MRI of Fetal and Maternal Diseases in Pregnancy 1st ed.

10. Fetal Cardiovascular Magnetic Resonance

Mike Seed 

(1)

Departments of Pediatrics and Diagnostic Imaging, Hospital for Sick Children, Toronto and University of Toronto, Toronto, ON, Canada

Mike Seed

Email: mike.seed@sickkids.ca

10.1 Background and Rationale

Since its initial inception in the early 1980s, the widespread use of ultrasound for imaging fetal cardiovascular anatomy and physiology has resulted in major improvements in our ability to treat fetal arrhythmia and diagnose congenital heart disease (CHD) prenatally. The result has been a reduction in fetal deaths attributable to supraventricular tachycardia and complete heart block, improvements in perinatal outcomes in pregnancies affected by CHD, and the option of termination of pregnancy in the setting of serious cardiac and associated congenital malformations [10]. In recent years, we have learned how the natural history of severe forms of CHD may be modified with minimally invasive in utero surgical procedures, a development that is entirely attributable to the development of fetal echocardiography. Doppler ultrasound has also improved the detection and management of intrauterine growth restriction (IUGR) through the identification of the changes in fetal cerebral, peripheral, and placental vascular resistances that occur in response to acute fetal hypoxia [757]. However, while Doppler aids in the detection of fetal hypoxia by identifying fetal circulatory adaptations to placental insufficiency, one drawback of the modality is that it does not provide any direct information about fetal oxygenation. Furthermore, animal studies suggest that chronic fetal hypoxia is associated with a reduction in fetal oxygen consumption (VO2) and normalization of blood flow distribution, resulting in potentially falsely reassuring findings on Doppler ultrasound [343942]. By contrast, MRI offers the potential to directly quantify the oxygen content of fetal blood and may therefore provide more sensitive measures of chronic placental insufficiency [6162]. Fetal cardiovascular MRI may also be helpful as an adjunct to conventional ultrasound assessment in the setting of CHD. The abnormal cardiac connections and obstructions of flow that characterize CHD have long been suspected of disrupting oxygen transport across the fetal circulation, and MRI has provided a new way to examine the relationships between fetal hemodynamics and organ growth and development [53].

10.2 History of Fetal CMR: Development of Cardiac Gating and MR Oximetry

While MRI has been used to image the fetal brain and body for several decades, fetal cardiovascular magnetic resonance (CMR) has only recently been attempted, and the technique currently remains more of a research tool than a clinical imaging modality. This is in part due to the challenges of imaging this small and rapidly moving target with MRI. Following the development of fast imaging techniques such as steady-state free precession (SSFP) that offer good contrast between the blood pool and the myocardium, cardiac structures have been well visualized in static images of the fetal thorax during the second and third trimesters [945]. However, with average fetal heart rates in the 140–150 beats per minute range, even with the fastest methods, a scan time of several heartbeats is still required to obtain a single image with acceptable spatial resolution, and cardiac motion therefore results in significant artifact. When imaging the postnatal heart, this problem can be overcome with cardiac triggering techniques, which allow the data comprising the image to be collected from a short period of the cardiac cycle during a number of consecutive heartbeats, a technique known as cardiac triggering or gating, which has the effect of freezing cardiac motion. In the postnatal setting, the scanner is able to organize the data acquisition in this way by timing its imaging to the subject’s electrocardiographic (ECG) signal, and when gated images are produced at each cardiac phase and then played as a movie, this results in high-resolution images of the beating heart.

Cardiac triggering is more problematic in the fetus, because of the difficulties of acquiring the usual ECG signal. A number of solutions to this problem have been proposed which include ultrasound-based technology and self-gating approaches [5960]. Another potential approach is to oversample the data with an artificial trigger and then reconstruct through a range of candidate heart rates, identifying the best fit through the lack of artifact in the final images using an image metric [18]. This approach, which we have called metric optimized gating (MOG), requires a postprocessing software package that is available as an open-source internet resource [27]. Figure 10.1 shows a schematic description of the steps involved in MOG, and examples of the resulting images can be found on our website [26]. We have used MOG to obtain cine anatomic SSFP images of the fetal heart [43] and cine phase-contrast cardiovascular magnetic resonance (PC CMR) flow measurements in fetal vessels [2537404853].

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Fig. 10.1

Metric optimized gating. A synthetic trigger with longer R-R interval is used to acquire the k-space data. Hypothetic trigger locations are then retrospectively applied to the data and iteratively reconstructed with the correct average R-R interval identified as the reconstruction with the least image artifact

A second important milestone in the evolution of fetal CMR has been the recognition that information about fetal oxygenation might be obtained from taking advantage of the different magnetic properties of diamagnetic oxygenated hemoglobin and paramagnetic deoxyhemoglobin. This effect results in a shorter T2 and T2* of blood samples containing more deoxygenated hemoglobin. Sorensen et al. have used blood oxygen-dependent imaging (BOLD) to detect changes in T2* in various fetal organs in response to changes in the inspired oxygen content of the pregnant ewe and human [49]. A similar approach has been used by Wedergartner et al., who have also shown the feasibility of making measurements of the T2 of blood in the cardiac ventricles of fetal lambs as the basis of a fetal oximetry technique [56].

10.3 Fetal MR Oximetry

The Luz-Meiboom model defines the physical basis for the relationship between the relaxation of the MRI signal and the proportion of hemoglobin in blood that is bound to oxygen [25]. Wright et al. derived a term that relates T2 to oxygen saturation (SaO2) [58]:

 $$ \frac{1}{\mathrm{T}2}=\frac{1}{\mathrm{T}2\mathrm{o}}+K\cdot {\left(1-\frac{{\mathrm{SaO}}_2}{100\kern0.24em \%}\right)}^2 $$

where T2o is the T2 of fully oxygenated blood for a given hematocrit and K is a constant that is dependent on the magnetic field strength and the refocusing interval of the T2 preparation sequence used to measure T2. We have shown good agreement between MR oximetry and conventional blood gas measurements made in the large mediastinal vessels of children undergoing cardiac catheterization [33]. Since this work, modern sequences have been developed for performing MR relaxometry that produce maps allowing ready placement of a region of interest (ROI) within the vessel lumen for measuring the T2 of blood. Stainsby et al. have provided guidance on the requisite conditions for avoiding contamination of the signal from structures surrounding the vessel, which include a minimum of six voxels across the diameter and a slice thickness no greater than the vessel diameter [51]. This poses a challenge to imaging fetal vessels because shorter scan times are required to avoid excessive motion artifact, resulting in the usual trade-off between signal-to-noise ratio and spatial resolution. However, innovations in sequence design have helped to make the technique feasible in the larger vessels of late gestation fetuses. One such innovation is a sequence designed for myocardial relaxometry that employs a rapid SSFP readout following the T2 preparation and a nonrigid registration motion correction algorithm [1213]. The fast readout provides individual T2 preparation images that are free from motion artifact. However, it is only with motion correction, which adjusts for small fetal and maternal movements occurring during the several second intervals required for magnetization recovery between the acquisition of individual T2 preparation images, that the straightforward determination of T2 from the T2 map becomes feasible. Without motion correction, accurate T2 values could presumably still be obtained by placing individual ROIs over the vessel lumen on each individual T2 preparation image, although this would be more time consuming. One aspect of using the imaging sequence devised by Giri et al. is that the magnetization recovery intervals and triggers for acquiring the readout are based on an ECG signal. For fetal imaging, it is therefore necessary to produce an artificial ECG signal to run the acquisition. Most modern MRI systems have the facility to produce such a signal, and the R-R interval can be programmed according to the estimated fetal heart rate, a process we have termed pseudo-gating. We generally measure the fetal heart rate with a cardiotocograph for several minutes prior to MRI in order to determine the average fetal heart rate for each case and use this for the sequences requiring pseudo-gating. A second longer R-R interval is chosen for the sequences using MOG, to ensure that the k-space data used to reconstruct these images is oversampled.

