Effect of fetal gender on first-trimester ductus venosus blood flow
Recent reports have suggested that nuchal translucency (NT) measurements in the first trimester may be influenced by fetal gender. Since both NT and central venous blood flow are considered to be related to fetal cardiac function, we investigated gender-related differences in first-trimester ductus venosus Doppler indices.
A total of 73 male and 79 female normal fetuses at 10–14 weeks of gestation were included in the study. The pulsatility index for veins (PIV), peak velocity during ventricular systole (S-wave), time-averaged maximum velocity (TAMV) and A-wave velocity (A-wave) were recorded in each case and converted to the corresponding Z-scores.
The mean Z-score values of PIV, S-wave and TAMV were significantly lower in male fetuses compared to female fetuses (P < 0.01 for all three indices). By contrast, A-wave velocities were not different in the two groups. The correlation between S-wave velocity and TAMV was significant in both male (P < 0.001) and female (P < 0.001) fetuses, while PIV did not appear to be related to TAMV either in males (P = 0.90) or in females (P = 0.49). A-wave velocity had a significant negative correlation with PIV in both groups. Finally, PIV was significantly correlated with S-wave velocity in female fetuses (P < 0.01) but not in males (P = 0.14).
These findings suggest that early cardiovascular development may be different in male and female fetuses. Copyright © 2003 ISUOG. Published by John Wiley & Sons, Ltd.
An increased nuchal translucency (NT) measurement at 10–14 weeks of gestation is known to be associated with fetal chromosomal abnormalities1 and other structural or genetic defects2. Recent findings have suggested that NT measurements may be influenced by fetal gender3, 4 but a smaller study was not able to replicate these results5.
One of the reported possible explanations for increased NT is the occurrence of temporary cardiac impairment, which could also cause an abnormal pattern of blood flow in the fetal ductus venosus6–11. The aim of this study was to investigate gender-related differences in first-trimester ductus venosus blood flow.
Ductus venosus Doppler flow measurements were performed on consecutive patients enrolled in the setting of a screening program for chromosomal abnormalities based on first-trimester combined test (NT, maternal serum pregnancy-associated plasma protein-A (PAPP-A) and free beta-human chorionic gonadotropin (free β-hCG))12. The study was approved by the local ethical committee, and all the patients gave their informed consent.
In each fetus, a midline sagittal view was obtained, and crown–rump length (CRL) and NT were measured. A careful search for fetal abnormalities was then performed. Ductus venosus Doppler studies were performed as previously described13. Briefly, the ductus venosus was identified by color Doppler imaging in a right ventral mid-sagittal plane. The pulsed Doppler gate was placed in the distal portion of the umbilical sinus, taking care to avoid contamination from neighboring central veins. For each measurement, at least three consecutive ideal Doppler waveforms with an insonation angle ≤30° were obtained.
Ultrasound examinations were performed transabdominally by a single examiner (F.P.) with a Toshiba SSA-340A Eccocee ultrasound device (Toshiba Co., Tokyo, Japan) equipped with a 5-MHz curvilinear probe. The high-pass filter was set at 50 Hz and a sample size of 1–2 mm was used for all recordings. Doppler measurements were performed online from the maximum frequency shift envelope. The pulsatility index for veins (PIV), peak velocity during ventricular systole (S-wave), time-averaged maximum velocity (TAMV) and A-wave velocity (A-wave) were calculated. Measurements were transformed to the corresponding Z-scores ((measurement − mean)/SD), representing the measurements expressed on a standard Gaussian scale, with the mean and SD both adjusted for gestation. Previously calculated regression equations for the mean and SD were used14.
All patients were given a follow-up questionnaire to return after delivery and were asked to inform us of any subsequently diagnosed health problems of the baby. Hospital records were also reviewed to determine delivery outcomes for each subject. All fetuses with abnormal karyotypes or major structural abnormalities were excluded from the study, as well as cases of pregnancy loss.
For intergroup comparison Student's t-test or the Mann–Whitney U-test were used, depending on the Gaussian or non-Gaussian distribution of the variables. Pearson's or Spearman's correlation coefficient were used to assess the degree of correlation between variables as appropriate. Values of P < 0.05 were considered statistically significant.
A total of 160 consecutive normal singleton fetuses were included in the study. Three fetuses subsequently miscarried, and five were lost to follow-up. Among the remaining 152 fetuses, no chromosomal or structural abnormalities were reported. The mean gestation was 12 + 2 (range, 10 + 4 to 14 + 0) weeks. The mean maternal age, CRL and NT measurement are shown in Table 1. Invasive karyotyping was performed in seven screen-positive pregnancies, and all the results were normal.
