Anat Biegon1 , Chen Hoffmann2, Michal Marianne Amitai2 and Gal Yaniv2
Department of Neurology and Radiology, Stony Brook University School of Medicine, Stony Brook, NY 11794-2565, USA
Department of Diagnostic Imaging, Sheba Health Center, Ramat Gan, 52622, Israel
Fetal MRIFetal MRSFetal DWIFetal fMRI
The concept of using nuclear magnetic resonance to form images was first formulated by Lauterbur  more than 40 years ago. Theoretical and technological advances soon followed and made MRI into a widespread medical diagnostic tool, especially in central nervous system and soft tissue imaging [36, 41, 65]. The history of fetal MRI in utero spans more than three decades, beginning with T1- and T2-weighted studies at relatively low magnetic field published in the 1980s [67, 94, 102, 107]. This was followed by early echoplanar imaging attempted in the early 1990s (e.g., [50, 66]). Throughout this period, the mainstay of fetal imaging for all organ systems has been ultrasound, but the better contrast resolution of MRI relative to ultrasound and the advantage, vis-a-vis CT; of not using ionizing radiation made it especially attractive for studies of the maternal–fetal unit. Progressive improvements in imaging hardware and software, resulting in shortened scan times and wider choice of imaging sequences, have made fetal MRI an increasingly valuable imaging tool in cases with uncertain diagnosis of CNS and other abnormalities (e.g., [20, 25]).
However, indiscriminate use of MRI techniques developed and validated for adults is not possible due to a combination of several factors specific to the maternal–fetal unit, including (1) safety considerations, (2) fetal motion, and (3) continuous changes in target organ size, location, and composition. These factors impact and shape the current status and the future of fetal MRI techniques discussed in this chapter.
2.2 Impact of Safety Consideration on Maternal/Fetal Imaging with MRI
Possible sources of safety concern inherent in all MRI techniques include static magnetic fields, radiofrequency fields, and electromagnetic fields, which may result in biological effects, increased tissue temperature, peripheral nerve stimulation, and acoustic noise (e.g., [5, 51, 59]). Some, though not all, animal studies demonstrated adverse effects of exposure to MRI during pregnancy on development (e.g., [62, 109]) resulting in recommendations of limitations on fetal MRI use during the first trimester [20, 92] though the few available human series performed to date have not demonstrated adverse effects [3, 14, 68, 72, 78]. Similarly, contrast media (gadolinium agents) administered in conjunction with MRI in a subset of indications/techniques are generally not recommended in pregnancy at any stage (e.g., [93, 101]) since studies have shown passage of gadolinium through the placenta and excretion of the material through the fetal genitourinary system to the amniotic fluids [74, 75, 85]. However, no teratogenic effect of gadolinium was found to date . To summarize, safety considerations impose limitations on the use of MRI techniques involving contrast (gadolinium) agents throughout pregnancy and the use of MRI in general in the first trimester, though MRI is still considered preferable to any imaging involving ionizing radiation.
2.3 Adaptation of MRI Techniques for Fetal Motion
The biggest problem in acquiring reliable, reproducible, and comprehensive MRI images of the fetus has been motion. Early studies attempted to overcome this problem by sedation of mother and/or fetus (e.g., ) although this approach has obviously limited the widespread use of the technique in clinical and research settings. Early use of echoplanar imaging (e.g., ) yielded insufficient contrast and resolution to be gainfully applied for studies of the brain. The breakthrough came with the development of faster imaging techniques and sophisticated methods for motion correction, which is still proceeding at a fast pace in the present ([6, 9, 31, 49, 53, 57, 63, 76, 87, 100]; Kim et al. 2008). The ultrafast sequences which have been implemented in the clinical setting, including single-shot fast spin echo (SSFSE), fast spin echo (FSE), and the half-Fourier single-shot turbo spin echo (HASTE) require a second or less per slice acquisition, reducing the impact of fetal motion. With these techniques, multiple stacks of slices are acquired at different orthogonal orientations (e.g., axial, coronal, and sagittal), providing a comprehensive view of the anatomy while allowing for manual adjustment to fetal motion and/or gating  to maternal breathing. Maternal breath hold can also be used to reduce motion artifacts from the latter source.
