Dual-Imaging Modality Approach to Evaluate Cerebral Hemodynamics in Growth-Restricted Fetuses: Oxygenation and Perfusion

Abstract

Objective:

To evaluate a dual-imaging modality approach to obtain a combined estimation of venous blood oxygenation (${\mathrm{S}}_v{O}_2$) using susceptibility-weighted magnetic resonance imaging (SWI-MRI), and blood perfusion using power Doppler ultrasound (PDU) and fractional moving blood volume (FMBV) in the brain of normal growth and growth-restricted fetuses.

Methods:

Normal growth (n=33) and growth-restricted fetuses (n=10) from singleton pregnancies between 20 and 40 weeks of gestation were evaluated. MRI was performed and ${\mathrm{S}}_v{O}_2$ was calculated using SWI-MRI data obtained in the straight section of the superior sagittal sinus. Blood perfusion was estimated using PDU and FMBV from the frontal lobe in a mid-sagittal plane of the fetal brain. The association between fetal brain ${\mathrm{S}}_v{O}_2$ and FMBV and the distribution of ${\mathrm{S}}_v{O}_2$ and FMBV values across gestation were calculated for both groups.

Results:

In growth-restricted fetuses, the brain ${\mathrm{S}}_v{O}_2$ values were similar, and the FMBV values were higher across gestation as compared to normal growth fetuses. There was a significantly positive association between ${\mathrm{S}}_v{O}_2$ and FMBV values (slope = 0.38 ± 0.12; r = 0.7; p =0.02) in growth-restricted fetuses. In normal growth fetuses, ${\mathrm{S}}_v{O}_2$ showed a mild decreasing trend (slope = –0.7 ± 0.4; p = 0.1), whereas FMBV showed a mild increasing trend (slope = 0.2 ± 0.2; p = 0.2) with advancing gestation, and a mild but significant negative association (slope = –0.78 ± 0.3; r = –0.4; p = 0.04) between these two estimates.

Conclusion:

Combined MRI (SWI) and ultrasound (FMBV) techniques showed a significant association between cerebral blood oxygenation and blood perfusion in normal growth and growth-restricted fetuses. This dual-imaging approach could contribute to the early detection of fetal “brain sparing” and brain oxygen saturation changes in high-risk pregnancies.

1. Introduction

The fetal brain blood circulation is usually evaluated using Doppler velocimetry in the middle cerebral artery (MCA) by calculating ratios based on blood velocities during the cardiac cycle such as the pulsatility (PI) or the resistance index (RI) (1, 2). A reduced MCA-PI or MCI-RI is considered a sign of vasodilatation and manifestation of blood redistribution to the fetal brain (3–6). A low MCA-PI in growth-restricted fetuses has been associated with an increased risk of perinatal complications and with adverse neurological outcomes (7–16). Hemodynamic changes in the fetal brain might occur before the MCA-PI reduction; therefore, other blood flow estimates, such as cerebral blood perfusion, could be a more sensitive biomarker of “brain sparing” at early stages of growth restriction (8).

Different ultrasound (US) techniques, including spectral, color, and power Doppler modalities, are used to evaluate hemodynamic changes in the fetal brain (7, 8). Power Doppler ultrasound (PDU), which is based on the amplitude of the backscattered signals, is a more sensitive approach for identification of slow blood flow originating from small vessels within the organs (17–20). The Fractional Moving Blood Volume (FMBV) algorithm originally proposed by Rubin et al. (21) compensates for the effect of depth and tissue interfaces on the PDU signals, thus providing an indirect but reliable estimate of tissue blood perfusion (22,23). FMBV has been found to be more sensitive in detecting cerebral blood flow (CBF) redistribution compared to Doppler indices in fetuses with growth restriction (24).

In addition to US and Doppler modalities, magnetic resonance imaging (MRI) can provide additional diagnostic information in the study of blood perfusion in the fetal brain (25). However, contraindications for contrast agents and the low temporal and spatial resolutions limit its use. Nevertheless, MRI has the capability of measuring blood oxygenation. Recent quantitative MRI-based work has measured blood oxygenation status in the human fetus using MR-susceptometry (26, 27), which exploits the paramagnetic nature of deoxyhemoglobin (dHb) that, in turn, is related to the amount of dHb present. The intra-vascular MRI phase signal from a spoiled gradient-echo (GRE) sequence, due to the presence of dHb, can be used to determine the magnetic susceptibility ($\Delta$) property of the blood. The $\Delta$ of the blood, in turn, together with the information of hematocrit and of the magnetic properties of blood, can be utilized for estimating the blood oxygenation (28). This method was recently applied in second- and third-trimester human fetuses to evaluate blood oxygenation ($S_v{O}_2$) in the superior sagittal sinus (SSS) (27) and showed that the obtained values were in close accordance with previously reported oxygenation estimates (26, 29).