Once the T2 of each vessel of interest is measured, a conversion to SaO2 can be undertaken. We are currently attempting to calibrate in vitro measurements of T2 to the SaO2 of human umbilical cord blood, in order to provide accurate human fetal MR oximetry. In the meantime, we have used the sequence developed by Giri et al. with the parameters shown in Table 10.1 to measure T2 in adult blood samples with a hematocrit matching late gestation fetal blood in order to convert T2 to SaO2. The samples were prepared by exposure to nitrogen gas to have a range of SaO2 to simulate blood in various fetal vessels. The calibration curve and a term fitting T2 to SaO2 are shown in Fig. 10.2. This conversion assumes that the magnetic properties of fetal and adult hemoglobin are the same, an assumption that is likely to be flawed, and until a calibration using fetal blood is obtained, it may be more appropriate to report MR oximetry in terms of vessel T2 rather than SaO2.

Table 10.1

Proposed sequence parameters for performing cardiovascular magnetic resonance in the late gestation fetus

Sequence

Type

Gating

Resp. comp.

Parallel imaging factor

NSA

TE (ms)

TR (ms)

Slice thick (mm)

Matrix size

FOV (mm)

Temp. resol. (ms)

Scan time (s)

3D-SSFP

3D

Breath-hold

2

1

1.74

3.99

2

256 × 205 × 80

400

13

Static SSFP

2D

1

1.3

6.33

4

320 × 211

350

1336

24 (15 slices)

Cine SSFP

2D

MOG

2

1

1.26

3.04

5

340 × 310

340

46

55 (10 slices)

Phase contrasta

2D

MOG

1

3.15

6.78

3

240 × 240

240

54

36

T2 mappingb

2D

PG

2

1

1.15c

3.97c

6

224 × 181

350

4000

12

NSA number of signal averages, TE echo time, TR repetition time, FOV field of view, PG pseudo-gating (based on estimated R-R interval), MOG metric optimized gating (R-R interval 545 ms)

aVelocity-encoding sensitivity tailored according to vessel: 150 cm/s for arteries, 100 cm/s for veins, and 50 cm/s for umbilical vein. Number of segments per cardiac cycle = 4

bT2 mapping used 4 T2 preparation times, tailored to span the expected T2 of a given vessel (0 ms, 0.33*T2, 0.66*T2, and 1.00*T2), with 4000 ms of magnetization recovery between successive T2 preparations

cRapid imaging of the T2-prepared magnetization was performed using a single-shot SSFP sequence with the indicated TE/TR values

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Fig. 10.2

Calibration of the relationship between T2 and SaO2. (a) T2 map of in vitro blood samples with (b) the corresponding calibration curve showing the relationship between T2 and SaO2. The T2 map in (a) was acquired with a T2 preparation sequence with SSFP readout and constructed from 5 images with a range of T2 preparation times spaced evenly between 0 and 200 ms, using a simulated ECG signal for triggering at the estimated fetal heart rate: TE 1.15 ms, TR 3.97 ms, parallel imaging factor 2, slice thickness 5 mm, matrix size 224 × 181, FOV 350 mm, interval between images 4 s, and scan time 16 s. Data points and error bars in (b) represent the mean and standard derivation obtained from a manually drawn region of interest (ROI) within each vial on the T2 map. The solid line represents the fitted relationship between T2 and SaO2. The equation for this relationship, which was used to calculate SaO2 values from fetal T2 measurements, is shown on the plot

10.4 MR Measurement of Fetal Hemoglobin Concentration

A potential source of error in the oximetry method described above is the requirement for an estimation of fetal hemoglobin concentration. While reference data indicates a fairly narrow range of hemoglobin concentration is present in utero [32], we are currently lacking sufficient data for reliable reference ranges in late gestation fetuses. Furthermore, fetal anemia resulting from allo-immunization and viral infection is not uncommon, and chronic hypoxia induces fetal polycythemia [42]. We recognize therefore that the use of an estimated fetal hemoglobin concentration represents a potentially important source of error in fetal MR oximetry based purely on the quantification of T2. However, there may be an elegant solution to this problem that takes advantage of the strong relationship that exists between the T1 relaxation of blood and its hematocrit with higher hematocrits resulting in shorter T1s [15]. Therefore, while the T2 of blood is primarily affected by SaO2, but weakly impacted by hematocrit, its T1 is primarily influenced by hematocrit, but weakly affected by SaO2. We have recently shown that these two relationships can be rearranged in a cubic polynomial equation whereby, with the exception of samples with very high SaO2, there is a single solution for SaO2 and hematocrit for any pair of T1 and T2 values that might coexist in an individual blood sample [38]. A computer simulation showing contour lines for oxygen saturation and hematocrit based on this solution is shown in Fig. 10.3. This work includes a validation of the technique, whereby good agreement is shown between conventional blood gas analysis of adult blood samples manipulated to have a range of oxygen saturations and hematocrits with values predicted for those samples based on their T1 and T2 values measured by MRI in vitro (Fig. 10.4). We anticipate further calibration using umbilical cord blood will confirm that the combination of T1 and T2 mapping will then form the basis of an accurate noninvasive technique for determining the oxygen content of fetal blood in vivo.

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Fig. 10.3

Contour plots of hematocrit (T1,T2) and SaO2 (T1,T2). Note the region of overlap between two solutions (as indicated by solid and dashed contour lines) in the right upper quadrant

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Fig. 10.4

Correspondence between true values of the hematocrit (HCt) and oxygen saturation (SaO2) and those obtained using in vitro T1 and T2 of adult blood indicating good agreement as the basis for a non-invasive technique for measuring the oxygen content of fetal blood in utero

