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Published online before print October 25, 2006, 10.1148/radiol.2413051168
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(Radiology 2006;241:737-745.)
© RSNA, 2006

Experimental Studies

Placental Perfusion and Permeability: Simultaneous Assessment with Dual-Echo Contrast-enhanced MR Imaging in Mice1

Fabienne Taillieu, MD, Laurent J. Salomon, MD, PhD, Nathalie Siauve, MD, PhD, Olivier Clément, MD, PhD, Nathalie Faye, MD, Daniel Balvay, PhD, Catherine Vayssettes, PhD, Guy Frija, MD, Yves Ville, MD and Charles A. Cuenod, MD, PhD

1 From the Université Paris Descartes, Faculté de Médecine, INSERM U494, Laboratory of Research in Imaging, site Necker, 156 rue de Vaugirard, 75015 Paris, France (F.T., L.J.S., N.S., O.C., N.F., D.B., C.V., G.F., C.A.C.); and Gynecologic-Obstetric Service, Centre Hospitalier Intercommunal de Poissy-St Germain, Poissy, France (L.J.S., Y.V.). Received July 12, 2005; revision requested September 19; revision received October 17; accepted October 26; final version accepted February 17, 2006. Address correspondence to F.T. (e-mail: fab.taillieu{at}noos.fr).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
Purpose: To assess placental perfusion and permeability in mice with magnetic resonance (MR) imaging.

Materials and Methods: This study was conducted according to French law and National Institutes of Health recommendations for animal care. Twenty-two pregnant BALB/c mice were examined at 1.5 T with a single-section dual-echo fast spoiled gradient-echo sequence. Two injection protocols were used: monophasic injection (double the clinical dose of contrast agent) and biphasic injection (quadruple the clinical dose). Signal intensities (SIs) were measured in the maternal left ventricle, placenta, and fetus (n = 16). At these high gadolinium doses, a T2* effect correction was used. SIs were converted to gadolinium concentrations and were analyzed by using a three-compartment model. Quantitative microcirculation parameters were calculated. Results with the monophasic and biphasic protocols were compared, and final arterial concentrations determined with MR imaging were compared with those determined with atomic emission spectrophotometry by using the unpaired Student t test.

Results: Perfusion and permeability parameters for monophasic and biphasic injections were similar: Mean placental blood flow was 180 mL/min/100 g, mean permeability surface coefficient from maternal placental to fetal placental compartment was 10.3 x 10–4 sec–1 ± 6.81 (standard deviation), mean permeability surface coefficient from fetal placental to maternal placental compartment was 4.65 x 10–4 sec–1 ± 4.37, and mean fractional volume of the maternal vascular placental compartment was 36.5% ± 0.9. Placental (146 vs 105 µmol/L, P < .004) and fetal (33.3 vs 19.1 µmol/L, P < .001) gadolinium concentrations were higher with the biphasic than with the monophasic protocol. Arterial gadolinium concentrations at MR imaging did not differ significantly from those at spectrophotometry for the monophasic (P = .254) or biphasic (P = .776) injection protocol.

Conclusion: Placental perfusion and permeability can be measured in vivo by using high gadolinium doses and a dual-echo MR imaging sequence.

Supplemental material: http://radiology.rsnajnls.org/cgi/content/full/2413051168/DC1

© RSNA, 2006


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
Although our understanding of the causes and pathogenesis of uteroplacental disturbances that may compromise pregnancy is limited, increased uterine vascular resistance and/or reduced uterine blood flow may lead to decreased placental perfusion and could predict fetal growth restriction and vascular complications during pregnancies (1–3).

Placental permeability is also of great importance, because the placenta is the only organ that permits exchange between the mother and the fetus, and altered permeability may be a key factor in inadequate nutrient transfer to the fetus, as well as in toxic or infectious pathways into the fetus (4–7). Because of the inaccessibility of the fetus, most studies of transplacental transfer have been performed in vitro (8–10). A noninvasive way of assessing placental function in vivo would be useful. Although placental permeability can be assessed in vivo by using nuclear medicine (11), concerns about both fetal and maternal safety put severe restrictions on such an approach.