2.4 Adaptations to Continuous Changes in Target Size, Location, and Composition
Imaging of the maternal abdomen during pregnancy is complicated by the potential progressive displacement of abdominal organs due to the growing fetus (e.g., [40, 98], Fig. 2.1). Adaptations also need to be made in indications that would normally be better diagnosed with the aid of contrast media, such as inflammation (Fig. 2.2). In addition, with increasing gestational age, the mother may not be able to lie in the preferred supine position, in which case the lateral decubitus position, which avoids compression of the inferior vena cava, needs to be used.
Displaced bowel loops in pregnant patients. Left: A 19-week pregnant patient with Crohn’s disease. The sigmoid colon (arrow) is displaced by the pregnancy upward and to the left. Right: A 32-week pregnant patient with suspected Crohn’s disease. Twin pregnancy displacing the bowel loops upward and to the left. Crohn’s disease was ruled out. Acquisition sequence: FIESTA (steady-state free precession sequence) in coronal plane. (TR/TE = 4.2–5/1.2–2.3 ms, slice thickness 6 mm, no gap, FOV of 36–44 cm2, acquisition matrix of 384 × 384, NEX o = 1, flip angle 60°
Inflammatory signs in a non-contrast-enhanced study of an 11-week pregnant patient with colitis. (a, b) Colonic mural thickening (arrows) coronal FIESTA. (c) Submucosal edema (arrow) Axial SSFSE T2 w TR 1680–3200, TE 92.7 ms
In the fetus, situs anomalies may occur as part of deranged development (e.g., ). The problem is compounded many fold by the inherently changing landscape of fetal size, anatomy, tissue composition, and organ physiology.
The small size of the fetus dictates using the smallest field of view (FOV) which encompasses the region of interest, though decreased signal-to-noise ratio at small FOVs may require an increase, such that the choice of FOV is ultimately sequence dependent. Similar considerations apply to matrix size and slice thickness, which determine the voxel size. While the size of the voxel needs to be appropriate for the target size, SNR is inversely related to matrix size and all of these parameters need to be adjusted so as to minimize imaging time, to reduce motion artifacts (above). Slice thickness as low as 1.6 mm (no gap) has been reported  with specific fast precession sequences, but generally slice thickness of less than 3 mm leads to substantial decreases in SNR.
There are no specialized MRI coils available for fetal imaging, so coils need to be used which can be placed in close proximity to the target. Coils used for fetal imaging include the 1.5T HDx GE coil, body coils, and cardiac coils, with best results achievable with flexible multichannel coils. This obviates some of the problem, but lateral decubitus position or obesity of the mother, increasing the distance between the fetal target and the coil, may still result in degraded image quality due to low signal intensity.
In contrast with adult size and anatomy, where the range of “normal” values is restricted, fast changes in fetal organ size and anatomy mean that norms and baselines need to be established for every week of pregnancy, a momentous task and ongoing effort pioneered by Garel and her group , who provided biometric data and continue with the creation of a spatiotemporal atlas of MR intensity, tissue probability, and shape of the fetal brain .
Tissue composition is also different in fetuses and changes through development. In the fetal brain, water content is relatively high and lipid content is extremely low since myelination is a relatively late-occurring phenomenon, requiring specific sequence adaptation with increasing fetal age as described below.
Several examples of sequences used in the production of the illustrations to this chapter, focusing on the brain, are given in Table 2.1. Additional sequences and protocols can be found in the literature (e.g., [80, 105]) and in subsequent chapters of this book.
