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Published online before print February 4, 2005, 10.1148/radiol.2351040192
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(Radiology 2005;235:73-80.)
© RSNA, 2005

Experimental Studies

Placental Perfusion MR Imaging with Contrast Agents in a Mouse Model1

Laurent J. Salomon, MSc, Nathalie Siauve, MD, PhD, Daniel Balvay, MSc, Charles A. Cuénod, MD, PhD, Catherine Vayssettes, PhD, Alain Luciani, MD, Guy Frija, MD, Yves Ville, MD and Olivier Clément, MD, PhD

1 From the Laboratoire de Recherche en Imagerie, INSERM U494, Faculté de Médecine Necker, Université Paris 5, 156 rue de Vaugirard, 75015 Paris, France (L.J.S., N.S., D.B., C.A.C., C.V., A.L., G.F., O.C.); and Service de Gynécologie-Obstétrique, Centre Hospitalier Intercommunal de Poissy-St Germain, Poissy, France (L.J.S., Y.V.). Received February 1, 2004; revision requested April 12; revision received May 6; accepted June 2. Address correspondence to O.C. (e-mail: clement@necker.fr).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 APPENDIX
 REFERENCES
 
PURPOSE: To quantitatively analyze placental perfusion by using magnetic resonance (MR) imaging with contrast agents in a mouse model.

MATERIALS AND METHODS: Study was conducted according to French law and in full compliance with National Institutes of Health recommendations for animal care. Thirty-six pregnant Balb/c mice at 16 days of gestation were injected intravenously with either a conventional or macromolecular gadolinium chelate, and 1.5-T single-section T1-weighted two-dimensional fast spoiled gradient-echo sequential MR imaging was then performed for 14 minutes. Images were analyzed qualitatively, and parametric map analysis was performed in the resultant 25 mice included in the study. Signal intensity was measured in maternal left ventricle (input function), placenta, and fetus on all images. After converting signal intensity into contrast agent tissue concentrations, a three-compartment model was developed with compartmental and numeric modeling software. Placental perfusion was calculated for conventional (n = 12) and macromolecular (n = 13) gadolinium chelates. Finally, placental and fetal gadolinium concentrations were assayed by means of atomic emission spectrophotometry (n = 15). Perfusion values and placental and fetal gadolinium concentrations for conventional and macromolecular chelates were compared by using an unpaired t test.

RESULTS: Based on a constant transfer parameter, estimated placental perfusion did not differ between procedures with conventional and macromolecular gadolinium chelates (0.99 mL/min/g ± 0.5 [standard deviation] and 1.28 mL/min/g ± 0.6, respectively, P = .22). Likewise, mean placental gadolinium concentrations did not differ after injection of conventional and macromolecular chelates. In contrast, mean fetal gadolinium concentration was 9.83 µmol/L after conventional chelate injection and below detection limit after macromolecular chelate injection.

CONCLUSION: Placental perfusion can be calculated by using dynamic contrast-enhanced MR imaging, as shown in this mouse model.

© RSNA, 2005


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
 DISCUSSION
 APPENDIX
 REFERENCES
 
An important challenge in prenatal care is the functional assessment of the placenta, which ensures nearly all exchanges of respiratory gases, nutrients, and waste between the maternal and fetal compartments. The rate of transplacental exchange depends primarily on the rate of maternal placental (uterine) and fetal (umbilical) blood flow (1). Increased uterine vascular resistance and/or reduced uterine blood flow are predictors of fetal growth restriction and high-risk pregnancies (2). Precise quantification of placental perfusion could be useful for determining the pathogenesis and severity of fetal growth restriction, predicting the outcome of a compromised pregnancy, and estimating the benefits of vasodilatory and antithrombotic treatments (3,4). However, attempts to study placental pathophysiology and perfusion in vivo have yielded disappointing results.

Placental blood flow can be measured in the umbilical and uterine arteries by means of Doppler ultrasonography (US) (5), an inexpensive, noninvasive, and widely available imaging method. However, Doppler flow velocity in the uterine artery has limited value in the prediction of preeclampsia, intrauterine growth restriction, and perinatal death (6). Moreover, Doppler US cannot be used to directly quantify placental perfusion, whichshould ideally be measured in milliliters per gram of placenta per minute. Placental function has been investigated in many ways, including the use of radioactive microspheres and angiography (7), but concerns for both fetal and maternal safety place severe restrictions on invasive research.

