T2*‐weighted placental MRI: basic research tool or emerging clinical test for placental dysfunction?

Placental dysfunction is a common obstetric problem that complicates 5–10% of all pregnancies1. It is a progressive condition, in which the supply of oxygen and nutrients to the fetus is insufficient to maintain normal growth and organ development. The association between low birth weight and adverse neonatal outcome is well described2. Moreover, there is evidence to support the hypothesis, known as Barker's hypothesis3, that common adult diseases, such as metabolic syndrome and cardiovascular disease, originate from abnormal fetal programming due to placental dysfunction. There is no treatment available currently to improve placental function. However, correct identification of placental dysfunction antenatally leads to a four-fold improvement in neonatal outcome, as it allows for timely delivery, thereby reducing the risk of irreversible fetal organ damage4. Antenatal screening for placental dysfunction focuses on fetal-weight estimates and fetal and umbilical Doppler flow measurements. However, fetal size does not reflect precisely placental function. In addition, in late-onset placental dysfunction, Doppler flow usually remains normal5. Therefore, additional markers that reflect directly placental function have the potential to improve considerably antenatal screening for placental dysfunction. There is increasing interest in placental magnetic resonance imaging (MRI), due to its potential to detect placental dysfunction in vivo. In particular, T2*-weighted MRI has proved to be a simple and useful method with which to assess placental health, either by measuring directly the value of the transverse relaxation time, T2*, or by assessing the relative change in the raw T2*-weighted signal in response to a given challenge (i.e. the blood-oxygen-level-dependent effect (ΔBOLD)). T2* depends primarily on oxygenation, but also on other tissue characteristics, including villus density, inhomogeneities in the distribution of oxygenated blood, magnetic field inhomogeneities and the presence of other paramagnetic molecules6. In this Opinion, we explain the physiological basis for changes in T2*-weighted signal intensity in the placenta. We review previous literature on T2*-weighted placental MRI and thereby provide reference values for scanning at 1.5- and 3-Tesla (T). We include practical guidance on how to optimize T2*-weighted scans, and outline the clinical potential of T2*-weighted MRI as a test of placental dysfunction. T2* is the time taken for the observed decay of transverse magnetization to reach 37%. It is a multifactorial, empirical measure that depends on many biological and physical features of the tissue. Specifically, in the placenta, T2* depends on the underlying fundamental nuclear magnetic resonance transverse relaxation time (T2), on the volume fractions of the maternal and fetal blood and the villous tissue, and on spatial variations in the magnetic field across each voxel. The T2 of blood depends on the oxygen saturation of hemoglobin, as well as factors such as water diffusion and exchange between water and other molecules, and water binding. Spatial variations in the magnetic field can be caused by a number of factors, but arise primarily from the heterogeneous distribution of deoxygenated blood. Oxyhemoglobin and tissue both have similar, slightly diamagnetic (negative), magnetic susceptibility, whereas deoxyhemoglobin has paramagnetic (positive) magnetic susceptibility. Variations in magnetic susceptibility will lead to variations in the induced magnetic field within a tissue. Therefore, any spatial variations in the concentration of deoxyhemoglobin across the placenta, for instance due to deoxygenated blood confined within fetal arterioles or deoxygenated maternal blood draining from the placental intervillous space, could lead to a variation in magnetic field across the voxel. In addition, most T2*-weighted images retain some residual dependence on the longitudinal relaxation time, T1, and dissolved oxygen may influence the T1 of blood, which could cause a further increase in signal in T2*-weighted imaging7, 8. Biologically, infarcts can contain intracellular methemoglobin, which is particularly paramagnetic, and fibrosis, which can also reduce T29. In some cases, incoherent movement of the blood during the echo time may reduce the signal intensity of T2*-weighted scans. Finally, large-scale magnetic field variations will affect T2*. While static effects can be minimized by shimming, maternal respiration can cause fluctuation in T2*, which may not be addressed by shimming. T2*-weighted images form the basis of the BOLD effect used in functional MRI (fMRI) of the brain, in which changes in blood oxygenation and blood volume in response to neuronal activation lead to a change in the observed MRI signal. In contrast to measuring the absolute value of T2*, the BOLD effect is a relative measure, usually obtained by monitoring the T2*-weighted signal intensity over time, to determine the percentage change in signal, relative to the baseline, in response to intervention. For instance, a number of studies have involved increasing the oxygen saturation of the maternal blood within the placenta by having the mother breathe 100% oxygen. Assuming that there is no other physiological effect of the hyperoxic challenge, then any change in the placental T2*-weighted signal (the BOLD effect) reflects the change in placental oxygenation. If T2* is measured quantitatively, then normal reference values can be established to differentiate between normal and pathological placentae. There are several ways in which to obtain T2*-weighted MR images of the placenta, including: fast gradient echo (GE) sequence or GE echo planar imaging (EPI) sequences, run in either single or multi-echo mode. Compared with EPI, GE sequences can achieve higher spatial resolution, but take longer to acquire, which makes them more sensitive to motion artifacts. For multi-echo EPI data, there is effectively no motion during the time (< 200 ms) required to acquire each slice, rendering it very robust to intraslice motion, although the spatial resolution achievable is generally lower than that possible on GE scans. At term, the whole placenta can be scanned with EPI during a single maternal breath-hold using multiband/simultaneous multislice approaches. In principle, GE-EPI will be affected by susceptibility artifacts in the abdomen, but the spherical nature of the pregnant uterus and the fluid filling