Dynamic magnetic resonance (MR) imaging is well suited for the analysis of vascular changes in oncology and has been used to measure several relevant parameters, such as microvascular volume, vascular permeability, and blood flow (12) in various tissues (13,14). These investigations involved the use of contrast agents and T1-weighted fast gradient-echo sequences to obtain kinetic concentration curves, which were analyzed with a mathematic compartmental model. To our knowledge, only one functional placental dynamic MR imaging study (15) has been reported to date. In this work, the authors obtained in vivo placental perfusion measurements but were unable to depict fetal contrast agent transfer or to determine placental permeability. We hypothesized that by using a dual-echo sequence to compensate for T2 and T2* effects, it might be possible to inject higher doses of contrast agent and detect fetal accumulation of contrast agent so that permeability parameters could also be assessed. Thus, the aim of this study was to assess placental perfusion and permeability in mice with MR imaging.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 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's laboratory (Janvier, Le Genest St Isle, France), and all MR imaging studies were performed at 16 days gestation (during a 21-day gestation).

We used a conventional gadolinium chelate (gadoterate meglumine, Dotarem; Guerbet, Aulnay-sous-Bois, France) and two injection protocols. In the monophasic protocol, 15 µL of the gadolinium chelate was injected as a bolus, with a saline flush of 150 µL, at a dose of 0.25 mmol gadolinium per kilogram of body weight—that is, twice the clinical dose of gadolinium used in previous work (15). In the biphasic protocol, 15 µL of the conventional gadolinium chelate was injected first as a bolus at a dose of 0.25 mmol gadolinium per kilogram with a 150-µL saline flush. Four minutes later, a slow perfusion of 150 µL of 0.25 mmol gadolinium per kilogram diluted 10% was administered over 20 seconds. Thus, a total of 0.5 mmol gadolinium per kilogram was injected. This second protocol allowed us to inject a total dose that was four times higher than the clinical dose employed in previous work (15), thus increasing gadolinium transfer to the fetus so we could measure placental permeability.

The contrast medium was injected manually during MR image acquisition by a single operator (F.T., who had 2 years of experience in mouse research) with a 28-gauge catheter that was prepositioned in a tail vein and connected to a 2-m delivery tube.

The study required a total of 48 mice. None of them were included in previous work (15). Twenty-six animals were excluded from the analysis because of catheter placement failure (n = 12), contrast agent injection failure (n = 7), or death because of anesthesia (n = 7). A contrast agent injection failure was considered to have occurred when there was no signal intensity (SI) modification in the maternal left ventricle and there was extravasation of gadolinium chelate in the murine tail. MR imaging was performed in the remaining 22 mice (the monophasic and biphasic injection protocols were used in 11 mice each), and exploitable kinetic data were obtained for 16 animals (nine in the monophasic protocol group and seven in the biphasic protocol group). The data in the other six animals were not assessable because of motion artifacts (regions of interest [ROIs] were difficult to place on the same volume for each section of the dynamic sequence, n = 4) or failure to visualize the maternal left ventricle, placenta, and fetus on the same coronal section (n = 2). Each mouse enabled analysis of one to four fetoplacental units (FPUs), for a total of 22 FPUs in the monophasic group and 17 FPUs in the biphasic group.

Imaging Procedure and Image Evaluation
MR imaging was performed with a 1.5-T unit (Signa; GE, Milwaukee, Wis). The animals were anesthetized (with xylazine 2% [Rompum; Bayer, Puteaux, France] and 50 mg/mL ketamine [Ketalar; Bayer]) and placed in a wrist quadrature phased-array surface coil. An anatomic MR imaging sequence was first performed to locate the maternal left ventricle, the placentas, and the fetal mice (coronal spin-echo T1-weighted sequence; repetition time msec/echo time msec, 500/13; matrix, 256 x 192; field of view, 7 x 7 cm; section thickness, 2 mm). A two-dimensional fast spoiled gradient-echo monosection sequence with a dual echo time was used for dynamic MR imaging (19.5/3.9, 6.7; flip angle, 60°; bandwidth, 31.25 kHz; matrix, 256 x 224 with a zero-filling interpolation of 512; field of view, 14 x 7 cm; section thickness, 3 mm; one section). The temporal resolution was 1.55 seconds per image of one echo time. After 10 baseline images were acquired, enhancement of the vascular input function (maternal left ventricle), the placenta, and the fetal mouse were monitored for at least 20 minutes. Mice were imaged for a mean of 25 minutes ± 4 (standard deviation).