Functional imaging is well suited to the analysis of vascular physiology and has been used to measure several relevant parameters, such as tissue blood flow and vascular permeability (8–13). Studies involving the use of contrast agents and T1-weighted fast gradient-echo magnetic resonance (MR) imaging sequences indicate that compartmental analysis of MR imaging–derived perfusion curves can be useful for quantification of organ perfusion (14). MR imaging is now used in clinical practice for perfusion assessment in stroke victims and might also prove useful in myocardial infarction, hepatic perfusion, and tumor investigation (15–18). To our knowledge, in vivo MR imaging measurements of placental perfusion with the use of contrast agents have not been reported. Thus, the purpose of our study was to quantitatively analyze placental perfusion by using MR imaging with contrast agents in a mouse model.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 APPENDIX
 REFERENCES
 
Animals and Contrast Agents
All studies were performed according to French law and in full compliance with National Institutes of Health recommendations for animal care. Balb/C mice were mated at the supplier laboratory (Elevage Janvier, Le Genest St Isle, France), and all MR imaging studies were performed at 16 days of gestation. Thirty-six mice were studied.

We used two contrast agents (Vistarem [gadomeritol] and Dotarem [gadoterate meglumine]; Guerbet, Aulnay-sous-Bois, France). Gadomeritol is a macromolecular gadolinium chelate with intravascular biodistribution and rapid urinary elimination (rapid clearance blood pool agent) (19,20) that is currently being tested in phase III clinical trials. It has a molecular weight of 6.47 kDa, and the particles are approximately 5 nm in diameter. It was used at a dose of 0.033 mmol of gadolinium per kilogram of body weight. Gadoterate meglumine is a conventional gadolinium chelate with good interstitial distribution owing to its low molecular weight (560 Da) and small particle diameter (1 nm). It was used at a dose of 0.125 mmol of gadolinium per kilogram.

The contrast media were injected manually as a bolus during MR imaging acquisition, via a 28-gauge catheter (Biosphère Médical, Roissy en France, France) placed in a caudal vein and connected to a 2-m delivery tube. We intended to inject 18 mice with conventional chelate and 18 mice with macromolecular chelate. Nine mice were excluded from MR imaging analysis because of failed catheter installation (n = 3) or failed contrast material injection (n = 6). MR imaging was performed in the remaining 25 mice (12 injected with conventional chelate, 13 injected with macromolecular gadolinium chelate), and the data obtained from these mice were used to build the quantitative model. Two mice with failed catheter installation were used as controls for gadolinium assay.

Imaging Procedure
MR imaging was performed with a 1.5-T unit (Signa; GE Medical Systems, Milwaukee, Wis). The animals were anesthetized (2% xylazine [Rompum; Bayer, France] and ketamine [Ketalar; Bayer, France] [50 mg/mL]) and placed in a dedicated mouse coil (9 cm long and 3-cm inner diameter). The following conventional spin-echo MR imaging sequences were used to locate the maternal left ventricle, the placentas, and the fetal mice: sagittal T1-weighted spin echo (repetition time msec/echo time msec, 500/2.2; matrix, 256 x 128; field of view, 12 x 12 cm; section thickness, 3 mm; intersection gap, 1.5 mm), coronal T1-weighted spin echo (500/2.2; matrix, 256 x 192; field of view, 6 x 6 cm; section thickness, 2 mm; intersection gap, 1 mm), and coronal T2-weighted fast spin echo (3000/95; matrix, 256 x 192; field of view, 6 x 6 cm; section thickness, 2 mm; intersection gap, 1 mm). For dynamic MR imaging, a two-dimensional fast spoiled gradient-echo sequence was used (15/2.2; flip angle, 60°; bandwidth, 31.25 kHz; matrix, 256 x 128; field of view, 7 x 3 cm; section thickness, 5 mm; one section acquired) with a temporal resolution of 1.13 seconds per image.