10.5 Measurement of Blood Flow Across the Fetal Circulation Using Phase-Contrast MRI

While fetal color and pulsed Doppler techniques provide a wealth of hemodynamic information about the fetal circulation and have been used to calculate combined ventricular output (CVO) and umbilical blood flow [19295055], ultrasound measurements of vessel flow are prone to inaccuracy [11]. Although inferior spatial resolution and motion artifact degrade flow measurements made with cine PC CMR and currently limit the technique to late gestation fetuses, this approach avoids some of the difficulties encountered with ultrasound flow measurements. These include problems with obtaining an adequate angle of insonation and inaccuracies resulting from difficulties in measuring vessel area and with accounting for the faster velocities of blood flow in the center of the vessel and slower flow adjacent to the vessel wall. Under ideal conditions, PC CMR is more accurate than ultrasound for blood flow quantification, and criteria for acquiring adequate temporal and spatial resolution to achieve accurate flow measurements in small vessels have been reported [1724]. We attempted to assess the accuracy of PC CMR with MOG using flow phantoms and by comparing measurements made in the neck vessels of exercising adult volunteers using conventionally gated PC CMR measurements with those made using MOG [1848]. The results of this comparison are shown in Fig. 10.5 and indicate that flow measurements made in the larger fetal vessels of a human fetus close to term are likely to be accurate. Further reassurance regarding the accuracy of fetal PC MRI is to be found in the good correlation between direct and indirect measurements of pulmonary blood flow made using PC CMR [40]. Figure 10.6 shows good agreement between pulmonary blood flows calculated as the difference between main pulmonary artery and ductus arteriosus flow versus the sum of the right and left pulmonary arteries in normal late gestation human fetuses.

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Fig. 10.5

Validation study of five adult volunteers comparing conventional vs MOG measurement of flow. Measurements from the common carotid arteries and jugular veins made using conventional cardiac-gated PC CMR compared with the same measurements made by PC CMR with MOG. The scatterplot shows agreement between the two methods, while the Bland-Altman plot reveals negligible bias. Flow curvesmeasured in the right common carotid and right internal jugular vein by the two methods for one volunteer are shown

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Fig. 10.6

Internal validation of flow measurements for all 40 fetuses comparing pulmonary blood flow measured directly as the sum of right and left pulmonary arterial flows versus an indirect measurement: the difference between main pulmonary artery and ductus arteriosus flows showing reasonable agreement between the two measures with no significant bias (bias: 10 ml/min/kg, SD of bias 57.3, 95 % limits of agreement from −102.4 to 122.4 ml/min/kg)

One approach to measuring the distribution of the fetal circulation is to use PC CMR flow measurements made in the ascending aorta (AAo), main pulmonary artery (MPA), ductus arteriosus (DA), right and left branch pulmonary arteries (RPA & LPA), superior vena cava (SVC), descending aorta (DAo), and umbilical vein (UV). The CVO can be derived from the sum of AAo and MPA flows, although we have always added 3 % to this figure to account for coronary blood flow, based on the reports of previous fetal lamb experiments [44]. Foramen ovale (FO) flow can be estimated as the difference between the left ventricular output and pulmonary blood flow, as FO flow and pulmonary blood flow are the two alternative sources of filling of the left heart. In order to measure umbilical flow, we target the UV in the liver, several centimeters beyond the umbilicus, but also well proximal to the porta hepatis. The UV takes a relatively straight course in its intrahepatic segment, and this permits PC CMR measurements that avoid the more complex flow patterns that occur in its free loops. Our approach has been to copy the PC CMR slice prescriptions to perform consecutive T2 maps in each of the larger branches (AAo, MPA, DA, SVC, DAo, UV) [46]. One approach to obtaining these flow measurements is shown in Fig. 10.7, and the imaging parameters for each of the sequences we use are shown in Table 10.1. An important principle to follow when acquiring the flow and oximetry measurements is to use two perpendicular long-axis views of each vessel in order to prescribe the slice position. This will ensure the imaging plane is acquired in a true short-axis orientation to the vessel, thus minimizing the chance of partial volume artifacts in the resulting images. We acquire surveys of the fetal thorax in three orthogonal planes using stacks of static SSFP slices with the sequence parameters shown in Table 10.1 in order to guide the subsequent PC and T2 prescriptions. These surveys may need to be repeated several times during the study to relocate the vessels accurately following fetal or maternal movement.

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Fig. 10.7

Orientation of phase-contrast (PC) and T2 acquisitions from coronal, sagittal, and axial localizers showing expected appearances of modulus PC images, representative flow curves and examples of T2 maps for each of the target vessels

Metric optimization of the PC CMR measurements is currently performed using a purpose designed MATLAB program, which is available as an open-source internet resource [27]. Following MOG, the individual PC files are transferred back to the magnet computer, which converts them to DICOM files that can be processed using conventional CMR software for flow quantification. We use Q-Flow (Medis, Netherlands) to place regions of interest around the target vessel in order to determine vessel flow in ml/min. Vessel flows can be indexed to fetal weight by measuring fetal volume. One such approach involves the acquisition of a three-dimensional SSFP acquisition of the whole fetus. The stark contrast between the high signal of amniotic fluid and dark signal of the fetal skin on this sequence makes automatic segmentation of the fetal envelope reasonably straightforward using a threshold approach. We use Mimics by Materialize (Leuven) for this and have traditionally applied the following previously reported conversion of fetal volume to fetal weight [3]:

 $$ \mathrm{Fetal}\;\mathrm{weight}\;\left(\mathrm{g}\right)=\left[\mathrm{fetal}\;\mathrm{volume}\;\left(\mathrm{ml}\right)+120\right]\times 1.03 $$

10.6 Calculation of Fetal Oxygen Delivery and Consumption

The combination of vessel flow and oximetry that is made possible using PC CMR and MR oximetry can be used to quantify placental function and fetal metabolism by allowing the measurement of fetal oxygen delivery (DO2) and consumption (VO2). Fetal DO2 is the product of UV flow and UV oxygen content. The oxygen bound to hemoglobin and oxygen dissolved in plasma comprises the oxygen content of blood. In adult blood, the contribution to blood oxygen content from oxygen dissolved in plasma is in the 2–3 % range, while in fetal blood, this proportion is even lower, so that fetal blood oxygen content can be assumed to be the amount of oxygen combined with hemoglobin [44]. For adult blood, the amount of oxygen bound to hemoglobin can be calculated from the oxygen saturation (SaO2) and hemoglobin concentration [Hb]:

 $$ \mathrm{Oxygen}\;\mathrm{content}\;\left(\mathrm{ml}\right)={\mathrm{SaO}}_2\times \left[\mathrm{H}\mathrm{b}\right]\times 1.36 $$

where 1.36 is the amount of oxygen in ml that can be bound to 1 g of hemoglobin at 1 atm [44]. This figure is likely to be similar for fetal blood, as the total oxygen-carrying capacity of fetal hemoglobin is the same as adult hemoglobin despite the higher affinity of fetal hemoglobin for oxygen.

Fetal VO2 is given by the product of UV flow (QUV) and the difference between the oxygen contents (ΔC) of the UV and the umbilical artery (UA):

 $$ Fetal\;V{O}_2={Q}_{UV}\times \varDelta {C}_{UV-UA} $$

Because of the small size of the UA, the T2 in the descending aorta (DAo) is used for this calculation.