Mouse anatomy was first evaluated qualitatively with the anatomic (spin-echo T1-weighted) MR imaging sequence by two authors (F.T. and N.S.; N.S. had 10 years of experience in mouse research). First, the maternal heart was identified and the uterus with its two uterine tubes was identified in the maternal abdomen. The observable FPUs were counted. In each FPU, the fetus, surrounded by amniotic fluid, was in the center and the placenta was located laterally. For the dynamic MR imaging sequence, the section plane corresponded to the plane in which the maternal left ventricle and the maximal number of FPUs could be best seen. On dynamic images, the spatial and temporal patterns of placental and fetal enhancement were observed qualitatively.

Kinetic Enhancement Curves
SIs were measured on all the dynamic images by using ROIs located in the maternal left ventricle (for measurement of the vascular input function) and in the placental and fetal regions. ROIs were as large as possible to cover the entire studied structure (approximately 10 mm2 for the left ventricle, 20 mm2 for the placenta, and 30 mm2 for the fetus). Amniotic fluid was not clearly differentiable from the fetus and was probably sometimes included in the fetal ROI. ROIs were placed manually in the first image by a single operator (F.T.) and were then repeated automatically in the other images with image software (Scion; Scion, Frederick, Md). Good placement of the ROIs was checked by one author (F.T.). High perfusion areas that presumably corresponded to large vessels were avoided.

T2* Effect Correction in Arterial Input Function
For gradient-echo images, the SI was given by using the following equation and was dependent on both T1 and T2* effects:

Formula 1(1)
where m0 is the equilibrium longitudinal magnetization in the sample, {alpha} is the flip angle, TE is the echo time, and TR is the repetition time.

In a vessel, the T2* effect is related to the magnetic field heterogeneity induced by the absence of penetration of contrast agent into red blood cells (16). With low concentrations of contrast agent, the T2* effect contributes little to the SI in T1-weighted images, and it can be considered that the SI reflects only the T1 effect. At high contrast agent concentrations, however, the magnetic field in blood is nonuniform, and the T2* becomes remarkably short (16) and contributes a nonnegligible part of SI. However, only SI related to the T1 effect must be taken into account when calculating the gadolinium concentration.

To differentiate the T1 and T2* effects, signals sampled during two consecutive echoes were used. T2*-dependent components were excluded by using SIT1 (T2*-compensated SI, dependent only on the T1 effect), which was defined by using the following equation (17):

Formula 2(2)
where ß = TE1/(TE1 – TE2); TE1 and TE2 are the echo times for the first and second gradient echoes, respectively; and SITE1 and SITE2 are the SIs measured at the first and second echoes, respectively.

The SIT1 was calculated by using Equation (2) when SITE1 and SIT1 were different.

SI Conversion
SI enhancement was converted into the relaxation rate (1/T1) by using a calibration curve described elsewhere (18). The curve was constructed after each imaging session and for each mouse by using tubes containing increasing concentrations of conventional gadolinium chelate (0.0, 0.2, 0.4, 0.6, 0.8, 1.0, 1.2, 1.4, 1.6, 1.8, 2, 4, 6, 8, 10, 15, and 20 mmol gadolinium per liter) and two-dimensional fast spoiled gradient-echo imaging, without modifying the imaging parameters. Variations in 1/T1 ({Delta}1/T1) were then computed by subtracting the postinjection values from the mean baseline value. The {Delta}1/T1 values thus obtained were directly proportional to the contrast agent concentration C, as follows:

Formula 3(3)
where r1 is the relaxivity of the contrast agent in blood at 1.5 T and 37°C (r1 = 4.9 L · mmol–1 · sec–1) (19). The same value of r1 was used to calculate the contrast agent concentration in all tissues.

Mean vascular, placental, and fetal gadolinium concentrations 20 minutes after the first bolus and the slope of gadolinium accumulation in the fetus (in micromoles per liter per minute) were calculated for the monophasic and biphasic protocols.

Compartmental Analysis
We used a three-compartment model (Fig 1) that is based on physiologic data (10,20) and has already been described and successfully used elsewhere (15).