Increased blood flow to the brain has been reported in growth-restricted fetuses as a result of blood flow redistribution [9]. Studies in animal models [30] and human adults [31] suggest a subsequent increase in venous blood oxygenation as a consequence of increased blood flow; however, such information is not yet available in growth-restricted fetuses. Hence, having the information of ${\mathrm{S}}_{\text{v}}{\text{O}}_2$ along with perfusion would provide a comprehensive understanding of the fetal cerebral metabolic status in growth-restricted fetuses and might contribute to the clinical management of these pregnancies. Therefore, in this study, we evaluated a dual-modal imaging approach to estimate the global cerebral blood perfusion and ${\mathrm{S}}_v{O}_2$ using FMBV and SWI-MRI techniques, respectively, in normal growth and growth-restricted fetuses.

2. Materials and Methods

2.1. Study Design and Participants

This was a cross-sectional study performed at the Center for Advanced Obstetrical Care and Research (CAOCR), Perinatology Research Branch of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services (NICHD/NIH/DHHS), Wayne State University (WSU) School of Medicine, and Hutzel Women’s Hospital, Detroit, Michigan, USA. All subjects provided written informed consent for US and MRI examinations and were enrolled in research protocols approved by the Human Investigation Committee of WSU and the Institutional Review Board of NICHD. A total of 33 pregnant women with an uncomplicated singleton pregnancy and 10 pregnancies with growth-restricted fetuses were evaluated between 20 and 40 weeks of gestation.

US and Doppler evaluations were performed using General Electric Voluson 8 and Vivid 9 (GE Healthcare, Milwaukee, WI, USA) US equipment with probes emitting at 2–5 or 4–6 MHz. Gestational age was estimated in accordance with the earliest US scan. Estimated fetal weight was calculated using the Hadlock formula (32). Doppler velocimetry was performed in the umbilical artery and in the MCA as previously described (33). Doppler recordings were obtained in the absence of maternal or fetal movements with an angle of insonation as close as possible to 0° and with a high-pass wall filter of 60 MHz. Three to five consecutive and regular waveforms were obtained, and the PI was calculated. For analysis, MCA-PI values were converted into z-scores according to normal reference values (34).

Normal fetal growth was defined as an estimated fetal weight within the 10^th and 90^th centiles for gestational age (GA), with normal fetal anatomy and normal Doppler velocimetry in the umbilical artery and in the MCA. Growth-restricted fetuses were considered as those with an estimated fetal weight <10^th percentile for GA (32) and an increased umbilical artery PI >95^th percentile (35, 36). SWI-MRI data were collected as part of an ongoing study evaluating novel sequences for fetal imaging. MRI examinations were performed within an average 2 ± 1.3 days after US examination.

2.2. Brain oxygenation using SWI

Fetal MRI was carried out on a 3.0T Verio (Siemens Healthineers, Erlangen, Germany) scanner using a six-channel body flex array coil, along with a spine coil. The modified fully flow-compensated two-dimensional (2D) and/or three-dimensional (3D) breathhold version of the SWI sequence (see Table 1) were used in this study.

Table 1:

Magnetic Resonance Imaging (MRI) parameters of 2D and 3D susceptibility-weighted magnetic imaging (SWI) sequence.

MRI Parameters	2D SWI	3D SWI
TR (msec)	280	23
TE (msec)	15–18.7	13.5–17.3
FA (o)	32	10
Matrix size	448×168–448×175	448×175
Resolution (mm3)	0.78×1.56–0.85×1.7	0.78×1.56
TH (mm)	3.5	3–3.5
Number of slices	10–11	16
BW (Hz/ px)	199	219
Scan Time (sec)	22–24	22–24

TR = repetition time; TE = echo time; FA = flip angle; TH = thickness; BW = bandwidth.