If it is assumed that the majority of the flow in the superior vena cava (SVC) is venous return from the brain, then fetal cerebral VO2 can also be approximated:

 $$ Fetal\; cerebral\;V{O}_2={Q}_{SVC}\times \varDelta {C}_{AAo-SVC} $$

10.7 Further Technical Considerations

10.7.1 Field Strength

Fetal CMR can be performed on 1.5 and 3 T systems. 1.5 T systems are less prone to SSFP banding artifacts resulting from magnetic field inhomogeneity. However, the increased SNR available at 3 T makes PC CMR more robust and facilitates MOG reconstruction. An important consideration is the effect of field strength on the relationship between T2 and SaO2, with shorter T2 values encountered at 3 T [22].

10.7.2 Patient Positioning and Coil Selection

A body-matrix coil placed on the maternal abdomen, as close to the fetal thorax as possible, combined with a spine coil provide the best signal for fetal imaging. The addition of a second surface coil placed around the mother’s back may help to improve signal across the whole field of view, if the mother is in a lateral decubitus position, which many women find most comfortable in later on in pregnancy.

10.8 The Normal Fetal Circulation

10.8.1 Existing Data

The interpretation of fetal flow and oximetry measurements requires an understanding of normal fetal cardiovascular physiology. Many of our concepts about the normal fetal circulation are derived from extensive experiments performed using invasive techniques in the ovine fetus. Abraham Rudolph and his collaborators used radioactive microspheres injected into different venous compartments in conjunction with conventional blood gas analysis from various arteries and veins to define the distribution of flow and blood oxygen content across the fetal circulation [44]. Further information about the distribution of flow in the human fetal circulation has been obtained by a number of groups using ultrasound [1920295055]. These confirm that in common with the lamb fetus, the human fetal circulation operates in parallel with shunts at the foramen ovale and ductus arteriosus resulting in blood bypassing the fetal lungs. This is tolerated in the fetal circulation because gaseous exchange occurs at the placenta. The fetus exists in a relatively low-oxygen environment but also has lower VO2 than the newborn due to lower demands for thermoregulation [44].

In fetal lambs, the SaO2 of blood in the left side of the fetal heart is approximately 10 % higher than the right due to a remarkable streaming mechanism where oxygenated blood returning from the placenta is preferentially directed across the foramen ovale via the left liver and ductus venosus [44]. This mechanism presumably exists to ensure a reliable source of oxygen to the developing brain and pumping heart. The less well-oxygenated blood returning from the SVC and lower body is preferentially routed towards the tricuspid valve and then onto the ductus arteriosus and pulmonary circulation. As pulmonary vascular resistance in the third trimester is inversely proportional to the oxygen content of the blood in the pulmonary arteries, a high pulmonary vascular resistance is maintained in the fetal lamb [44].

10.8.2 Distribution of Blood Flow

Based on a combination of measurements in fetal lambs and consideration of the greater size of the human brain, as well as ultrasound measurements of pulmonary blood flow in the human, Rudolph predicted the distribution of blood flow and oxygen saturations across the human fetal circulation [44]. A comparison of those estimates with our findings in 40 normal late gestation human fetuses is shown in Table 10.2. Reference ranges for the distribution of the normal late gestation human fetal circulation are shown in Table 10.3. The results of the MRI findings in this preliminary cohort are also shown in Figs. 10.8and 10.9. The MRI findings are remarkably similar to Rudolph’s estimates, with a mean CVO of 465 ml/min/kg, and suggest that as in lambs, the human right ventricle provides a slightly larger contribution to the CVO than the left. Two thirds of the right ventricular output passes across the DA, with the remainder passing into the pulmonary circulation. Pulmonary blood flow therefore accounts for about 15 % of the CVO or 75 ml/min/kg. About ¾ of the left ventricular output passes into the head and upper limbs and drains back to the SVC, which carries about 135 ml/kg/min, which is about 30 % of the CVO. The remaining 10 % of the CVO passes around the aortic isthmus, joining the ductus arteriosus flow to provide about 250 ml/min/kg, a little over half of the CVO to the DAo. According to our MRI measurements, a little over half of this DAo flow is directed back to the placenta via the umbilical circulation. This measurement is lower than Rudolph’s estimates but more in keeping with a number of subsequent ultrasound studies. One possible explanation for the finding of lower umbilical flow in the human compared with the lamb is the higher oxygen-carrying capacity of human fetal blood compared with the human resulting from the higher concentration of hemoglobin in human fetal blood [44]. This higher oxygen-carrying capacity would allow the placenta to deliver the same amount of oxygen to the fetus despite the lower umbilical flow.

Table 10.2

Comparison of the distribution of the fetal circulation in the late gestation human measured by phase-contrast MRI and the late gestation fetal lamb measured using radioactive microspheres [44]

   

CVO

MPA

AAO

SVC

DA

PBF

DAO

UV

FO

Mean flows (ml/min/kg)

Human MRI

465

261

191

137

187

74

252

134

135

Lambs

450

250

185

140

175

75

220

180

125

Mean flows (% of CVO)

Human MRI

 

56

41

28

41

15

54

29

29

Lambs

 

56

41

31

39

17

49

39

28

CVO combined ventricular output, MPA main pulmonary artery, AAo ascending aorta, SVC superior vena cava, DA ductus arteriosus, PBF pulmonary blood flow, DAo descending aorta, FO foramen ovale

Table 10.3

Means, standard deviations, and reference ranges (mean ± 2SD) of flows in 40 normal late gestation human fetuses measured by phase-contrast MRI expressed in ml/min/kg and as percentages and as modeled mean percentages of the combined ventricular output

 

CVO

MPA

AAO

SVC

DA

PBF

DAO

UV

FO

Mean flow (ml/min/kg)

465

261

191

137

187

74

252

134

135

SD

57

46

35

30

39

43

46

36

49

Mean ± 2 SD

(351,579)

(169,353)

(121,261)

(77,197)

(109,265)

(0,160)

(160,344)

(62,206)

(37,233)

Mean flow (% CVO)

 

56

41

29

40

16

55

29

29

SD

 

6

6

7

8

9

10

9

11

Mean ± 2 SD

 

(44,68)

(29,53)

(15,43)

(25,57)

(0,34)

(35,75)

(11,47)

(7,51)

Modeled mean flow (% CVO)

 

56

41

28

41

15

54

29

29

FO flow was calculated as the difference between the left ventricular output and pulmonary blood flow

CVO combined ventricular output, MPA main pulmonary artery, AAo ascending aorta, SVC superior vena cava, DA ductus arteriosus, PBF pulmonary blood flow, DAo descending aorta, FO foramen ovale

A330004_1_En_10_Fig8_HTML.jpg

Fig. 10.8

Distribution of the normal human fetal circulation measured by phase-contrast MRI in 40 late gestation fetuses expressed as mean flows (left) and converted to modeled mean percentages of the combined ventricular output (right). MPA main pulmonary artery, AAo ascending aorta, SVC superior vena cava, DA ductus arteriosus, DAo descending aorta, PBF pulmonary blood flow, UV umbilical vein, FOforamen ovale, UA umbilical artery, RA right atrium, LA left atrium, RV right ventricle, LV left ventricle. Coronary blood flow estimated based on fetal lamb findings (9), FO flow calculated as the difference between LV output and PBF