Figure 1
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  		Figure 1: Three-compartment model of placenta, consisting of maternal vascular compartment (Vpm) and fetal vascular compartment (Vpf) between which contrast medium may be exchanged. Maternal compartment is supplied by arterial input and drained by venous output. Fetal vascular compartment may exchange contrast agent with the fetus (Vf) itself through the umbilical cord. Exchanges between compartments are described by using transfer constants k(i,j). Because the initial gadolinium concentration in the fetus is zero and might increase only slowly during the experiment, the transfer constant k(3,4) from fetus to placenta was not considered. q = Quantity of contrast medium.

 
In this model, the placenta is consistent with a countercurrent exchange system between the maternal and fetal compartments. The maternal vascular compartment of the placenta is supplied by arterial input (the uterine arteries) and drained through venous output. The fetal vascular compartment of the placenta may exchange the contrast agent with the fetus itself through the umbilical cord. This 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 before or at the time of the injection. The differential equations for the model are shown in Appendix E1 (http://radiology.rsnajnls.org/cgi/content/full/2413051168/DC1).

The constant transfer parameters k(i,j) were adjusted by using a compartmental and numeric modeling program (SAAM; SAAM Institute, Seattle, Wash) to the 39 sets of concentration kinetic curves measured at MR imaging in the maternal left ventricle and the placental and fetal regions. The placental enhancement curve was adjusted and separated between maternal vascular and fetal vascular placental chambers by the software. Goodness of fit was examined qualitatively on the software-computed curves.

Calculation of Physiologic Parameters
From the rate of transfer k(i,j), the following physiologic parameters were computed as means ± standard deviations (see Appendix E1 [http://radiology.rsnajnls.org/cgi/content/full/2413051168/DC1] for details): placental blood flow (in milliliters per second per milliliter of tissue), the permeability surface area product per unit volume of tissue for the transfer of gadolinium from the maternal vascular placental chamber to the fetal vascular placental chamber (per second), the permeability surface area product per unit volume of tissue for the transfer of gadolinium from the fetal vascular placental chamber to the maternal vascular placental chamber (per second), and the fractional volume of the maternal vascular placental compartment (as a percentage).

The rate of transfer k(4,3) corresponds to the blood transfer from the fetal vascular placental chamber to the fetus itself through the umbilical cord.

Gadolinium Assay
Immediately after the imaging procedure, eight mice (four in the monophasic protocol group and four in the biphasic protocol group) were randomly designated to undergo blood gadolinium assay so that we could validate the MR imaging measurements. Mean gadolinium concentrations ± standard deviations in venous blood were determined with atomic emission spectrophotometry (Spectra DCP ARL Fisons; Guerbet).

Statistical Analysis
We used the unpaired Student t test to compare mean vascular, placental, and fetal gadolinium concentrations 20 minutes after the first bolus and the slope of gadolinium accumulation in the fetus (in micromoles per liter per minute) between the monophasic and the biphasic protocol. We also used the unpaired Student t test to compare rates of transfer k(i,j) obtained with the monophasic and biphasic protocols. Gadolinium concentrations determined with atomic emission spectrophotometry were compared with the concentrations estimated with MR imaging by using the Student t test.

For all tests, a P value of less than .05 was considered to indicate a statistically significant difference. We used software (Statistica, version 6, 2001; Statsoft, Tulsa, OK) for all statistical tests.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
Kinetic Curves and T2* Effect Correction of Arterial Input Function
With the fast spoiled gradient-echo dynamic sequence, enhancement of the maternal left ventricle and the placenta was easily seen (Fig 2). The left ventricle exhibited very strong and rapid enhancement, whereas the placenta showed slower enhancement. Although an increase in SI in the fetal ROI was measured later, it was not possible to detect fetal enhancement visually.


Figure 2
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  		Figure 2: Coronal spoiled gradient-echo MR images (19.5/3.9; flip angle, 60°; bandwidth, 31.25 kHz; matrix, 256 x 224; zero-filling interpolation, 512; field of view, 14 x 7 cm; section thickness, 3 mm; one section). Images 1–5 were obtained successively, 3.1 seconds apart. Before injection of contrast agent (image 1), the maternal left ventricle (arrow) was identified, but placental and fetal areas were not distinguishable. After injection (images 2–5), maternal left ventricle exhibited strong and rapid enhancement, whereas placentas (arrowheads) showed slower enhancement and it was not possible to see any enhancement of fetuses (dotted lines). One FPU (at bottom right of the mouse) was not analyzed because it was too small.