The process adapted to quantify the putative ${\mathrm{S}}_v{O}_2$ using the intravascular phase of SSS has been explained elsewhere (27). The SWI phase images of the fetal brain were processed using a mild homodyne filter (48×48) to remove the unwanted background phase. Thereafter, the sagittal orientation of the fetal image was examined to determine the best angle to visualize the cross-section of the SSS for quantification. The phase of the SSS was obtained using a free-hand region of interest (ROI), which was drawn inside the SSS containing at least 10 voxels. The ROI was carefully drawn to exclude the edge voxels to avoid contamination due to partial volume effects. The ${\mathrm{S}}_v{O}_2$ measurements were performed in at least two consecutive slices, and the mean and standard error were calculated from the ROI from all the volumes acquired for each fetal case. The resulting average phase was used to calculate the magnetic susceptibility ($\Delta {\chi }_v$) of the vessel using the Eq.(1):

$$\Delta {\chi }_v=\frac{6.\left|\Delta {\phi }_{sss}\right|}{\left(3{cos}^2\theta -1\right).\left|\gamma B_o\right|.TE}$$ (1)

where $\Delta {\phi }_{sss}$ is the phase difference between the SSS and immediate brain parenchyma, $\theta$ is the angle made by the long axis of the vessel with the main magnetic field (B₀), which was calculated using the image DICOM header, TE is the echo time, and $\text{γ}$ is the gyromagnetic ratio.

Finally, using the fetal hematocrit ($Hct$) obtained from an established nomogram (37) and assuming the magnetic susceptibility of fully oxygenated and fully deoxygenated fetal blood, ($\Delta {\chi }_{do}$) is the same as that of adult blood ($\Delta {\chi }_{do}$=0.27ppm, cgs units) (38), and the putative brain oxygenation was calculated via:

$${\mathrm{S}}_v{O}_2=1-\left(\frac{\Delta {\chi }_v}{\Delta {\chi }_{do}.Hct}\right)$$ (2)

Figure 1 shows representative images of the magnitude and phase images used to measure ${\mathrm{S}}_v{O}_2$ in the fetuses.

Figure 1.

Magnitude (a, b) and phase (c, d) images (high-pass filtered) of the second (22 weeks; a, c) and third trimester fetuses (31 weeks; b,d) are shown. The superior sagittal sinus (SSS) could be easily seen on the posterior aspect of the brain as shown by the arrow heads.

2.3. Brain perfusion using FMBV

Fetal brain blood perfusion was estimated in a mid-sagittal plane of the fetal brain (Figure 2). The power Doppler color box was adjusted to cover the ROI, i.e., the frontal lobe. The PDU settings were set at: standard gray-scale image for obstetrics, pulse repetition frequency = 610 Hz, medium wall filter, and gain just below the presence of noise (39). A video sequence from the mid-sagittal plane of the fetal brain, containing at least 20 (median=35; range=20–114) consecutive images with PDU information, was obtained. The temporal resolution of the video was 5 frames/ sec. The video sequence in AVI (Audio Video Interleave) format was stored and analyzed offline with specifically designed software developed in MATLAB^®. The frontal lobe area was delineated in the first image of the video sequence and considered as the brain region anteriorly from the beginning of the second segment of the anterior cerebral artery (40). FMBV was estimated by evaluating the pixels with PDU information within the ROI. In each pixel, the intensity of the green color channel (RGB: red, green, and blue) was evaluated as it better represents changes in PDU information and blood perfusion than the other two color components (40). FMBV was then estimated using the approach originally described by Rubin et al. (21). To define the normalization value (NV), the algorithm created a cumulative distribution of all PDU intensity values and applied a two-tangent line technique (Figure 3) (22). In the higher point of the cumulative distribution, the PDU intensity signals of blood movements from the center of the vessels are located, and in the lower point of the distribution, those with low intensity from blood movement originated close to the vessel walls. All PDU intensity values above the NV were assigned a value of 1 (they were considered similar to the NV), and all PDU values below the NV were converted to fractions of the NV (21). The average of all normalized PDU intensity values per the number of pixels gave the final FMBV estimation (40). This estimate ranges from 0 to 1 and, when converted into a percentage, expresses the fraction of the ROI occupied by moving blood. The algorithm calculated FMBV in all images from the video sequence. Figure 4 shows a PDU representative image prior to FMBV estimation (Figure 4a) and after FMBV calculation (Figure 4b). The green color represents high-power Doppler values after the normalization process.

Figure 2.