After acquisition of 10 baseline images, enhancement of the vascular input function (maternal left ventricle), the placenta, and the mouse fetus was monitored for 14 minutes (750 images). The mouse anatomy was first studied qualitatively. The maternal heart was recognized first, and the uterus with its two uterine tubes was identified in the maternal abdominal region. The observable fetoplacental units were counted. Each unit was centered on the fetus, surrounded by amniotic fluid and the placenta laterally. On dynamic MR images, the spatial and temporal patterns of placental enhancement were observed qualitatively. The visualization of the central arterial canal in the center of the placenta meant that the MR imaging section was precisely in the middle of the placental region. Regions of interest were designated manually by one operator (L.J.S.) and were made as large as possible to cover the entire studied structure (approximately 10 mm2 for placentas and 30 mm2 for fetuses). High-perfusion areas, presumably corresponding to vessels, were avoided.

Parametric Map Analysis
Parametric maps of the placenta were computed to highlight the placental physiology. The first 50 images of the dynamic acquisition were used to analyze first-pass enhancement. The enhancement kinetics of each pixel were fitted with a 6th-order polynomial to exclude marginal values. Then, "time to peak intensity" and "peak intensity" maps were computed as the time to maximum and the maximum of each polynomial function fitting a pixel, respectively.

Kinetic Curves and Signal Conversion
Signal intensities of regions of interest located in the maternal left ventricle (vascular input function) and the placental and fetal regions were measured on all of the 750 dynamic images. The fetus and corresponding placentas were selected and studied only if they were both identified clearly on the same section. Signal intensity was converted into the relaxation rate (1/T1) by using a calibration curve, as described elsewhere (11). The curve was constructed after each imaging session and for each mouse by using tubes containing increasing concentrations of conventional gadolinium chelate (0, 0.5, 0.8, 1.0, 2.0, 4.0, 6.0, 8.0, 10.0, 15.0, and 20.0 mmol of gadolinium per liter) or macromolecular gadolinium chelate (0, 0.05, 0.08, 0.1, 0.2, 0.4, 0.6, 0.8, 1.0, 1.5, and 2.0 mmol of gadolinium per liter) and two-dimensional spoiled gradient-echo MR imaging, without modifying the imaging parameters. Variations in 1/T1 (D1/T1) were then computed by subtracting the postinjection values from the baseline value. The D1/T1 values obtained were thus directly proportional to the contrast agent concentration C, as follows: D1/T1 = r1 · C, where r1 is the relaxivity of the contrast agent in blood at 1.5 T and 37°C (r1 = 23.5 L · mmol–1 · sec–1 for the macromolecular chelate [20] and r1 = 4.9 L · mmol–1 · sec–1 for the conventional chelate [21]). The same value of r1 was used to calculate contrast agent concentration in all tissues.

Compartmental and Statistical Analysis
Data were analyzed with a compartmental and numeric modeling program (SAAM software; SAAM Institute, Seattle, Wash) (see details in the Appendix). We developed a three-compartment model (Fig 1) based on physiologic data (22–24), in which the hemochorial placenta of the mouse consists of a maternal vascular compartment and a fetal vascular compartment into which the contrast medium can diffuse. Grossly, maternal blood enters the uterus through radial arteries that branch into spiral arteries. Spiral arteries converge together, and blood is then carried via canals that pass to the base of the placenta. Maternal blood then percolates back to the maternal side of the placenta in the labyrinth. Fetal blood passes through the labyrinth in the opposite direction of that of the maternal blood.



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  		Figure 1. Diagram shows three-compartment model. Software was used to calculate the transfer constant k(i,j) on the basis of enhancement kinetics. Placenta consists of a maternal vascular compartment (Vpm) and a fetal vascular compartment (Vpf), between which contrast media may exchange. Maternal compartment is supplied by an arterial input and drained by a venous output. Fetal vascular compartment may exchange contrast agent with the fetus itself (Vf) through the umbilical cord. Because the initial gadolinium concentration in the fetus is zero and might only slowly increase during the experiment, the transfer constant k(3,4) from the fetus to the placenta was neglected. q = quantity of contrast agent.

 
The placenta is then essentially consistent with a countercurrent exchange system between the maternal and fetal compartments. The maternal compartment is supplied by arterial input (uterine arteries) and drained through venous output. The fetal vascular compartment may exchange contrast agent with the fetus itself through the umbilical cord. The analysis assumes that the volume of each compartment is constant during the experiment and that the mixing time within each compartment is short compared with the tracer transfer rate between compartments.