 
The maternal left ventricle SI at the first echo did not exhibit a high peak because of the T2* effect. Calculation of SIT1 yielded the actual increase in SI at T1 (Fig 3). After the first-pass peak, SI and SIT1 were comparable. Therefore, correction for T2* effect was not necessary after the first 100 seconds because of the decrease in SI after the bolus. The calculation was also not necessary for the placental and fetal curves because the low gadolinium concentrations yielded negligible T2* effects. In the left ventricle, the first-pass peak was highlighted and SIT1 declined slowly thereafter (Fig 4). The slow perfusion of the biphasic protocol led to a second, lower peak and a slower decline in SI (Fig 4b).


Figure 3
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  		Figure 3: Example of SI curves in maternal left ventricle with monophasic protocol before and during first 100 seconds after injection of contrast medium at first echo (TE1) (echo time, 3.9 msec) and with T2* effect suppression. At first echo, SI during bolus injection showed a small increase followed by slow decline. There was no peak because of marked T2* effect, which decreased SI of the images. T2* effect suppression allowed us to obtain an SI that depended only on the T1 effect and showed a peak during the bolus. Rapidly after the bolus, both curves were superimposable; calculation of SIT1 was not necessary thereafter.

 

Figure 4
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  		Figure 4a: Examples of maternal left ventricle SIT1 after conventional gadolinium chelate injection with (a) monophasic protocol and (b) biphasic protocol. First-pass peak was marked with both protocols, and SI declined slowly thereafter. Biphasic protocol resulted in a second lower peak followed by slowly declining SI.

 

Figure 4
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  		Figure 4b: Examples of maternal left ventricle SIT1 after conventional gadolinium chelate injection with (a) monophasic protocol and (b) biphasic protocol. First-pass peak was marked with both protocols, and SI declined slowly thereafter. Biphasic protocol resulted in a second lower peak followed by slowly declining SI.

 
With the monophasic injection protocol, the placental tissue exhibited gradual uptake of contrast agent, followed by a slow decline (Fig 5a). This aspect of the placental gadolinium concentration curve was similar to that described in a previous study (15). With the biphasic injection protocol, biphasic uptake of contrast material was found in the placenta (Fig 5b). The fetus exhibited gradual and regular gadolinium uptake with the two injection protocols (Fig 5).


Figure 5
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  		Figure 5a: Examples of FPU gadolinium concentration curves after (a) monophasic and (b) biphasic injection of contrast agent in two mice. Placental tissue concentration indicates gradual uptake of contrast agent followed by gradual decline, whereas fetus shows slow gradual uptake of contrast agent. With the biphasic injection protocol, biphasic uptake of gadolinium was seen in placenta.

 

Figure 5
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  		Figure 5b: Examples of FPU gadolinium concentration curves after (a) monophasic and (b) biphasic injection of contrast agent in two mice. Placental tissue concentration indicates gradual uptake of contrast agent followed by gradual decline, whereas fetus shows slow gradual uptake of contrast agent. With the biphasic injection protocol, biphasic uptake of gadolinium was seen in placenta.

 
Mean arterial concentrations 20 minutes after injection were similar between the biphasic and monophasic protocols (175 µmol/L ± 54 for the biphasic protocol and 152 µmol/L ± 72 for the monophasic protocol, P = .493). In contrast, mean placental concentrations at 20 minutes were higher with the biphasic protocol (146 µmol/L ± 44) than with the monophasic protocol (105 µmol/L ± 39) (P < .004). Also, mean fetal concentrations were higher with the biphasic protocol (33.3 µmol/L ± 12) than with the monophasic protocol (19.1 µmol/L ± 9) (P < .001). Mean gadolinium accumulation in the fetus was stronger after the biphasic protocol (1.29 µmol/L/min ± 0.465) than after the monophasic protocol (0.753 µmol/L/min ± 0.355) (P < .002).