Blood perfusion in the frontal lobe evaluated with FMBV showing normalized power Doppler signals in a mid-sagittal plane of the fetal brain at 22 weeks (a) and 31 weeks (b) of gestation. These are the same fetuses as shown in Figure 1. The white line delineates the posterior boundary of the frontal lobe based on the beginning of the anterior cerebral artery. The branching and number of vessels are increased at 31 weeks of gestation.

Figure 3.

Normalization process for FMBV; cumulative distribution of all pixels in the region of interest with power Doppler information plotted in relation to pixel intensity. The peak of the “knee” of the distribution is the normalization value (NV) and can be defined using 1) a two-tangent method (continuous lines) or 2) the maximum value of the pixels over-passing the fit line (dashed lines). The lowest NV is used (continuous line: intensity 53).

Figure 4.

Blood perfusion evaluation of the frontal lobe in a mid-sagittal plane of the fetal brain. (a) Power Doppler Ultrasound; (b) Fractional Moving Blood Volume (FMBV); the green color shows the normalized power Doppler signals for depth and tissue interphases.

2.4. Statistical analysis

Regression models were applied to evaluate the association between FMBV or MCA-PI z-scores with ${\mathrm{S}}_v{O}_2$ in the brain of normal growth and growth-restricted fetuses, and the best fit was analyzed. The correlation between FMBV or MCA-PI z-scores with ${\mathrm{S}}_v{O}_2$ was estimated by Pearson’s correlation coefficient. Fetal blood perfusion estimates and fetal brain ${\mathrm{S}}_v{O}_2$ values were plotted in relation to gestational age (weeks), and the associations between FMBV and ${\mathrm{S}}_v{O}_2$ with gestational age were evaluated using a generalized linear regression model. The two-tailed student’s t-test was applied to estimate differences in MCA-PI z-scores and FMBV between normal growth and growth-restricted fetuses.

FMBV and ${\mathrm{S}}_v{O}_2$ values obtained at 20–22 weeks of gestation and >35 weeks of gestation were compared to estimate differences at mid-pregnancy and close to delivery. Normality of FMBV and ${\mathrm{S}}_v{O}_2$ distributions was assessed using the Kolmogorov-Smirnov test; differences in FMBV and ${\mathrm{S}}_v{O}_2$ across gestation were evaluated using Mann-Whitney or student’s t-test as appropriate. A p value less than 0.05 was considered statistically significant. Analyses were performed using SPSS^® Version 19 (IBM Corp., Armonk, New York, USA) and Med Calc^® 9.0.1.0 (MedCalc Software bvba, Ostend, Belgium) statistical software.

3. Results

Demographic characteristics of the study population are shown in Table 2. Most of our subjects were of African-American ethnicity (39/43; 91%), and 22/43 (51%) were in their first pregnancy. Growth-restricted fetuses were delivered at early gestational ages (median range [weeks]: 36 [34–39] versus 39 [37–41], respectively) and had a lower birthweight percentile (median, range: 10 [3–25] versus 42 [12–90]) than normal growth fetuses.

Table 2:

Demographical information of the subjects included in the study.

	Normal fetal growth (n = 33)	Fetal growth restriction (n = 10)
Maternal age (years)	25 (18–41)	26 (17–40)
Gestational age at ultrasound (weeks)	29 (20–40)	35 (30–40)
Gestational age at MRI (weeks)	30 (20–40)	36 (30–40)
Estimated fetal weight percentile	42 (12–90)	10 (3–10)
Gestational age at delivery (weeks)	39 (37–41)	36 (34–39)
Birthweight (g) (mean ± SD)	3384 ± 235	2754 ± 435
Birthweight percentile	40 (10–75)	10 (3–25)

Data presented as medians (ranges) or mean ± SD.

MRI, magnetic resonance imaging.

3.1. FMBV and ${\mathbf{S}}_{\mathit{v}}{\mathit{O}}_2$ changes during pregnancy

The average FMBV and ${\mathrm{S}}_v{O}_2$ values in normal growth fetuses were 21.9 ± 1.1 and 63.9 ± 3.2%, respectively. In growth-restricted fetuses, the mean FMBV and ${\mathrm{S}}_v{O}_2$ were 26.9 ± 3.9 and 60.6 ± 5.3%, respectively. No significant difference ( p = 0.44) in ${\mathrm{S}}_v{O}_2$ values between normal growth and growth-restricted fetuses was found; however, marginally higher levels of FMBV ( p = 0.09) were observed in growth-restricted fetuses as compared to normally grown fetuses. Changes in FMBV and ${\mathrm{S}}_v{O}_2$ in normal growth and growth-restricted fetuses in relation to gestational age re shown in Figure 5 and Figure 6, respectively. In normal growth fetuses, the mean FMBV at 20–22 weeks was 19.9 ± 2.7% and increased to 24.8 ± 2.5% at ≥35 weeks of gestation (p = 0.1), whereas ${\mathrm{S}}_v{O}_2$ at 20–22 weeks was 71.7 ± 3.2% and decreased to 58.6 ± 4.8% (p = 0.06) at ≥35 weeks of gestation.