Table 1. Maternal age, crown–rump length and nuchal translucency measurements from 152 normal fetuses at 10–14 weeks of gestation. Ductus venosus Doppler measurements for the pulsatility index for veins, S-wave velocity, time-averaged maximum velocity and A-wave velocity are expressed as Z-scores ((measurement − mean)/SD). Mean and range or SD are shown for variables with a non-Gaussian and Gaussian distribution, respectively
|Maternal age (years)||30 (21–42)||30 (21–35)||30 (21–42)||0.76*|
|CRL (mm)||60.2 (39.7–87.6)||59.8 (39.7–80.9)||60.6 (40.8–87.6)||0.59*|
|NT (mm)|| 1.6 (0.7–4.2)|| 1.5 (0.7–2.9)|| 1.6 (0.7–4.2)||0.18*|
|PIV Z-score|| 0.10 ± 1.01||−0.14 ± 1.02|| 0.32 ± 0.95||0.005†|
|S-wave Z-score||−0.03 ± 1.01||−0.29 ± 1.00|| 0.22 ± 0.96||0.002†|
|TAMV Z-score||−0.07 ± 0.97||−0.31 ± 1.01|| 0.15 ± 0.88||0.003†|
|A-wave Z-score||−0.14 ± 1.18||−0.13 ± 1.15||−0.15 ± 1.22||0.90†|
There were 73 (48%) male and 79 (52%) female fetuses. The NT measurements and Z-scores for ductus venosus PIV, S-wave velocity, TAMV and A-wave velocity in the two groups are shown in Table 1. A statistically significant difference between male and female fetuses was observed for PIV, S-wave velocity and TAMV but not for A-wave velocity and NT. NT had no statistically significant correlation with the Doppler parameters. The correlation between S-wave velocity and TAMV was significant in both male (r = 0.96; P < 0.001) and female (r = 0.95; P < 0.001) fetuses, while PIV did not appear to be related to TAMV either in males (r = −0.01; P = 0.90) or in females (r = 0.08; P = 0.49). A-wave velocity significantly correlated positively with S-wave velocity and TAMV both in male (r = 0.54 and P < 0.001; r = 0.63 and P < 0.001, respectively) and female fetuses (r = 0.39 and P < 0.001; r = 0.48 and P < 0.001, respectively). As expected, A-wave velocity had a significant negative correlation with PIV in both males (r = −0.50; P < 0.001) and females (r = −0.53; P < 0.001). Finally, PIV was significantly correlated with S-wave velocity in female fetuses (r = 0.34; P < 0.01) but not in males (r = 0.18; P = 0.14).
We observed a statistically significant gender difference in ductus venosus blood flow in a population of normal fetuses. Male fetuses showed lower values for ductus venosus PIV, S-wave velocity and TAMV when compared to female fetuses. However, A-wave velocities and NT measurements were not significantly different in the two groups.
These findings must be interpreted in view of previous reports from two large series describing a statistically significant trend for higher NT values in male as compared to female fetuses3, 4. These observations were not confirmed in a smaller study5 that probably, in common with the present series, lacked the power to disclose such a difference. The gender-related difference in NT measurements, even if hardly clinically significant due to the difficulties in assigning fetal sex at ultrasound in the first trimester, raises interesting questions regarding the mechanisms of fetal cardiovascular development.
It is known from animal studies that myocardial structure and function change during intrauterine development, and that fetal myocardium is stiffer than that in the adult15. In humans, by 10 weeks of gestation, significant changes in myocardial function have already taken place, as shown by a change from a monophasic (A-wave) to a biphasic (A- and E-waves) Doppler pattern across the atrioventricular valves16. These changes in cardiac function are paralleled by a progressive increase of blood flow through the ductus venosus with gestation14, 17–19.
It is possible that if normal myocardial development and the normal process of myocardial maturation were delayed, persistence of a less compliant myocardium beyond 10 weeks could lead to impaired diastolic filling with raised atrial pressures and, ultimately, fluid accumulation10. A similar mechanism, even if at a lower scale, could explain the gender differences in ductus venosus blood flow and NT measurements: a relatively delayed myocardial maturation in male fetuses compared to females could be the cause of the reduced blood flow in the ductus venosus and of the increased NT values.
We tried to further investigate the physiology of ductus venosus flow in fetuses of both sexes by examining the correlations between the Doppler parameters. As expected, A-wave velocity had a significant negative correlation with PIV in both males and females, while the positive correlation between S-wave velocity and TAMV was significant in both sexes. However, contrary to our expectations, PIV did not appear to be related to TAMV either in males or in females, while PIV did significantly correlate with S-wave velocity in female fetuses only, but not in males.
It is difficult to conclude whether these discrepancies from the expected relationship between ductus venosus flow velocities and PIV are due to real physiological phenomena or to a lack of power of the correlation tests related to the limited sample size. The similar A-wave velocities in male and female fetuses would suggest that right diastolic pressures during atrial contraction are not different in the two groups. However, it is more difficult to hypothesize why PIV, S-wave velocity and TAMV are lower in males. These findings suggest a reduced ductus venosus blood flow in male fetuses, which is related to lower velocities rather than to an increased pulsatility. This may be due to differences in venous or early diastolic atrial compliance, ductus venosus diameter, peripheral resistance or overall cardiac output.
The observation of gender-related differences in fetal cardiovascular development raises new questions which can only be addressed by further studies.
This research was supported by a Marie Curie Fellowship of the European Community Quality of Life Programme under contract number QLGA-CT-2000-52145.