A330004_1_En_10_Fig9_HTML.gif

Fig. 10.9

Plot of individual vessel flows measured by phase-contrast MRI in 40 late gestation normal human fetuses expressed in ml/min/kg. The boxes show median and interquartile ranges, and whiskers show ranges of flows for each vessel. CVO combined ventricular output, MPA main pulmonary artery, AAo ascending aorta, SVC superior vena cava, DA ductus arteriosus, DAodescending aorta, PBF pulmonary blood flow, UV umbilical vein, FO foramen ovale

10.8.3 Oxygen Saturations

In keeping with prior invasive oximetry measurements performed in fetal lambs, our MR oximetry measurements suggest a similar mechanism for transporting oxygen from the placenta to the fetal cerebral and coronary circulations is present in the human. Although the spatial resolution of the current MR technique is not adequate to quantify the oxygen content of the vessels comprising the fetal hepatic circulation, we found saturations 11 % higher in the AAo than the MPA, suggesting the same streaming of oxygenated blood from the UV to the left heart via the ductus venosus and FO operates in human fetuses. The results of MR oximetry performed in 30 normal late gestation human fetuses compared with reference data from fetal lambs are shown in Table 10.4. Two differences we found in SaO2 in the human compared with the lamb where higher UV and SVC SaO2 than those reported in lambs. These may be due to inaccuracies in our MR oximetry technique, as we are yet to calibrate our oximetry for fetal hemoglobin, and because the SVC is the smallest vessel we attempted to measure. With a diameter of around 5 mm close to term, our imaging parameters result in a spatial resolution below the recommended limit for the SVC for making T2 measurements that are free from partial volume artifact [51]. However, the findings could also presumably reflect real differences in the two species, especially considering the different experimental conditions under which the measurements were made in anesthetized instrumented lambs versus unsedated humans. With regard to the UV SaO2, this conclusion is perhaps supported by the similar numbers we obtained for fetal DO2 and VO2 in humans compared with lambs [44]. These results are shown in Table 10.5, which also includes our measurements of fetal cerebral VO2. In keeping with estimates made by Rudolph, who noted that the human fetal brain is approximately five times larger than the lamb brain, our results would indicate that fetal cerebral VO2 accounts for about half of all fetal VO2 in the human. Our results for total fetal VO2 are also very similar to those obtained in human fetuses using a combination of conventional umbilical cordocentesis blood gas analysis and ultrasound UV flow measurements obtained at the time of delivery [1]. In this previous study, the investigators obtained a lower value for fetal DO2 than the measurements made using MRI, which was primarily due to the lower UV flow they observed. Indeed the ultrasound flow measurements reported in this previous study are among the lowest of any reported ultrasound measurements. We wonder whether this reflects a change in umbilical flow resulting from increasing uterine contractions in the period leading up to labor in these fetuses. The oxygen extraction fraction (OEF) in these fetuses at the time of delivery, given by the ratio of fetal VO2 to fetal DO2, is higher than the value of about 1/3 reported in previous fetal lamb studies and by our MRI method.

Table 10.4

Comparison of preliminary mean and SD oximetry values by MRI compared with reference data based on lamb studies [44]

 

UV

AAO

MPA

SVC

DAO

MRI T2 (ms)

201 ± 22

125 ± 18

105 ± 17

89 ± 16

108 ± 15

Mean MRI SaO2 (%)

88 ± 4

67 ± 7

56 ± 9

46 ± 10

58 ± 8

Mean reference SaO2 (%)

80

65

55

40

60

UV umbilical vein, AAo ascending aorta, MPA main pulmonary artery, SVC superior vena cava, DAo descending aorta, SaO2 oxygen saturation

Table 10.5

Mean (SD) fetal oxygen delivery (DO2), oxygen consumption (VO2), and cerebral oxygen consumption (CVO2) in the late gestation human fetus by MRI (ml/min/kg) with reference data from the fetal lamb [44]

 

DO2

VO2

CVO2

Human MRI

20.4 (3.5)

6.4 (1.7)

3.6 (0.8)

Lamb reference

~20

7–8

 

10.8.4 Hypoxic Pulmonary Vasoconstriction

One reassuring finding in terms of the preliminary results of our approach to assessing fetal hemodynamics using a combination of oximetry based on T2 mapping and flow quantification using PC CMR is the demonstration of the expected relationship between the blood oxygen content of pulmonary arterial blood and pulmonary blood flow. This relationship, whereby oxygen tension in the pulmonary arteries is inversely related to pulmonary vascular resistance, was initially demonstrated by Rudolph et al. in fetal lambs [44]. The biochemical pathways involved in this response have since been largely determined in lambs and include the release of nitric oxide by the pulmonary arterial endothelium which results in pulmonary arteriolar smooth muscle relaxation through cyclic GMP [16]. Rasanen et al. showed that this response is also present in the normal human fetal circulation during acute maternal hyperoxygenation [41]. In our preliminary MRI studies, we found a reasonable correlation between MPA T2 and pulmonary blood flow, in keeping with this known relationship. Of interest, we also found a similar relationship between UV T2 and pulmonary blood flow, suggesting that pulmonary blood flow in late gestation fetuses could also be related to subtle variation in placental function. The relationships we found between UV and MPA T2 and are shown in Fig. 10.10.

A330004_1_En_10_Fig10_HTML.gif

Fig. 10.10

Relationships between main pulmonary artery (MPA) and umbilical vein (UV) T2 and pulmonary blood flow (PBF) in 30 normal late gestation human fetuses by T2 mapping and phase-contrast cardiovascular magnetic resonance with metric optimized gating

A new finding of the MRI data is the wide variation of pulmonary blood flow we found in the normal late gestation human fetal circulation [40]. Pulmonary blood flow varied from as low as 15 ml/min/kg (2 % of the CVO) up to 185 ml/min/kg (>30 % of the CVO). Interestingly, this variation was found in the setting of rather stable AAo flow. As left ventricular output is supplied by venous return to the left heart from both the pulmonary circulation and from the right-to-left shunt across the foramen ovale, the range of pulmonary venous return and stable AAo flow suggests an inverse relationship exists between pulmonary blood flow and foramen ovale shunt in the normal fetal circulation. This is demonstrated by scatterplot showing the relationship between these variables shown in Fig. 10.11. Given our observation about the relationship between UV T2 and pulmonary blood flow, it follows that there may also be some variation in the degree of streaming of oxygenated blood across the foramen ovale whereby there is increased streaming in the setting of lower umbilical vein oxygen content and reduced streaming in well-oxygenated fetuses. Well-oxygenated fetuses with high pulmonary blood flow and low FO shunts would then be well adapted to making the transition to the in-series postnatal circulation, while low pulmonary blood flow may be a useful sign of late-onset placental insufficiency [52].