Figure 5.

Distribution of Fractional Moving Blood Volume (FMBV) values in the fetal brain in normal growth (blue) and growth-restricted fetuses (red) across gestation. An increasing (slope = 0.2 ± 0.2) and a decreasing (slope = −2.2 ± 1.1) trend was observed in normal growth and growth-restricted groups, respectively.

Figure 6.

Distribution of venous blood oxygenation values in the fetal brain in normal growth (blue) and growth-restricted (red) fetuses across gestation. A decreasing (normal growth: slope = −0.7 ± 0.4; growth restriction = −1.2 ± 0.65) trend was observed in both groups, but it was not statistically significant (normal growth: p = 0.1; growth restriction: p = 0.1).

3.2. FMBV and ${\mathbf{S}}_{\mathit{v}}{\mathit{O}}_2$ correlation

Cerebral blood perfusion/FMBV and ${\mathrm{S}}_v{O}_2$ showed a mild but significant negative correlation (slope = −0.78 ± 0.3; r = −0.4; p = 0.04) in normal growth fetuses. Despite the fact that ${\mathrm{S}}_v{O}_2$ and FMBV values were within the normal range (26, 41), fetuses having ${\mathrm{S}}_v{O}_2$ values on the lower part of the distribution showed higher values on blood perfusion, and fetuses with ${\mathrm{S}}_v{O}_2$ values in the higher part of the distribution showed lower blood perfusion values. In contrast, a significant positive association between FMBV and ${\mathrm{S}}_v{O}_2$ (slope = 0.38 ± 0.12; r = 0.7; p = 0.02) values was found in growth-restricted fetuses with higher cerebral ${\mathrm{S}}_v{O}_2$ values corresponding to higher FMBV values (Figure 7).

Figure 7.

Association between blood perfusion (Fractional Moving Blood Volume; FMBV) and venous oxygenation in the fetal brain of normal-growth fetuses (slope = −0.78 ± 0.3; r = −0.4; p = 0.04) and in growth-restricted fetuses (slope = 0.38 ± 0.12; r = −0.7; p=0.02).

3.3. Time interval between FMBV and examinations

FMBV and SWI were not obtained on the same day in all fetuses. In 16 fetuses, both techniques were performed with a one-day difference. The association between perfusion and oxygenation was still significant among these 16 cases (slope = −0.5; p = 0.43). This suggests that, despite such a small sample size, the two physiological parameters still showed a moderate dependency on each other; nevertheless, the dispersion of the data suggests an important variability among the two estimates.

3.4. Correlation of MCA-PI z-scores with FMBV and ${\mathrm{S}}_v{O}^2$

Despite a lower MCA-PI z-score in growth-restricted fetuses (mean = –0.11 ± 0.9) than in normally grown fetuses (mean = –0.001 ± 0.2), no statistical significance was reached (p = 0.7). In normally grown fetuses, no significant correlation was observed between MCA-PI z-scores and FMBV (r = 0.1; p = 0.5) or between MCA-PI z-scores and ${\mathrm{S}}_{\text{v}}{\text{O}}_2$ (r = 0.07; p = 0.7). In growth-restricted fetuses, a negative association was observed between MCA-PI z-scores and ${\mathrm{S}}_{\text{v}}{\text{O}}_2$ (r = –0.6; p = 0.06) and between MCA-PI z-scores and FMBV values (r = –0.5, p = 0.07); however, no statistical significance was reached (Figures 8 and 9, respectively).

Figure 8.

Association between blood perfusion (fractional moving blood volume; FMBV) and MCA-PI z-scores in the fetal brain of normal growth fetuses (slope = 0.66 ± 1.1; p = 0.5) and in growth-restricted fetuses (slope = –7.6 ± 3.5; p = 0.07).

Figure 9.