Compartmental and Statistical Analysis
The goodness of fit of all software-computed curves was examined qualitatively and was satisfactory. Modeling of the placental enhancement curve enabled separation of the placenta into maternal vascular and fetal vascular placental chambers (Fig 6). There was no statistically significant difference in any of the transfer rates (Table) between the monophasic and biphasic injections (P > .05 in all cases).


Figure 6
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  		Figure 6: Typical fit and modelization of placental concentration kinetic curve with compartmental analysis. Experimental placental concentration kinetic curve of gadolinium chelate ({square}) is fitted by upper dotted line and is modeled as the sum of the curves of two components. Solid line = effect of gadolinium contained in maternal vascular compartment of the placenta, lower dotted line = effect of gadolinium contained within fetal vascular compartment of the placenta. The quantity of gadolinium in the maternal vascular compartment of the placenta first increased rapidly and then declined parallel to the arterial concentration. The gadolinium chelate then diffused slowly into the fetal vascular compartment of the placenta through the placental membrane.

 

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  		Transfer Rates Obtained with Compartmental Modeling

 
Physiologic Parameters
Mean placental blood flow was estimated as 180 mL/min/100 g of placental tissue. The mean permeability surface coefficient for conventional gadolinium from the maternal placental to the fetal placental compartment was 10.3 x 10–4 sec–1 ± 6.81, and that from the fetal placental to the maternal placental compartment was 4.65 x 10–4 sec–1 ± 4.37.

The rate of transfer k(4,3) between the fetal vascular compartment of the placenta and the fetus was 3.96 x 10–4 sec–1 ± 2.69.

The mean fractional volume of the maternal vascular placental compartment was 36.5% ± 0.9.

Gadolinium Assay
Mean blood gadolinium concentrations determined with atomic emission spectrophotometry after imaging were not significantly different from those at MR imaging, despite the large range of values: 72.5 µmol/kg ± 30 at spectrophotometry versus 109.3 µmol/kg ± 50 at MR imaging (P = .254) for the four mice in the monophasic protocol and 97 µmol/kg ± 46 at spectrophotometry versus 114.8 µmol/kg ± 85.8 at MR imaging (P = .776) for the four mice in the biphasic protocol.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
ADVANCES IN KNOWLEDGE
 References
 
The results of this study, which are based on functional MR imaging and contrast agent injection, demonstrate that it is possible to determine several placental physiologic parameters that, to our knowledge, have never been explored simultaneously in vivo. In addition to confirming MR imaging perfusion measurements obtained in a previous study (15) that involved contrast-enhanced MR imaging and those obtained in a study by Gowland et al (21) that involved high-speed inversion-recovery echo-planar imaging, we were able to determine placental permeability. To our knowledge, results of in vivo evaluation of placental permeability have not been previously published, although they might be of high importance for placental function assessment. Because no parameters of placental permeability measured in vivo have previously been published for gadolinium, we were unable to compare our results with previous data.

The physiologic importance of k(4,3), which is related to transfer between the fetal vascular compartment of the placenta and the fetus, is complex. It does not correspond directly to the umbilical flow. It takes into account the exchanges between the fetal vascular compartment of the placenta and the fetus. The return flow from the fetus to the fetal placental compartment and the leakage in the amniotic fluid were not determinable in our study from the fetal kinetic curves. Determination of these parameters would require more informative fetal kinetic curves, which could be obtained with a better signal-to-noise ratio in the fetal ROI.

We estimated the fractional volume of the maternal vascular placental compartment as 36.5%, which is very similar to the 35.3% obtained in a morphometric study (22) of placentas sampled during cesarean section. Dynamic MR imaging could also offer a new way to explore the pathophysiology of fetal growth restriction, because altered perfusion at uterine Doppler ultrasonography fails to explain an important proportion of cases (23–26). It has been suggested that fetal growth restriction may be related to a decrease in the intervillous space (27).

We chose a contrast agent with interstitial distribution because of its low molecular weight and small particle diameter, which allowed it to cross the placental barrier (15). The biphasic injection protocol, in which more contrast agent was used, led to significantly higher fetal and placental concentrations. This shows that higher doses might be used in mice to increase fetal uptake and thereby facilitate permeability measurements. It is noteworthy that the biphasic protocol did not alter our results for perfusion and permeability, which remained similar with the two injection protocols.