The model also assumes that the contrast agent is not taken up by cells and that no contrast agent is present in tissues prior to or at the time of injection. The differential equations for the model are shown in the Appendix.

The constant transfer parameters k(i,j) were adjusted by the software to the concentration changes measured with MR imaging in the left heart ventricle and the placental and fetal regions. Goodness-of-fit was examined qualitatively with the software-computed curves. Placental blood flow per unit tissue volume (perfusion in milliliters per second per milliliter) was calculated from the transfer rate k(2,1). Calculated perfusion values obtained with the conventional and macromolecular gadolinium chelates were compared by using an unpaired t test. Mean placental perfusion value based on the overall results was calculated.

Gadolinium Assay and Statistical Analysis
Immediately after the imaging procedure, mice were killed and dissected for comparison with MR imaging findings. Fifteen placentas and fetuses (injected with conventional [n = 7] or macromolecular [n = 8] gadolinium chelate) were selected randomly. These samples were removed, rinsed with distilled water to avoid maternal blood contamination, and stored at –80°C until use. Two placentas and two fetuses were also removed from mice that had failed catheter installation and did not undergo MR imaging study to serve as negative controls.

Tissue gadolinium concentrations were determined by using atomic emission spectrophotometry (Spectra DCP ARL; Fisons Instruments, Beverly, Mass) by a trained technician blinded to the contrast agent used or to no agent used (controls). Placental and fetal concentrations were compared between the two types of chelate by using an unpaired t test.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 APPENDIX
 REFERENCES
 
With conventional spin-echo MR imaging sequences, study of mouse anatomy was feasible. The two uterine tubes were easily recognizable (Fig 2a). Placental tissue had a signal intensity comparable to that of muscle on T1- and T2-weighted MR images and was visible, as was the umbilical cord (Fig 2b). Fetus shape was distinguished easily on T1-weighted images (Fig 2c). Image analysis required adequate visualization of the maternal left ventricle and the placental and fetal regions and a total absence of mouse movement throughout the acquisition. The number of placentas varied from four to 10. The median number of observable placentas on spoiled gradient-echo MR images was two (range, 0–4).



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  		Figure 2a. MR imaging-anatomic comparison. (a) Two uterine tubes containing multiple fetoplacental units are well visualized on a T1-weighted coronal MR image (500/2.2; field of view, 6 x 6 cm) (left). Anatomy is illustrated on right. (b) T2-weighted transverse MR image (3000/95; field of view, 6 x 6 cm) shows placenta (large arrow) with a signal intensity comparable to that of muscle, together with umbilical cord (small arrow). (c) Fetal sagittal shape is well recognized on this T1-weighted coronal MR image (500/2.2; field of view, 6 x 6 cm) (left) correlating to anatomic image (right).

 


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  		Figure 2b. MR imaging-anatomic comparison. (a) Two uterine tubes containing multiple fetoplacental units are well visualized on a T1-weighted coronal MR image (500/2.2; field of view, 6 x 6 cm) (left). Anatomy is illustrated on right. (b) T2-weighted transverse MR image (3000/95; field of view, 6 x 6 cm) shows placenta (large arrow) with a signal intensity comparable to that of muscle, together with umbilical cord (small arrow). (c) Fetal sagittal shape is well recognized on this T1-weighted coronal MR image (500/2.2; field of view, 6 x 6 cm) (left) correlating to anatomic image (right).

 


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  		Figure 2c. MR imaging-anatomic comparison. (a) Two uterine tubes containing multiple fetoplacental units are well visualized on a T1-weighted coronal MR image (500/2.2; field of view, 6 x 6 cm) (left). Anatomy is illustrated on right. (b) T2-weighted transverse MR image (3000/95; field of view, 6 x 6 cm) shows placenta (large arrow) with a signal intensity comparable to that of muscle, together with umbilical cord (small arrow). (c) Fetal sagittal shape is well recognized on this T1-weighted coronal MR image (500/2.2; field of view, 6 x 6 cm) (left) correlating to anatomic image (right).

 
When the MR imaging section was positioned precisely in the middle of the placental region, the enhancement on dynamic images appeared stereotypic (Fig 3). Maternal blood flow toward the placental base was enhanced first, and blood then bounced back through the intervillous space of the labyrinth, leading to enhancement of the entire placental region.