Examples of fetal brain MRI protocols on 1.5 GE OPTIMA, 750-W scanner
Flip angle (degrees)
Number of slices
2.4.1 Structural (T2- and T1-Weighted) Fetal MRI
T2-weighted sequences are the most amenable to studies of fetal anatomy. Single-shot fast spin echo (SSFSE) are very useful in clinical studies of anatomical malformations since the information for an entire image is acquired in less than 1 s, with good contrast and resolution (Fig. 2.3), although sequence parameters need to be continuously adjusted to fetal age, with longer TEs required for younger fetuses with higher water content . When fetal motion is restricted, better contrast can be achieved with fast-recovery fast spin echo T2-weighted sequences (Fig. 2.4). In addition, T2* imaging is useful for evaluating vascular lesions, hemorrhages, and calcifications (Fig. 2.5). Fluid-attenuated inversion recovery (FLAIR) sequences, useful for visualizing white matter pathology in adults, is not very useful in fetuses due to the high water content. With water suppression, it may have some use in differentiating gray and white matter lesions.
Agenesis of the corpus callosum detected with SSFSE T2-weighted 28-week GA fetus with agenesis of the corpus callosum. Left: coronal view, note parallel lateral ventricles. Middle: axial view. Ventricles are parallel, the atria are dilated. Right: sagittal view. The corpus callosum is missing in the midline and midline sulci extend all the way to the third ventricle
Optimizing gray/white contrast in fetal CNS. Normal fetus, 30 weeks GA. Left: axial image acquired with fast-recovery fast spin echo (FRFSE) T2-weighted sequence, most suitable for detection of cortical abnormalities in fetuses with limited motion. Note the sharp gray/white contrast. Right: same fetus imaged with SSFSE T2-weighted sequence
Visualization of blood with T2* imaging. A 30-week GA fetus with ventricular enlargement and grade III intraventricular hemorrhage. Note prominent appearance of blood inside the ventricle
T1-weighted images are of lower signal intensity-to-noise ratio and require longer acquisition times (18 s), with consequent increased susceptibility to both maternal and fetal motion. Consequently, the utility of T1-weighed imaging to fetal MRI is limited relative to adults. Still, T1-weighted imaging is necessary to visualize the small amount of myelinated tissue present in the fetal brain (Fig. 2.6). Fast multiplanar gradient-recalled echo techniques, such as FMPSPGR (fast multiplanar spoiled gradient-recalled acquisition in the steady state), are useful for detection of hemorrhaging or calcification in brain and other organs (e.g., , Fig. 2.7). For best results, images are acquired during a single maternal breath hold with the shortest feasible times.
Visualization of myelin with a T1-weighted sequence. A 32-week GA normal fetus. Myelinated white matter (hyperintense area) can be observed in the posterior part of the brainstem
Comparison of T1 and T2 sequences in visualization of fetal AVM. A 35-week GA fetus with AVM (confirmed postmortem after termination of pregnancy). The subacute blood appears hyperintense in the T1 FSPGR sequence (left) and hypointense in the T2 sequence (right)
2.4.2 Diffusion Weighted Imaging
Diffusion weighted imaging is uniquely sensitive to acute ischemia, thus capable of visualizing fetal strokes before they lead to signal changes in T2- and T1-weighted sequences (; Fig. 2.8). Similarly, progressive increases in diffusion anisotropy of white matter tracts from premyelinated to myelinating stages facilitate the visualization of white matter tracts weeks before they are visible on T1- and T2-weighted images . The technique is also useful in detection of blood products (Fig. 2.9) since echoplanar DWI is extremely sensitive to susceptibility effects. Due to high water content in the fetal brain, best contrast of echoplanar DWI images is achieved with relatively low bvalues, in the range of 400–700 .
