 < 95th centile87 (45.6)
 ≥ 95th centile104 (54.4)
DV-PIV (n = 110) 
 Mean ± SD1.5 ± 0.7
 < 95th centile65 (59.1)
 ≥ 95th centile45 (40.9)
Genotype/phenotype 
 Normal karyotype120 (62.8)
 Normal phenotype71 (37.2)
Gender (n = 190) 
 Male116
 Female74
Cardiac follow-up (n = 188) 
 Postnatal echocardiogram65 (34)
 Clinical examination only113 (59.2)
 Postmortem examination4 (2.1)
Deaths (n = 10) 
 Termination of pregnancy7 (4 with worsening hydrops; 3 with very large NT)
 Intrauterine death2 (1 with chorioamnionitis; 1 unexplained)
 Stillbirth1 (partus prematuras)

Three-hundred and ten cardiac function studies were performed. One echocardiogram was performed on 107 fetuses (56.0%), two on 53 (27.8%) and at least three, (one per trimester), were performed on 31 (16.2%) fetuses. Table 2 shows the distribution of cardiac studies, stratified according to gestational age.

Table 2. Distribution of echocardiograms stratified by gestational age and nuchal translucency thickness
 Gestational age (weeks)
Nuchal translucency11.0–13.914.0–17.918.0–21.922.0–27.928.0–35.9
< 95th centile3219381620
≥ 95th centile5336531429
Total8555913049

Measurements

The results of the reproducibility studies are available online in Tables S1 and S2. The reproducibility varied from very poor to very good depending upon the parameter measured and the pregnancy duration at time of measurement. In the interobserver study the intraclass correlation coefficient was ≥ 0.6 in nine of the 18 measured parameters. The intraobserver study showed better reproducibility: 15 of the 18 measured parameters had an intraclass correlation ≥ 0.6.

Table 3 shows the parameters of cardiac function measured at 11–15, 18–22 and 28–32 weeks' gestation for the whole population. Overall, the A-wave velocities were significantly higher than the E-wave velocities across the AVs (P < 0.001, mean difference = 17 for both ventricles). The E- and A-wave velocities for the TV (P < 0.001 for both, mean difference = 2.8 for the E-wave and mean difference = 3 for the A-wave) and the SV and CO of the RV were significantly higher than for the left ventricle (LV) (P < 0.001 for both; mean difference = 0.26 for SV and mean difference = 38 for CO).

Table 3. Cardiac function parameters stratified by gestational age and linear multilevel regression analysis for cardiac function and gestational age
 Gestational age (weeks)  
Cardiac function parameter11–15 (n = 120)18–22 (n = 98)28–32 (n = 35)β-inclination gestational ageP
  • Data presented as mean ± SD or mean (95% CI); n = number of studies.

  • *

    11–14 weeks.

  • Log10 of the parameter.

  • P≤0.05.

  • §

    ln of parameter.

  • A, peak A-wave velocity; AoV, aortic valve; AT, acceleration time; CO, cardiac output; E, peak E-wave velocity; LV, left ventricle; MPI, myocardial performance index; MV, mitral valve; PV, pulmonary valve; RV, right ventricle; SV, stroke volume; TV, tricuspid valve; TVI, time velocity integral; Vel, peak velocity.