the uterine and fetal cavities make GE-EPI a very robust sequence for use in pregnancy, even at 3 T. It is preferable, however, to use image-based B0 shimming for GE-EPI at 3 T when available. We recommend using a transaxial imaging plane, with the field of view aligned with the scanner coordinates to simplify planning. While coronal and sagittal imaging planes may also be used, the transaxial plane is commonly the most useful, as it assures coverage of the main functional placental direction (maternal basal plate to fetal chorionic plate) within each image, without having to consider movement between slices. It is important that the field of view covers the whole of the abdomen, in order to avoid artifacts from parallel imaging reconstruction techniques (e.g. SENSE artifacts). In addition, good fat suppression is required, for which the B0 shim box must cover all of the maternal subcutaneous fat. In addition, we suggest that the subject lies in the left lateral position (10°–20° tilt), mainly to avoid caval vein compression, as even minor changes in the maternal circulation may have a detectable impact on the placental T2* value. A recent study by Humphries et al.10 found that a maternal supine position in late pregnancy reduced the flow in the inferior caval vein by 85% compared with the left lateral position. While the venous return in the azygos vein was increased, probably to compensate, cardiac output was reduced by 16%. We also find that the left lateral position makes it easier to image posterior placentae, as often it allows placement of the receiver coils closer to the placenta. If the woman is scanned in a supine position, we recommend ensuring frequent monitoring of maternal blood pressure, heart rate and oxygen saturation, using MR-compatible monitoring equipment. In addition, splitting the scanning session into shorter sessions, each lasting no longer than 30–45 min, will improve maternal comfort. Accurate recording of the position and tilt angle is important for analysis purposes, given the possibility that the maternal position may influence her physiology. Using this approach, a baseline T2*-weighted dataset covering the entire placenta can be acquired in under 5 min, from the time the woman enters to the time she leaves the scanning room, which suggests that this simple measurement could be used for rapid monitoring of placental health. Regarding the optimal field strength for placental imaging, 1.5 T is the field strength used in most placental MRI studies reported so far. However, systems with a field strength of 3 T are replacing the 1.5-T systems in many centers and it is likely that 3 T will be used increasingly in future placental MRI studies. As the field strength increases, the sensitivity of MRI increases, and the sensitivity to the BOLD contrast increases superlinearly. 3-T images can provide exquisite detail on oxygenation in the human placenta. Yet, for a standard clinical test of placental dysfunction, 1.5 T can give sufficient information, while the intrinsically shorter T2* values at higher field strength can make it difficult to acquire data at sufficiently short echo times as to be sensitive enough to pick up changes in T2*. In addition, at 3 T, the radiofrequency (RF) fields can be highly inhomogeneous, leading to signal dropout in the center of the field of view, particularly when scanning the larger abdomen at late gestation, and this can make it harder to image posterior placentae. Higher field strength also increases the risk of geometric distortion due to air–tissue interfaces, requiring special attention to B0 shimming, especially if using high-resolution EPI. While RF heating and acoustic noise are general safety concerns for fetal MRI, 3 T magnets tend to have stronger gradient coils and hence higher acoustic output. Based on current knowledge, we recommend using Level-0 normal operating mode of RF, i.e. 2 W/kg, labeled by some vendors as ‘low SAR’ or ‘fetal MRI’, since the fetus has reduced heat-loss mechanisms compared with the adult. Similarly, we recommend not using parallel transmit approaches unless the system vendor explicitly advises their use in pregnancy. We also recommend using the scanner's options for reduced acoustic noise. For more detailed placental assessment, it may be preferable to measure the absolute T2* relaxation time rather than just acquiring a T2*-weighted image, since quantitative measurements make the results more comparable over time for longitudinal studies, between patients in cross-sectional studies and between scanners and sites for a given field strength in multicenter studies. We generally assume that T2* describes a monoexponential decay. As such, in principle, T2* can be estimated by a measurement at two echo times, the first being the shortest possible echo time and the second being an echo time equal to T2* of the particular tissue of interest. The two echoes can be collected either from a single RF pulse (double-echo sequence) or by repeating a single echo acquisition at two echo times. T2* can then be estimated by calculating –dTe ln (S1/S2), where S1 and S2 are the signals from the first and second echo images, respectively, and dTe is the difference in the echo times of these two images. Alternatively, multiple echoes can be fitted for T2*. Comparing the signal decay to a monoexponential function will highlight any systematic errors in the data, for example from shimming errors or high noise floors due to Riccian noise. We therefore recommend sampling the signal decay of at least three echo times (with the longest echo time providing a signal that is above the noise floor). If the data are fitted for a monoexponential decay, then a weighted linear fit should be used and efforts should be made to eliminate data points influenced by the noise floor. Alternatively, the data could be fitted to a more complex function, for instance, to take into account the effects of through-slice dephasing11. Multi-echo sequences are automatically recorded simultaneously, but will be more sensitive to motion during the acquisition, while repeated single-echo acquisitions allow a wider range of echo times to be explored, which can provide better discrimination of the signal decay of the heterogeneous nature of placental tissue and placental oxygenation, we recommend including as placental tissue as possible in the of interest to improve the of the T2* measurements. If a volume should be or the T2* should be on an of at least three across the placenta. 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