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  		Figure 3. Typical pattern of placental enhancement after gadoterate meglumine injection on magnified spoiled gradient-echo coronal dynamic MR images (15/2.2; flip angle, 60°; bandwidth, 31.25 kHz; matrix, 256 x 128; field of view, 7 x 3 cm; section thickness, 5 mm; one section acquired); one image was acquired every 2.2 seconds (images 1 to 5). Before injection (image 1), placenta could not be visualized. It started to enhance a few seconds after injection, with maternal blood flow bouncing back to placental base (images 2 and 3). Thereafter, the entire area enhanced gradually (images 4 and 5). Image 6: placental area (gray) and fetal area (black) are represented schematically.

 
On spoiled gradient-echo MR images acquired before and after contrast material injection, there was no qualitative difference between the maternal left ventricle and placental enhancement in the conventional and macromolecular chelate groups (Fig 4). Qualitatively, no fetal enhancement was detected after conventional or macromolecular chelate injection. Time to peak intensity maps showed the gradual placental enhancement (Fig 5a). On peak intensity maps, the center of the placenta was the area of highest signal intensity (Fig 5b).



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  		Figure 4. Example of coronal images obtained during spoiled gradient-echo MR sequences (15/2.2; flip angle, 60°; bandwidth, 31.25 kHz; matrix, 256 x 128; field of view, 7 x 3 cm; section thickness, 5 mm; one section acquired). On left image, acquired before injection, left ventricle and placental and fetal areas cannot be identified. On right image, after conventional gadolinium chelate injection, enhancement of left ventricle ({star}), placental area (arrows), and fetal area ({circ}) can be measured.

 


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  		Figure 5a. Parametric map analysis obtained from series of images shown in Figure 3. Note central arterial canal (arrow) on time-to-peak intensity map. (a) Pixels that reach peak intensity early are represented in red; scale is in seconds. On peak-intensity map, maximum is reached in center of placenta, corresponding to labyrinth region that contains only blood. (b) Red represents pixels that reach highest intensity; scale is in signal intensity.

 


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  		Figure 5b. Parametric map analysis obtained from series of images shown in Figure 3. Note central arterial canal (arrow) on time-to-peak intensity map. (a) Pixels that reach peak intensity early are represented in red; scale is in seconds. On peak-intensity map, maximum is reached in center of placenta, corresponding to labyrinth region that contains only blood. (b) Red represents pixels that reach highest intensity; scale is in signal intensity.

 
Kinetic enhancement curves were obtained (Fig 6a was obtained after conventional chelate injection; Fig 6b was obtained after macromolecular chelate injection). With regard to maternal left ventricle kinetics, the first-pass peak was highlighted, and the tissue concentration of the contrast agents then decreased gradually. Placental tissue analysis showed gradual uptake of contrast agent. Quantitatively, no fetal enhancement was observed.



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  		Figure 6a. Examples of enhancement curves obtained after contrast agent injection in two fetuses in two mice (a) Conventional gadolinium chelate. (b) Macromolecular gadolinium chelate. For left ventricle kinetics, first-pass peak is highlighted, and contrast agent tissue concentration decreases slowly thereafter. Placental tissue concentration shows gradual uptake of contrast agent, followed by gradual decay; no enhancement is seen in the fetus.

 


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  		Figure 6b. Examples of enhancement curves obtained after contrast agent injection in two fetuses in two mice (a) Conventional gadolinium chelate. (b) Macromolecular gadolinium chelate. For left ventricle kinetics, first-pass peak is highlighted, and contrast agent tissue concentration decreases slowly thereafter. Placental tissue concentration shows gradual uptake of contrast agent, followed by gradual decay; no enhancement is seen in the fetus.