A330004_1_En_10_Fig11_HTML.gif

Fig. 10.11

Scatterplot showing inverse relationship between pulmonary blood flow and foramen ovale shunt in 40 late gestation fetuses by phase-contrast MRI

10.8.5 Oxygen Delivery and Consumption, UV Flow, and Arteriovenous Difference

The combination of MR oximetry and flow quantification provides some interesting insights into the relationships between the various parameters that determine fetal DO2 and VO2. Figure 10.12 shows the relationship between the T2 of UV and DAo blood and the relationship between the differences between these two and UV flow in 30 normal late gestation human fetuses. This data suggest that these two measurements are strongly associated, resulting in a stable arteriovenous difference of about 25 % across the fetal circulation. Interestingly, this relationship appears to be unaffected by changes in umbilical vein flow, suggesting that both fetal DO2 and fetal VO2 are largely determined by fetoplacental perfusion. Indeed, although caution should be exercised in the interpretation of the relationship between two measurements that are not independent of each other (fetal DO2 and VO2 both include the same measurement of UV flow and UV T2), there appears to be a matching of fetal VO2 and DO2 in the normal fetal circulation, which is largely an expression of the volume of UV flow. Such dependence of fetal oxygenation on UV flow has been observed in fetal animal models, while blood pressure is noted to be an important determinant of UV flow in normal lamb fetuses [2144]. We would therefore suggest that UV flow may be somewhat analogous to lung ventilation in the postnatal circulation and may vary according to the fetal metabolic requirement for oxygen. During sleep, when fetal VO2 is low, fetal autonomic tone and blood pressure are low, resulting in lower UV flow and therefore fetal DO2. By contrast, when the fetus is active, parasympathetic activity is reduced and sympathetic innervation increased, resulting in higher blood pressure and UV flow and higher DO2.

A330004_1_En_10_Fig12_HTML.gif

Fig. 10.12

Correlation between umbilical vein (UV) and descending aortic (DAo) T2 in 30 normal late gestation human fetuses (left). Arteriovenous difference in T2 (UV-DAo) does not appear to be affected by UV flow in the normal fetal circulation (right)

10.9 Fetal Circulatory Response to Acute Hypoxia

The presence of connections between the systemic and pulmonary sides of the fetal circulation allows for a unique circulatory response to acute hypoxia that has been well characterized in the fetal lamb and observed in human fetuses affected by placental insufficiency [74457]. This so-called “brain-sparing” physiology is driven by opposing changes in the vascular resistance of the different vascular beds and results in dramatic redistribution of the fetal circulation. These changes in resistance are mediated through carotid chemoreceptors which effect cerebral vasodilation as well as catecholamine-induced increases in peripheral vascular resistance and the hypoxic pulmonary vasodilation previously discussed. The result is that despite only modest increases in cardiac output, the fetus is able to maintain oxygen delivery to the fetal brain and heart in the face of significant reductions in the oxygen content of fetal blood.

We have observed brain-sparing physiology in fetuses with established late-onset intrauterine growth restriction using phase-contrast MRI [54]. In our small preliminary group of fetuses with IUGR, we found significant increases in SVC flow and reductions in pulmonary blood flow and umbilical vein flow as shown in Fig. 10.13. In more dramatic examples, SVC flow may reach double the normal mean, with UV flow halved.

A330004_1_En_10_Fig13_HTML.gif

Fig. 10.13

MRI measured major vessel flows in 14 IUGR and 26 normal fetuses. (CVO: combined ventricular output, MPA: main pulmonary artery, AAo: ascending aorta, SVC: superior vena cava, DA: ductus arteriosus, DAo: descending aorta, PBF: pulmonary blood flow, UV: umbilical vein.) IUGR fetuses showed flow redistribution: high superior vena caval flow and low pulmonary blood flow. Low UV flow indicated possible placental insufficiency– * indicates significantly different result

10.10 Fetal Metabolic Response to Chronic Hypoxia

While “brain-sparing physiology” may maintain cerebral and cardiac DO2 in the setting of acute hypoxia, it does so at the expense of oxygenation of other fetal organs, presumably exposing them to an increased risk of hypoxic ischemic injury. Animal experimental models of chronic fetal hypoxia reveal some resolution of the circulatory redistribution that characterizes the acute response to hypoxia [42]. Known secondary adaptions to chronic hypoxia include changes in fetal behavior, with a reduction in fetal activity and a reduction in fetal growth. In fetal lamb models of chronic hypoxia achieved with reductions in maternal FiO2, VO2 is reduced by 20 % with cessation of growth, a reduction in fetal movements account for a further 20 % drop in fetal VO2. As blood flow to the cerebral circulation diminishes, there is a similar reduction in fetal cerebral VO2 achieved through downregulation of neuronal metabolism [34]. In a lamb preparation of chronic fetal hypoxia achieved by carunclectomy prior to mating known as the placental restriction model, the distribution of the fetal circulation is normal with the exception of an increase in adrenal blood flow [39]. In these pregnancies, which result in asymmetrically growth-restricted fetuses, the only hemodynamic indicator of placental insufficiency is the reduction in the oxygen tension of fetal blood. If similar circumstances were to occur in human fetal pregnancies, the only chance of identifying such a fetus, which would likely be at increased risk of stillbirth and abnormal brain development, would be to document poor growth, an observation that generally requires serial ultrasound measurements. A further hindrance in this regard is the poor performance of ultrasound-based fetal biometry towards the end of the pregnancy.

In a preliminary cohort of 40 fetuses, we showed significant reductions in UV T2 and fetal DO2 in 10 small for gestational age (SGA) fetuses compared with the 30 appropriately grown (AGA) fetuses [61]. While the majority of SGA fetuses had supportive placental histopathologic and neonatal anthropomorphic evidence of IUGR, there was no difference between the two groups in terms of their fetal Doppler parameters. Comparisons of fetal CMR and Doppler parameters in the SGA and AGA groups are shown in Fig. 10.14. Figure 10.15 shows the results of serial Doppler, MRI, and fetal weight measurements in one of the subjects, whose pregnancy was thought to be uncomplicated on routine clinical monitoring, but where a careful analysis of the MRI data indicates the presence of significant late-onset IUGR [62]. Although the Doppler parameters and distribution of blood flow by MRI were normal during three consecutive late gestation scans, the stepwise reduction in T2 and fetal DO2 and VO2 indicates that a decline in placental function was responsible for the drop in fetal weight centile from just below the 50th centile at 34 weeks to a birth weight around the 5th centile at 39 weeks gestation. Placental histology in this case revealed low-normal placental weight with overcoiling of the umbilical cord and dysmaturity of chorionic villi. These data suggest that fetal CMR may have some utility for the diagnosis and monitoring of late-onset IUGR, a subject that remains an active area of research.