Association between venous blood oxygenation and MCA-PI z-scores in the fetal brain of normal growth fetuses (slope = –0.99 ± 2.6; p = 0.7) and in growth-restricted fetuses (slope = –3.9 ± 2.0; p = 0.06).

4. Discussion and Conclusions

The principal findings of this study indicated: 1) fetal cerebral ${\mathrm{S}}_v{O}_2$ showed no changes across gestation in normal growth and growth-restricted fetuses; 2) fetal cerebral FMBV did not show significant differences across gestation in normal growth fetuses, yet it was slightly higher in growth-restricted fetuses; 3) a mild but significant negative association was observed between FMBV and ${\mathrm{S}}_v{O}_2$ in normal growth fetuses; 4) a significant positive correlation between FMBV and ${\mathrm{S}}_v{O}_2$ was observed in growth-restricted fetuses; and 5) a negative trend was observed between MCA-PI z-scores and FMBV, and between MCA-PI z-scores and ${\mathrm{S}}_v{O}_2$ values in growth-restricted fetuses, yet such a trend was not observed in normally grown fetuses. The association between FMBV and ${\mathrm{S}}_v{O}_2$ in normal growth fetuses is weak, suggesting that in normal circumstances the maintenance of ${\mathrm{S}}_v{O}_2$ values does not imply major changes in blood perfusion. In growth-restricted fetuses, the redistribution of blood significantly increases blood perfusion to the brain to maintain normal oxygen saturation.

Results in the context of what is already known

Our results are in accordance with experimental studies that evaluated the effect of hypoxia or reduced blood flow supply to the fetus (42, 43). The fetus/neonate implements a hemodynamic process to maintain normal oxygen saturation in the brain, adrenals, and heart (the brain- and heart-sparing effects) (44, 45). As the hypoxic insult persists, the sparing effect is no longer effective and the risk of hypoxic damage increases. Our results are also in close accordance to those reported by Vyas et al. (13) in growth-restricted fetuses where a fetal blood sample was obtained by cordocentesis and blood gas values were correlated with Doppler velocimetry of the MCA. The results showed significantly lower oxygen saturation in the umbilical cord and increased blood flow to the brain manifested by reduced MCA-PI/ MCA-RI indices. Our study contributes further, showing that the combination of MRI and US modalities might improve the evaluation of hemodynamic changes in compromised fetuses.

Fetal brain oximetry using MRI

MR susceptometry was used for measuring ${\mathrm{S}}_v{O}_2$ in the fetal brain across gestation. The average ${\mathrm{S}}_v{O}_2$ value obtained in this study is in close agreement with other human fetal results (26, 29). The observed trend of decreasing cerebral venous saturation was in accordance with previous in-vivo studies of blood oxygenation (both pO₂ and SO₂) in umbilical venous blood samples, taken by cordocentesis, also showing a reduction in ${\mathrm{S}}_v{O}_2$ with advancing gestational age (27, 46, 47). More recent research using non-invasive MR susceptometry also pointed to the same trend (albeit, not statistically significant) in the fetal SSS (48). Furthermore, it is also known that the CBF to the human fetal brain increases from the second to the third trimester of pregnancy (49). Taken together, the blood flow and oxygen saturation changes may fulfill the increased metabolic demand observed during the third trimester of pregnancy.

We found no difference in the average ${\mathrm{S}}_v{O}_2$ and its trend across gestation in growth-restricted fetuses as compared to normally grown fetuses. This is consistent with a recent MRI study showing no change in the oxygen extraction fraction (OEF) between healthy and hypoxic-ischemic neonates (50), whereas a significant increase in the cerebral metabolic rate of oxygen was observed in hypoxic-ischemic neonates mainly due to elevated CBF. Moreover, the CBF was also found to increase in relation to neonatal age in both groups with no changes in the oxygen extraction fraction.

FMBV and fetal organ blood perfusion

FMBV is a reliable technique to estimate blood perfusion changes in the fetal organs. Changes in FMBV in the adrenal gland of the experimental lamb model exposed to reduced umbilical artery blood flow showed a significant correlation with blood perfusion changes estimated using radio-labeled microspheres (51). FMBV has been applied in the fetal lung in fetuses with congenital diaphragmatic hernia to estimate the risk of lung hypoplasia and in the fetal brain of growth-restricted fetuses (52). This is the first study to correlate FMBV against blood oxygen saturation values in the fetal brain using non-invasive and cross-modality techniques.