Moreover, we were able to use high doses of gadolinium because we applied a T2* effect correction method (17). Changes in MR SI after administration of gadolinium chelates occur because of the shortening of T1 and T2* relaxation times. The effects of T1 and T2* shortening compete with each other: T1 shortening usually leads to increased SI, while T2* shortening results in decreased SI, an effect that is more marked as the gadolinium concentration increases. In our model, gadolinium concentrations were obtained from the effect of T1 on SI. The T2* effect can be neglected when the gadolinium concentration is low (<0.5 mmol gadolinium per liter), and the SI can be considered to be related solely to the T1 effect. This is not true when high gadolinium concentrations are reached, such as in the vascular input function during the first-pass peak. This is why we used a dual-echo sequence that permitted T2* effect corrections (17). This essential correction of the T2* effect at high concentrations required the use of a dual-echo sequence.

Our study had limitations. The use of contrast agent during pregnancy is, to date, not recommended so as to prevent potential deleterious effects to the fetus. However, there is no evidence that conventional gadolinium agents (gadopentate dimeglumine, gadoteridol, gadobenate dimeglumine, and gadoversetamide) cause chromosomal damage (28), teratogenic effects, or effects on postnatal development (29–33). Only one study (34) with gadobenate dimeglumine indicated a slightly higher incidence of early intrauterine deaths, retinal abnormalities, and bone malformations in rabbit fetuses. Such effects, however, were observed after a daily intravenous injection of a high dose of gadobenate dimeglumine to mated female rabbits. This contrast agent is a hepatospecific gadolinium chelate and has a structure that is different from that of the gadolinium chelate used in our study. No adverse effects in the human fetus have been documented when conventional gadolinium agents have been given intravenously for MR studies during pregnancy (35–38). Recently, the Contrast Media Safety Committee of the European Society of Urogenital Radiology reviewed the literature (39) and concluded that, when MR imaging is necessary, gadolinium media may be given to the pregnant mother.

The permeability as measured with a conventional gadolinium chelate in our study may not reflect the permeability of the placenta to other molecules of different size, charge, or composition.

Because some transfer rate measurements were made in the same mice when several placentas were observable, the assumption of independence among observations might be violated. However, this is not likely to substantially modify our findings, and mice with several observable placentas were probably randomly distributed among groups.

The variability of our measurements was due in part to the statistical heterogeneity of the mice and the placental and fetal structures, as well as to the subjective choice of ROIs. Fast acquisition with high temporal resolution is required to model blood flow (40). This was achieved in our study by using a fast two-dimensional single-section spoiled gradient-echo sequence capable of a temporal resolution of 1.55 seconds. On the other hand, the use of such single-section fast sequences restricted the choice of ROIs. Moreover, precision might have been hampered by the section thickness, which induced some volume averaging. It would be interesting to develop a three-dimensional sequence if the same temporal resolution as that of the two-dimensional sequence could be achieved.

In conclusion, we have described an imaging tool to explore and quantify placental microcirculation in vivo.

Practical application: This approach, involving functional MR imaging and a contrast medium, can provide noninvasive access to placental microvascular parameters, including the permeability of the placental barrier. It holds promise in the elucidation of intrauterine growth restriction pathogenesis and may help in the management of vascular disturbances of the placenta, which may compromise pregnancies.


   ADVANCES IN KNOWLEDGE
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
References
 


   ACKNOWLEDGMENTS
 
We thank R. Santus of Guerbet, Aulnay-sous-Bois, France, for his technical support.


   FOOTNOTES
 

Abbreviations: FPU = fetoplacental unit • ROI = region of interest • SI = signal intensity

Authors stated no financial relationship to disclose.

See also Science to Practice in this issue.

Author contributions: Guarantor of integrity of entire study, C.A.C.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; approval of final version of submitted manuscript, all authors; literature research, F.T., L.J.S., N.S., O.C., C.V., Y.V., C.A.C.; experimental studies, F.T., L.J.S., N.S., N.F., D.B., C.V., G.F., C.A.C.; statistical analysis, L.J.S., D.B., Y.V.; and manuscript editing, F.T., L.J.S., N.S., O.C., G.F., Y.V., C.A.C.


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 

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Has the Time Arrived to Image Placental Perfusion?
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