A330004_1_En_10_Fig14_HTML.gif

Fig. 10.14

Fetal MRI and Doppler hemodynamic parameters in small for gestational age (SGA) versus appropriate for gestational age (AGA) fetuses

A330004_1_En_10_Fig15_HTML.gif

Fig. 10.15

Doppler and MRI parameters and fetal circulatory and metabolic adaption to placental insufficiency in a case of clinically occult late-onset intrauterine growth restriction

10.11 Fetal Circulation in Congenital Heart Disease

While gray-scale ultrasound provides superlative anatomic imaging for the diagnosis and characterization of fetal CHD and Doppler provides a wealth of hemodynamic information, there are relatively few reports regarding the impact of CHD on the distribution of blood flow and oxygen across the fetal circulation. This is perhaps surprising, given the level of speculation regarding the impact of CHD on these parameters and their associated effects on fetal brain and lung development [1044]. The presence of fetal pulmonary vascular disease is associated with high rates of mortality in the setting of hypoplastic left heart syndrome and transposition [237], while variation in the growth of the pulmonary arteries in the setting of tetralogy of Fallot has important long-term implications. There is also mounting evidence that the delayed fetal brain maturation seen in CHD is associated with an increased risk of perioperative brain injury and long-term neurodevelopmental delay [48]. We have used the combination of flow and oximetry to investigate the impact of CHD on the distribution of blood flow and oxygen across the fetal circulation [53]. When these parameters are combined with fetal organ volumetry, information is obtained about the relationship between placental function, cardiovascular disease, fetal metabolism, and fetal organ growth and development.

10.12 Effect of CHD on Fetal Vessel Flow and Oxygen Saturation

The preliminary results of a fetal hemodynamic assessment by MRI in 51 fetuses with a range of common forms of cyanotic congenital heart disease compared with 33 normal late gestation fetuses are shown in Table 10.6 [35]. Our findings include lower CVO in fetuses with CHD associated with one very underdeveloped ventricle, often referred to as single-ventricle physiology, with the lowest CVO found in fetuses with Ebstein’s anomaly. SVC flow and pulmonary blood flow are reasonably stable across all patient groups. As expected, fetuses with hypoplastic left heart syndrome (HLHS) have lower AAo and higher MPA and DA flow, while fetuses with tetralogy of Fallot (TOF) have higher AAo flow and lower MPA and DA flow. The SaO2 throughout the fetal circulation is lower in CHD than in normal, including lower UV SaO2 and AAo SaO2. While there remain some limitations of the technique relating to the reliance on an assumed hematocrit and the general challenges of fetal MRI, these limitations probably apply equally to each patient group and a compelling picture of the hemodynamic impact of CHD emerges. The low CVO in single-ventricle patients is in keeping with previous ultrasound findings and presumably reflects an upper limit on the compensatory increase in cardiac output provided by the functioning ventricle in these fetuses. Their ability to maintain normal cardiac output is likely to be further affected by the presence of significant atrioventricular valve regurgitation, as demonstrated in the Ebstein’s anomaly group. The dependence of umbilical blood flow on fetal blood pressure, which in turn is influenced by cardiac output, presumably explains the lower UV flow seen in SV patients. Low CVO does not explain why fetuses with tricuspid atresia had lower placental blood flow than other single-ventricle patients. The reason for this is unclear, and the result may be spurious, resulting from the small sample size. The changes in the distribution of AAo and MPA flow in TOF and HLHS are expected in the setting of the right (TOF) and left (HLHS) ventricular outflow tract obstruction that characterize these lesions. The reduction in UV SaO2 found in many fetuses with CHD may result from placental abnormalities, which appear to be very common in fetuses with CHD [14]. However, the reduction in AAo SaO2 is also due to failure of the normal streaming of oxygenated blood from the placenta to the left ventricle and aorta via the DA and FO as shown in Fig. 10.16.

Table 10.6

Blood flow and oxygen saturations in the major vessels of the normal human fetus and fetuses with cyanotic congenital heart disease

 

Blood flow in ml/min/kg (mean ± SD; n)

Oxygen saturation in % (mean ± SD: n)

 

CVO

AAO

MPA

SVC

DAO

UV

DA

PBF

UV

AAo

MPA

DAo

SVC

Normal

469 ± 57 (33)

208 ± 42 (33)

246 ± 40 (33)

137 ± 33 (33)

237 ± 44 (33)

130 ± 31 (33)

180 ± 52 (33)

71 ± 33 (33)

80 ± 5 (33)

59 ± 6 (33)

52 ± 7 (33)

53 ± 6 (33)

45 ± 6 (33)

HLHS

429 ± 119 (14)

56 ± 53 (13)

368 ± 121 (14)

141 ± 42 (15)

220 ± 62 (14)

120 ± 37 (14)

298 ± 110 (12)

78 ± 43 (12)

80 ± 10 (5)

48 ± 4 (3)

48 ± 8 (4)

50 ± 9 (5)

36 ± 10 (5)

TOF

482 ± 80 (12)

387 ± 88 (12)

84 ± 51 (11)

129 ± 35 (12)

261 ± 84 (11)

140 ± 53 (11)

78 ± 117 (6)

79 ± 89 (8)

68 ± 13 (10)

53 ± 11 (9)

50 ± 16 (5)

50 ± 11 (10)

38 ± 12 (8)

TGA/IVS

498 ± 102 (13)

272 ± 62 (13)

211 ± 49 (13)

170 ± 72 (13)

250 ± 60 (13)

133 ± 25 (13)

133 ± 55 (11)

83 ± 90 (10)

71 ± 8 (7)

46 ± 13 (7)

53 ± 13 (7)

49 ± 10 (7)

39 ± 11 (7)

Ebstein’s anomaly

285 ± 115 (5)

207 ± 58 (5)

150 ± 212 (2)

101 ± 16 (5)

162 ± 57 (6)

112 ± 40 (6)

110 ± 125 (2)

71 ± 69 (2)

78 ± 10 (6)

46 ± 2 (4)

44 ± 0 (1)

45 ± 8 (6)

33 ± 5 (4)

Tricuspid atresia

414 ± 53 (7)

229 ± 102 (7)

173 ± 115 (7)

138 ± 46 (7)

195 ± 44 (7)

80 ± 41 (7)

125 ± 82 (6)

73 ± 43 (7)

73 ± 8 (5)

47 ± 11 (5)

50 ± 13 (3)

47 ± 11 (5)

36 ± 12 (5)

HLHS hypoplastic left heart syndrome, TOF tetralogy of Fallot, TGA/IVS transposition of the great arteries, CVO combined ventricular output, AAo ascending aorta, MPA main pulmonary artery, SVC superior vena cava, DAodescending aorta, UV umbilical vein, DA ductus arteriosus, PBF pulmonary blood flow

A330004_1_En_10_Fig16_HTML.gif

Fig. 10.16

Fetal hemodynamics in representative examples of transposition (TGA), hypoplastic left heart syndrome (HLHS), and tetralogy of Fallot (TOF) by MRI. In TGA, streaming of oxygenated blood across the foramen ovale results in lower saturations in the ascending aorta. In HLHS, no streaming is possible as there is a single outlet, and lower umbilical flow exacerbates the reduction in the oxygen content of blood supplied to the brain. In TOF, right-to-left shunting at the ventricular septal defect also results in dilution of the oxygen content of blood supplied to the cerebral circulation

10.13 Association of Abnormal Fetal Cerebral Hemodynamics with Fetal Brain Size

In 30 of these fetuses with CHD and 30 age-matched controls, the oximetry and flow measurements were combined to calculate fetal DO2, VO2, fetal OEF, and fetal cerebral DO2, VO2, and OEF. In the same two groups of fetuses, these hemodynamic parameters were compared with fetal brain weight, estimated from segmentation of the 3D SSFP acquisition used to calculate fetal weight. The results reveal convincing evidence of a hemodynamic basis for the brain dysmaturation typical of CHD, with reductions in umbilical vein oxygen content and failure of the normal streaming of oxygenated blood from the placenta to the AAo associated with a mean reduction in AAo SaO2 of 10 %, while cerebral blood flow and cerebral oxygen extraction were no different from controls. This accounted for the mean 15 % reduction in cerebral oxygen delivery and 32 % reduction cerebral VO2 in CHD fetuses, which were associated with a 13 % reduction in fetal brain volume. Fetal brain size correlated with ascending aortic oxygen saturation and cerebral VO2. The results of this analysis are shown in Fig. 10.17 and Table 10.7.