DV-PIV1.5 ± 0.7*
PV-Vel (cm/s)35.6 ± 7.552.0 ± 10.767.1 ± 15.20.016 (0.012–0.020)< 0.001
PV-AT (ms)31.3 ± 12.034.1 ± 10.141.7 ± 9.60.283 (−0.122 to 0.688)0.168
RV-SV (mL)0.08 ± 0.040.55 ± 0.282.55 ± 1.440.211 (0.184–0.237)§< 0.001
RV-CO (mL/min)12.9 ± 7.982.7 ± 41.5358.5 ± 210.70.091 (0.078–0.104)< 0.001
TV-E (cm/s)22.7 ± 6.327.4 ± 6.838.1 ± 8.40.980 (0.690–1.271)< 0.001
TV-A (cm/s)39.6 ± 8.845.3 ± 8.254.7 ± 10.80.908 (0.479–1.337)< 0.001
TV-E/A0.57 ± 0.090.60 ± 0.110.71 ± 0.100.010 (0.005–0.014)< 0.001
TV-E/TVI (sv/s)7.2 ± 1.96.4 ± 1.56.3 ± 0.90.018 (−0.044 to 0.081)0.567
RV-MPI0.35 ± 0.140.32 ± 0.160.35 ± 0.220.005 (−0.002 to 0.013)0.180
AoV-Vel (cm/s)37.9 ± 11.354.9 ± 12.769.4 ± 14.60.017 (0.012–0.021)< 0.001
AoV-AT (ms)37.9 ± 12.441.0 ± 10.847.1 ± 9.80.961 (0.540–1.383)< 0.001
LV-SV (mL)0.07 ± 0.050.45 ± 0.281.87 ± 0.840.211 (0.183–0.238)§< 0.001
LV-CO (mL/min)11.6 ± 7.131.3 ± 12.0264.2 ± 114.30.088 (0.076–0.100)< 0.001
MV-E (cm/s)20.3 ± 6.066.6 ± 42.132.9 ± 7.90.907 (0.635–1.179)< 0.001
MV-A (cm/s)37.2 ± 8.141.0 ± 8.548.4 ± 10.81.066 (0.661–1.471)< 0.001
MV-E/A0.54 ± 0.100.60 ± 0.110.69 ± 0.150.006 (0.001–0.011)0.007
MV-E/TVI (sv/s)7.0 ± 2.06.3 ± 1.36.1 ± 1.1− 0.048 (−0.109 to 0.013)0.123
LV-MPI0.36 ± 0.120.31 ± 0.120.31 ± 0.15− 0.001 (−0.005 to 0.005)0.815

Linear multilevel analysis (Table 3) showed that in all fetuses the peak velocity over the semilunar valves, the SV and CO of both ventricles, the aortic valve (AoV) AT and the E- and A-wave velocity and the E/A ratios over the AVs increased significantly with gestational age. The PV-AT, E/TVI ratio and MPI remained constant during gestation.

When NT-MoM was used as a continuous variable, the TV-E/A ratio, TV-E/TVI and AoV-AT increased, and the PV-AT decreased significantly with increasing NT-MoM between 11 and 14 weeks' gestation (Figure 1). This relationship was not constant throughout gestation, inverting after midgestation (Table 4). The addition of quadratic terms to the model did not improve the model fit. The results of the longitudinal observations of the 31 fetuses that had at least three examinations are presented in Figure 2.

Figure 1.

Relationship between cardiac function parameters measured at 11–15, 18–22 and 27–33 weeks' gestation and nuchal translucency measurement expressed in multiples of the median (NT-MoM). (a) Acceleration time (in ms) over the aortic valve (AoV-AT). (b) Acceleration time (in ms) over the pulmonary valve (PV-AT). (c) Tricuspid valve E/A velocity ratio (TV-E/A). (d) Tricuspid valve E/time velocity integral (TVI) ratio (TV-E/TVI).

Figure 2.

Longitudinal data from 31 fetuses (21 with nuchal translucency (NT) ≥ 95th percentile (equation image) and 10 with NT < 95th centile (equation image)) who underwent at least three cardiac function measurements. (a) Acceleration time over the aortic valve (AoV-AT). (b) Acceleration time over the pulmonary valve (PV-AT). (c) Tricuspid valve E/A velocity ratio (TV-E/A). (d) Tricuspid valve E/time velocity integral (TVI) ratio (TV-E/TVI). Median and interquartile range (IQR) are shown, along with the range excluding outliers (whiskers) and outliers more than 1.5 × IQR (•) or 3 × IQR (*) from the upper or lower quartile.

Table 4. Multilevel regression analysis for cardiac function corrected for nuchal translucency and for gestational age
 NT-MoM β-coefficient (95% CI)PNT-MoM and gestational age β-coefficientP
  • *

    P≤0.05.

  • A, peak A-wave velocity; AoV, aortic valve; AT, acceleration time; CO, cardiac output; E, peak E-wave velocity; LV, left ventricle; MoM, multiples of the median; MPI, myocardial performance index; MV, mitral valve; NT, nuchal translucency; PV, pulmonary valve; RV, right ventricle; SV, stroke volume; TV, tricuspid valve; TVI, time velocity integral; Vel, peak velocity.