 
Among the 25 mice studied with MR imaging, we were able to analyze quantitatively only 13 mice, yielding 32 sets of kinetic data (12 after conventional chelate injection and 20 after macromolecular chelate injection) for different placentas and fetuses. All 32 sets of kinetic data were then analyzed with the software. The transfer rate k(2,1) was calculated in every case (Table 1). The mean k(2,1) was 1.65E-02 mL/sec/mL ± 0.93E-02 (standard deviation) in the macromolecular chelate group and 2.13E-02 mL/sec/mL ± 1.24E-02 in the conventional chelate group. On the basis of the constant transfer parameter, placental perfusion did not differ according to whether the conventional or macromolecular chelate was used (0.99 mL/min/g ± 0.5 and 1.28 mL/min/g ± 0.6, respectively; P = .22). The other transfer rates could not be computed accurately because of excessive variability, especially of k(2,3) and k(3,2), the constants related to permeability. This variability did not affect curve fitting, however, which was always assessed qualitatively by the experimenter. Mean placental perfusion value based on the overall results was 1.10 mL/min per gram of placental tissue ± 0.60.


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  		TABLE 1. Calculated Transfer Rates Based on Our Experimental Model and Concentration Kinetics

 
Mean placental and fetal gadolinium concentrations determined by means of atomic emission spectrophotometry are shown in Table 2. There was no significant difference in placental gadolinium concentrations between the conventional and macromolecular chelate groups (P = .16). In contrast, fetal gadolinium uptake was undetectable after macromolecular chelate injection, whereas the mean fetal gadolinium concentration after conventional chelate injection was 9.83 µmol/L ± 5.1. There was no detectable gadolinium in the placentas and fetuses of control mice.


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  		TABLE 2. Placental and Fetal Concentrations of Gadolinium 20 Minutes after Injection, as Determined by Using Atomic Emission Spectrophotometry

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
APPENDIX
 REFERENCES
 
This study shows that placental perfusion can be studied in mice with dynamic MR imaging. Several recommendations (25) and other requirements must be respected when assessing placental perfusion. Baseline signal intensity must be measured prior to contrast material injection, and the highest spatial and temporal resolution must be used (25). Rapid bolus injection is required (26), and then the time course of blood and tissue contrast enhancement must be measured (25). Finally, the relationship between enhanced signal intensity and contrast agent concentration (25) must be determined before compartmental analysis can be conducted.

Placental function is crucial for normal fetal growth (27) but is currently difficult to evaluate. By using fast-acquisition MR imaging, Panigel et al (28) described maternal blood flow "sprouting" into the monkey placenta but did not use compartmental analysis. Marcos et al (29) described placental enhancement in patients undergoing MR imaging for suspected uterine or placental abnormalities.

We were able to study blood flow in a much smaller placenta, and our findings are in keeping with those of Adamson et al (22), who recently depicted placental circulation on the basis of vascular casts and histologic studies. The latter authors reported that the central arterial canal carried maternal blood, which then percolated back through the intervillous space of the labyrinth toward the maternal side of the placenta, in the opposite direction of fetal capillary flow. Our qualitative study of placental enhancement is in keeping with this description. This vascular physiology is highlighted on our time to peak intensity maps, which clearly illustrate the gradual filling of the intervillous space and the central arterial canal. In addition, our peak intensity maps show that maximum enhancement is reached in the center of the placenta, probably because this central area contains mainly blood (22); the tissue concentration of contrast agent is therefore maximal and comparable to that of large maternal vessels.

We modeled the placental physiology, allowing us to establish the characteristics of transfer rate linked to perfusion. Perfusion, estimated after conventional and macromolecular gadolinium chelate injection, was 0.99 mL/min/g ± 0.5 and 1.28 mL/min/g ± 0.6, respectively. Indeed, Doppler US techniques currently used to evaluate blood velocity waveforms in the uteroplacental arteries (5) only provide an indirect estimate of placental function. There is growing evidence that Doppler US is unable to demonstrate the origins of intrauterine growth restriction or to allow prediction of the outcome of compromised pregnancies (6).

Three MR imaging–based approaches might be used to measure placental perfusion, as described by Gowland et al (30). The first, which was used here, is based on contrast agents. The second uses gradient sensitization, a method first described by Le Bihan et al (31). The third, adopted by Gowland et al (30), uses changes in apparent T1 due to the inflow of equilibrium magnetization. In this study, mouse placental perfusion was 1.10 mL/min per gram of placental tissue ± 0.60. By using high-speed echoplanar imaging to measure human placental perfusion, Gowland et al (30) obtained a mean perfusion rate of 1.76 mL/min/g. However, the technique they used did not separate fetoplacental flow from maternal-placental flow, and the fetus was exposed to very strong magnetic fields and switching rates, which might be deleterious for the fetal heart and audition (32).