A330004_1_En_10_Fig17_HTML.gif

Fig. 10.17

Fetal cerebral hemodynamics and brain size in fetuses with congenital heart disease compared with normal controls

Table 10.7

Comparison of fetal hemodynamic parameters and brain size in fetuses with CHD versus controls

 

CHD (n = 30)

Normal (n = 30)

p value

Mean gestational age at MRI

36 (1.0)

36 (1.0)

0.5

Mean estimated fetal weight (kg)

2.9 (0.5)

3.1 (0.3)

0.16

Mean fetal brain volume (ml)

279 (46)

319 (30)

0.0001

Mean combined ventricular output (ml/min/kg)

433 (81)

459 (46)

0.14

Mean superior vena caval flow (ml/min/kg)

132 (35)

137 (33)

0.6

Mean ascending aortic saturation (%)

48 (9)

58 (6)

0.0001

Mean umbilical vein SaO2 (%)

73 (9)

79 (5)

0.0004

Mean umbilical vein flow (ml/min/kg)

115 (29)

129 (28)

0.03

Mean fetal oxygen delivery (ml/min/kg)

17.1 (4.4)

20.4 (4.2)

0.006

Mean fetal oxygen extraction fraction (%)

36 (8)

35 (7)

0.93

Mean fetal oxygen consumption (ml/min/kg)

5.8 (1.4)

6.9 (1.6)

0.007

Mean cerebral oxygen delivery (ml/min/kg)

10.2 (4.2)

12.0 (3.4)

0.08

Mean cerebral oxygen extraction fraction (%)

32 (20)

34 (8)

0.53

Mean cerebral oxygen consumption (ml/min/kg)

2.7 (1.2)

4.0 (1.2)

0.0001

Statistical analysis performed with student t-test

10.14 Relationship Between Fetal Hemodynamics and Neonatal Brain MRI in CHD

Fetal brain size remains a crude measure of brain maturation compared with the array of neonatal brain MRI parameters of brain development that are now available. These include morphologic scoring systems that include graded measures of white matter myelination and cortical folding such as the Total Maturation Score, as well as measures of brain microstructure (diffusion tensor imaging) and metabolism (magnetic resonance spectroscopy) [2330]. Early results of comparisons between fetal hemodynamic parameters and neonatal brain MRI indices shown in Fig. 10.18 also support a relationship between reductions in fetal and fetal cerebral VO2 and abnormalities on neonatal brain MRI [31]. The relationship between higher SVC flow and higher white matter mean diffusivity (ADC) suggests that a combination of CHD and late gestational placental disease may be a risk factor for hypoxic ischemic injury for the perinatal brain. Indeed, in fetuses with evidence of brain-sparing physiology, we have found a high incidence of periventricular leukomalacia on neonatal brain imaging [28].

A330004_1_En_10_Fig18_HTML.gif

Fig. 10.18

Correlation between fetal hemodynamic parameters and indices of neonatal brain development in fetuses with congenital heart disease and normal controls

10.15 MRI Assessment of Hemodynamic Changes Associated with Fetal Interventions

One early insight gained from the application of MRI to fetuses with CHD was the identification of pulmonary lymphangectasia on conventional T2W fast spin echo imaging of the lungs in the setting of pulmonary venous obstruction [47]. This finding, which is reported in the pathologic literature, is thought to reflect failure of involution of the pulmonary lymphatics in the setting of increased hydrostatic pressure and lymphatic flow in the pulmonary circulation. It results in high signal linear branching structures that follow the bronchovascular structures and extend out to lung surface via the interlobular septa on T2-weighted imaging (Fig. 10.19). It may be associated with chylous pleural effusions, in which case the characteristic “cobblestone” appearance of the surface of the lung may be appreciated. The presence of pulmonary lymphangectasia in the setting of HLHS with a highly restrictive or intact atrial septum is a marker of pulmonary vascular disease with arterialization of the pulmonary veins and hypoplasia and thickening of the pulmonary arteries. Pulmonary venous obstruction is reliably identified by the demonstration of increased atrial wave reversal in the pulmonary veins using Doppler, and both this finding and the presence of lymphangectasia on MRI are predictive of a poor outcome [2].

A330004_1_En_10_Fig19_HTML.jpg

Fig. 10.19

Pulmonary lymphangectasia in the setting of in utero pulmonary venous obstruction at 28 weeks’ gestation on T2W fast spin echo

The poor prognosis for patients with HLHS with an intact atrial septum has led to the development of fetal interventions that aim to decompress the pulmonary veins by creating an unobstructed pathway for the pulmonary venous return across the atrial septum [6]. Fetal MRI has revealed improvements in pulmonary blood flow following these in utero interventional procedures, which have been associated with improved oxygenation and hemodynamic stability following birth, although their impact on long-term survival remains uncertain.

Recent interest in the potential of chronic maternal hyperoxygenation to prevent the progression of borderline left ventricular hypoplasia to hypoplastic left heart syndrome has also been investigated with MRI. In one fetus with a small left ventricle, we administered an FiO2 of approximately 60–70 % to the mother during MRI and observed a doubling of pulmonary blood flow [5]. In this case, the desired increase in AAo was not observed; rather, we found reversal of flow across the FO, indicating a degree of restriction to left heart filling. As a biventricular repair was eventually possible in this patient following a period of the typical pulmonary vasodilation that occurs after birth, the possibility that a prolonged course of maternal hyperoxygenation might have resulted growth of left heart structures remains of interest. In keeping with animal and human ultrasound data confirming increased placental oxygen transfer during maternal ventilation with high concentrations of oxygen, we recently showed increases in UV T2 and pulmonary blood flow in 20 fetuses with CHD and 17 normal fetuses, demonstrating the potential of MRI to participate in the future investigation of this form of fetal intervention [36].

10.16 Conclusion

In this brief essay, a personal experience of the potential of MRI to explore the fetal cardiovascular system is reported. The focus on a single center’s approach to this application reflects the small scale of current fetal CMR practice. However, while fetal CMR is currently a research tool rather than a clinical imaging modality, its potential to supplement ultrasound in the assessment of cardiovascular and placental disease is promising. Indeed, if we consider the advancing versatility of MRI, it would appear likely that we are only just beginning to appreciate the potential of MRI to enhance our understanding of the fetal and uteroplacental circulations. Future technical developments resulting in faster imaging and other methods to overcome motion artifact will play a key role in making this exciting new tool more robust and applicable to imaging fetuses at earlier gestations.

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