Log10 (PV-Vel)− 0.015 (−0.047 to 0.017)0.3590.00020.787
PV-AT− 3.392 (−6.784 to − 0.0004)0.050*0.1890.034*
ln(RV-SV)− 0.122 (−0.354 to 0.109)0.298− 0.0090.686
Log10 (RV-CO)− 0.044 (−0.160 to 0.072)0.4500.00070.820
TV-E1.474 (−0.703 to 3.650)0.184− 0.0800.213
TV-A0.076 (−3.321 to 3.472)0.965− 0.0170.857
TV-E/A0.034 (0.002–0.065)0.036*− 0.0020.093
TV-E/TVI0.751 (0.243–1.258)0.004*− 0.0360.009*
RV-MPI0.035 (−0.024 to 0.093)0.244− 0.0010.375
Log10 (AoV-Vel)− 0.018 (−0.053 to 0.017)0.3060.00000.999
AoV-AT4.184 (0.591–7.776)0.023*− 0.2180.017*
ln(LV-SV)0.079 (−0.144 to 0.303)0.485− 0.0050.355
Log10 (LV-CO)0.035 (−0.067 to 0.137)0.497− 0.0070.391
MV-E1.700 (−0.365 to 3.764)0.106− 0.0810.182
MV-A2.573 (−0.515 to 5.661)0.102− 0.1650.070
MV-E/A0.003 (−0.032 to 0.038)0.8660.00060.580
MV-E/TVI0.042 (−0.465 to 0.548)0.8720.0010.916
LV-MPI0.010 (−0.030 to 0.050)0.617− 0.0010.648

The DV-PIV was measured at 11–14 weeks' gestation in 110 (57.6%) fetuses and was ≥ 95th centile in 45 (40.9%) (in 10/44 (22.7%) fetuses with a normal NT and in 35/64 (54.7%) with an enlarged NT). The DV-PIV increased significantly with increasing NT measurement at 11–14 weeks gestation, (P < 0.001; r = 0.388) (Figure 3).

Figure 3.

Relationship between ductus venosus pulsatility index measured at 11–14 weeks' gestation and nuchal translucency measurement expressed in multiples of the median (NT-MoM).

Discussion

This is the first study to investigate the relationship between cardiac function and NT measurement in normal fetuses with normal hearts throughout gestation. In early gestation the TV-E/A velocity ratio, the TV-E/TVI ratio, the AoV-AT and the DV-PIV increase, and the PV-AT decreases, with increasing NT thickness. Between 20 and 35 weeks' gestation, the observed relationships invert, resulting in an increasing PV-AT and a decreasing TV-E/A velocity ratio, TV-E/TVI ratio and AoV-AT with increasing NT. The MPI and other measured cardiac function parameters are not related to NT thickness. Furthermore, we confirmed a maturational change in AV E- and A-wave velocities and the E/A ratio, semilunar valve peak velocity, SV and CO between 11 and 35 weeks' gestation30–32.

Cardiac function in first-trimester fetuses is still relatively unexplored and therefore caution is required in interpreting the hemodynamic and clinical significance of our findings. Moreover, the finding of significance in isolated parameters in a multivariate analysis may not necessarily reflect physiologically relevant modifications.

Diastolic function is complex and its interpretation by Doppler investigation is challenging. Pseudo-normalization may mask severe dysfunction with reduced compliance and relaxation33. Furthermore, Doppler flow velocity patterns are influenced by loading conditions25, 34–36. This is especially relevant in first-trimester fetuses with less compliant immature ventricles burdened by increased preload and afterload, as a result of rapidly increasing blood volume, immature kidneys and high placental resistance37–39. Therefore, we also measured the AV valve E/TVI ratio (peak filling rate normalized to SV), which is independent of heart rate and changes in CO25, 36 and is thus more representative of changes in intrinsic diastolic function (relaxation and compliance). This study confirmed that the reproducibility of Doppler measurements is problematic21–23, 40, especially at early gestation. In contrast to another study18 where measurements were performed on stored Doppler tracings, in this study each operator obtained new Doppler traces before making measurements. This may increase the source of variability, probably in view of small differences in caliper placement, as suggested by our better intraobserver variability. Interestingly, the measurement of SV and CO, requiring accurate measurements of great vessel diameters which are then squared27, potentially amplifying measurement inaccuracies, had good reproducibility in this study.