We detected no leakage of contrast agent into the fetus. This was confirmed by means of gadolinium assay after macromolecular gadolinium chelate injection: No gadolinium was detected in the fetus by using atomic emission spectrophotometry. With regard to conventional gadolinium chelate, an earlier physiologic study (33,34) showed that a small amount of agent might reach the fetus. It could not be detected with MR imaging, however, whereas a small amount of gadolinium was detected with spectrophotometry. Therefore, it was not possible to accurately calculate permeability transfer constants (k[2,3], k[3,2], or k[4,3]). Although the maximum concentration in the fetus is reported to occur after only 5 minutes (33), it might be too low to be detected with two-dimensional fast spoiled gradient-echo MR sequences. However, in pathologic situations associated with increased placental permeability, such as placental infection (35), or by using more sensitive sequences, our model could be used to assess both permeability and perfusion.

This study has some limitations. Part of the variability in our measurements might have been due to (a) heterogeneity between mice and within the placenta and (b) the subjective choice of regions of interest. Although we paid particular attention to the choice of regions of interest—that is, avoiding areas of high perfusion (presumably corresponding to vessels)—the use of single-section imaging restricted the choice of regions of interest.

Moreover, precision might have been hampered by section thickness, which induced some volume averaging. Advances in fast multisection acquisition and three-dimensional gradient-echo sequences (36) could offer volume acquisition with good temporal resolution and therefore help with region of interest selection. Finally, the use of contrast agents during pregnancy is controversial, as it might be deleterious for the fetus. However, there is increasing evidence that MR imaging is useful and safe during pregnancy (37,38), and toxicologic data found in the literature suggested that contrast agents might be harmless during pregnancy (39–42). Organized toxicologic studies of MR contrast agents will probably never occur in humans. Nevertheless, contrast agents that have already been used during pregnancy might have a growing place in the future (43). The use of macromolecular gadolinium chelate to determine placental perfusion would further reduce the risk of adverse effects, as these agents do not cross the placenta.

In conclusion, we describe a technique for dynamic placental perfusion studies. If this approach is feasible and safe in humans, it may have potential for investigation of the origin and course of intrauterine growth restriction and for the management of compromised pregnancies.

Practical application: This approach of MR functional imaging shows promise for real-time studies of human placental perfusion in vivo. Studies of placental perfusion could be useful for evaluation of high-risk pregnancies. MR imaging could provide new insights into the pathogenesis of growth restriction and placental dysfunction.


   APPENDIX
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 APPENDIX
REFERENCES
 
SAAM (SAAM Institute) is a compartmental and numeric modeling software program that allows development and use of models to analyze data. It permits creation of models and design and simulation of experiments. It is based on the creation of systems of ordinary differential equations from the compartmental model structure. The model is solved and fitted to data by using traditional mathematic and statistical techniques.

Differential equations for the compartmental model are described in Figure 1.

For the placental maternal vascular compartment,

{r05mr22e01}
where q is the quantity of contrast agent. For the placental fetal vascular compartment,

{r05mr22e02}

For the fetal compartment,

{r05mr22e03}


   ACKNOWLEDGMENTS
 
We thank Jacques Bittoun, MD, PhD, and his team at CIERM (Kremlin-Bicêtre, France) for their help with MR imaging; and Philippe Robert, PhD, and Robin Santus (Guerbet, Aulnay, France) for their technical support.


   FOOTNOTES
 
Authors stated no financial relationship to disclose.

Author contributions: Guarantors of integrity of entire study, C.A.C., O.C., G.F.; study concepts and design, L.J.S., N.S., C.A.C.; literature research, L.J.S.; experimental studies, L.J.S., C.V., D.B.; data acquisition, L.J.S., C.V., D.B.; data analysis/interpretation, L.J.S., N.S., C.A.C., Y.V.; statistical analysis, L.J.S., D.B.; manuscript preparation, L.J.S., N.S., A.L.; manuscript definition of intellectual content, L.J.S., N.S., C.A.C., G.F., O.C., Y.V.; manuscript editing, L.J.S., N.S., O.C.; manuscript revision/review, L.J.S., N.S., C.A.C.; manuscript final version approval, L.J.S., N.S.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 APPENDIX
 REFERENCES
 

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