The process of blood redistribution in the fetal brain was also identified using MCA-PI. Despite not showing significant differences in MCA-PI z-scores, growth-restricted fetuses had lower MCA-PI values than normally grown fetuses. In normally grown fetuses, no correlation between MCA-PI with FMBV or ${\mathrm{S}}_{\text{v}}{\text{O}}_2$ was observed, but in growth-restricted fetuses, a trend between reduced MCA-PI z-scores and increased FMBV with increased ${\mathrm{S}}_{\text{v}}{\text{O}}_2$ was noted. These findings support previous reports on the association between brain vasodilation and low oxygen saturation in umbilical cord blood in growth-restricted fetuses (13).

Association between FMBV and oxygen saturation

Evaluation of blood perfusion using FMBV might reflect changes in cerebral ${\mathrm{S}}_v{O}_2$ estimated by using SWI. Blood perfusion and ${\mathrm{S}}_v{O}_2$ in the fetal brain remained quite stable during pregnancy with a mild increase in perfusion toward the end of pregnancy (27, 29, 41). The mild negative association between these two variables in normally grown fetuses cannot be considered as a direct response to each other. Changes in heart rate might help to compensate for mild changes in oxygen saturation.

In contrast, in growth-restricted fetuses with an increased PI in the umbilical artery, a significant increase in the CBF occurs to maintain normal oxygen saturation in the tissues. Under these circumstances, the association between these two variables becomes significant; the fetal response to an increase in blood flow is characterized by a dilation of small-caliber vessels, such as arterioles, to provide a higher amount of blood to maintain oxygen saturation within normal values. Our results showed that US and MRI by means of FMBV and SWI can be combined to provide valuable insight about changes in the cerebral metabolism of healthy and growth-restricted fetuses.

Limitations

There are some shortcomings and challenges in this study. FMBV measurements are related to the quality of the obtained PDU signals; factors such as increased maternal body mass index, fetal movements, and artefacts can affect the perfusion results. The FMBV algorithm compensates for physiological parameters but not for artefacts produced by motion. MR susceptometry-based oxygenation measurement is based on a cylindrical approximation model. Large vessel curvature and oblique fetal head orientation might pose a challenge, particularly in young fetuses. A model- and orientation-independent approach, such as quantitative susceptibility mapping, would be better suited for fetal oximetry. In addition, we used $\Delta {\chi }_{do,adult}$ value in our ${\mathrm{S}}_v{O}_2$ measurements. Recently, it has been shown that $\Delta {\chi }_{do,fetal}$ was 10% lower than adult blood (53). This will decrease our ${\mathrm{S}}_v{O}_2$ measurements; however, it will not affect the correlation and gestation-based trend; hence, the conclusion of this study will not change. Our results might also be affected by the relatively small number of participants; nevertheless, the number of cases (normally grown fetuses, n = 33; growth-restricted fetuses, n = 10) showed clear differences in the association of blood perfusion and oxygen saturation. A larger sample size should be used in the future to further refine this association.

Clinical and Research Implications

The combination of US and MRI physiological parameters might improve the identification of fetuses at risk of abnormal clinical outcome and neurodevelopment. Fetuses with growth restriction, congenital anomalies, and intra-amniotic infection might benefit from the study of brain oxygen saturation/blood perfusion. FMBV showed a stronger correlation with ${\mathrm{S}}_{\text{v}}{\text{O}}_2$ than MCA-PI. This is in accordance with previous studies showing earlier changes in FMBV than in MCA-PI in growth-restricted fetuses (8). Overall FMBV showed higher associations with the fetal brain oxygen saturation in normally grown and growth-restricted fetuses than MCA-PI.

The combination of MRI-SWI and FMBV can provide more complete information of hemodynamic changes in the fetal brain. If the two techniques cannot be performed, perfusion values in the fetal brain obtained with US might provide useful information on the changes in fetal brain venous blood oxygen saturation. US is a widely available imaging technique for evaluating fetuses; therefore, FMBV values could be easily obtained in the fetal brain. However, it should be acknowledged that MRI is a more accurate technique to estimate direct changes in oxygen saturation in fetal venous blood.

In this dual-imaging modality study, we found a significant positive association between changes in oxygen saturation and blood perfusion in the brain of growth-restricted fetuses. This approach could be significantly beneficial for the early detection of brain sparing in pathological conditions.