The results suggest that fetuses with an increased NT have better active RV relaxation and increased RV afterload, but reduced LV afterload, at 11–14 weeks' gestation. In the fetus, the RV-CO exceeds the LV-CO and it pumps against systemic resistance (via the ductus arteriosus). Increased afterload (distal to the aortic isthmus) when the NT is increased, could explain the decreased PV-AT found and the reported increased incidence of tricuspid regurgitation41. It is unclear if downstream placental resistance is altered in fetuses with increased NT, as reports are contradictory37, 42. In early gestation, major changes in placental development occur along with the establishment of the intervillous circulation43. At this stage, significant changes in umbilical artery blood volume are required before a change in pulsatility index (PI) is recordable39, suggesting that the PI may be more representative of trophoblastic villous development rather than true vascular resistance. The increased AoV-AT in fetuses with increased NT suggests reduced afterload in the ascending aorta. This supports the theory of over-perfusion of the head and neck, based on findings of aortic isthmal narrowing and ascending aortic widening in fetuses with increased NT3, 14. The failure to find a relationship between carotid artery PI (over-perfusion) or jugular vein PI (venous congestion) at 11–14 weeks' gestation and an increased NT38 counts against the over-perfusion theory. However, flow and resistance are different parameters that cannot be used interchangeably.

Interestingly, our findings in 11–14-week-old fetuses with increased NT are analogous to the cardiovascular changes reported in second- and third-trimester severely growth-restricted fetuses with increased placental impedance, showing blood-flow redistribution and dilatation of the DV in response to hypoxemia44–47. Hypoxia has also been proposed as an environmental insult linking the increased NT and CHDs48.

After midgestation the cardiac function studies in fetuses with increased NT showed an increased PV-AT, but reduced AoV-AT and decreased TV-E/A and E/TVI ratios. This is compatible with increased LV afterload but reduced RV afterload and relaxation. The nuchal fluid has usually disappeared at this stage and this may coincide with reduced over-perfusion of the head and a steadily decreasing RV afterload. Increased umbilical flow, along with reduced placental resistance, is also suggested by the tendency of fetuses with enlarged NT to have higher birth weights49.

Three other studies measured cardiac function at 11–14 weeks' gestation. One study found a positive correlation between mitral valve E- and A-wave and TV-E-wave velocities and NT thickness17, whereas another found no difference in AV flow velocities19. The large study of Huggon et al.18 found no significant differences between MPI, AV-E-wave velocity and AV-E/A ratio between chromosomally normal fetuses with and without an increased NT. The different statistical approach (comparison of means) may also explain the differences between this study and theirs.

Rizzo et al. measured cardiac function at 20–23 weeks' gestation in chromosomally normal fetuses that had had an increased NT16. In accordance with their findings we observed significantly decreased E/A and E/TVI ratios in these fetuses at 20 weeks' gestation, suggesting diastolic dysfunction as a result of reduced myocardial relaxation, but only for the RV.

Further studies, possibly using newer techniques, are therefore required to support and clarify our findings. Whether cardiac function changes are found postnatally in babies who had an increased NT as a fetus is a subject worth further investigation.

In conclusion, this study has shown that, in normal fetuses with normal hearts, the DV-PIV, TV-E/A and TV-E/TVI ratios and AoV-AT increase, and the PV-AT decreases, with increasing NT in early gestation. After 20 weeks' gestation the relationships invert. These findings suggest better RV relaxation at 11–14 weeks' gestation, reduced RV relaxation in later gestation and discordant ventricular afterload in the fetuses with increased NT.

SUPPORTING INFORMATION ON THE INTERNET

The following supporting information may be found in the online version of this article:

Table S1 Interobserver variability per measured cardiac function parameter.

Table S2 Intraobserver variability per measured cardiac function parameter.

Ancillary