Acute ischemia detected by DWI. A 23-week GA fetus surviving the demise of an MCBA twin was imaged with T2-weighted (SSFSE) sequence 4 days later. MRI (left) as well as US appeared normal. DWI (right) demonstrated abnormal signal in the posterior part of the right hemisphere, consistent with acute ischemic insult
Detection of hemorrhage with DWI. A 23-week GA fetus with small amount of bleeding in the germinal matrix bilaterally, seen as hyperintense spots on DWI (left image, arrows). In the T2 image (right), the blood is hypointense (arrows)
2.4.3 Summary: Clinical Applications
Safety considerations impose limitations on the use of MRI techniques involving contrast agents throughout pregnancy and the use of MRI in general in the first trimester, though MRI is still considered preferable to any imaging involving ionizing radiation. Due to motion, current clinical fetal brain imaging relies heavily on fast T2 sequences, with a more limited but important role for T1- and diffusion-weighted sequences in the detection of specific pathologies. In all cases, sequence parameters need to be optimized for gestational age and indication.
2.5 Where the Future Lies: Quantitative Mapping of Regional and Cellular Patterns of Fetal Maturation
An early study using the Cavalieri method to estimate fetal and whole brain volumes in a small cohort of third trimester fetuses  described a linear relationship between gestational age and whole brain volume, with a growth rate averaging 2.3 mL/day. This impression was dispelled as soon as newer sequences and image analysis methods, allowing volumetric measurements of smaller regions, were applied to larger cohorts of second and third trimester normal fetuses ([17, 26, 32, 34, 42, 90]). The findings from these studies consistently demonstrate region-specific, nonlinear growth trajectories which can be obtained with manual drawing of regions of interest on 2D images (; Fig. 2.10) as well as automatic segmentation of motion-corrected, 3D-reconstructed MRI scans . In the clinical setting, volumetry was successfully used to describe changes in brain and body volumes in fetuses exposed to cytomegalovirus (CMV) infection in early pregnancy (, Fig. 2.10), as well as fetuses with ventriculomegaly [77, 91] and intrauterine growth restriction .
Effect of CMV infection on regional brain volumes. MRI volumetry was employed to measure brain and temporal lobe size in 27 CMV-infected fetuses and 52 gestational age matched controls. The ratio of temporal lobe to whole brain was computed for each fetus. Top: example of manual ROI placement on temporal lobe, used for volume calculation. Bottom: temporal lobe/whole brain volume ratio was significantly reduced in fetuses infected with CMV during the first and second, but not the third trimester
2.5.2 Shape Changes/Cortical Development
Recent studies of fetal cortical development using advanced techniques reiterate the theme of region-specific, nonlinear maturation ([16, 35, 42, 43, 82]). Thus, Hu et al. (2011) provide a regional quantification of cortical shape development reporting faster shape changes in the occipital lobe than in other regions, while findings by Clouchoux et al.  demonstrate an exuberant third trimester gyrification process and suggest a nonlinear evolution of sulcal development. The same group also reported on delayed cortical development in fetuses with congenital heart disease . Adaptation of tensor-based morphometry revealed that fetal brain development exhibits a distinct spatial pattern of anisotropic growth, with the most significant changes in the directionality of growth occurring in the cortical plate at major sulci. The authors also report significant directional growth asymmetry in the perisylvian region and the medial frontal lobe of the fetal brain .
2.5.3 Measurement of Apparent Diffusion Coefficients (ADC Mapping)
Regional differences and developmental changes in apparent diffusion coefficients (ADC) of normal fetuses have been the subject of several studies conducted and published during the last decade [7, 8, 10, 11, 39, 64, 83, 88]. All of the published studies report absolute values for ADC in a similar range and detect a trend toward a reduction in ADC with increased GA (Figs. 2.11 and 2.12), which could be explained by progressive myelination. However, the relationship between ADC and GA appears to be region dependent and nonlinear. Thus, in a study of 50 normal fetuses between 19 and 37 weeks’ gestation, ADC values remained constant in the basal ganglia, frontal, parietal, temporal, and occipital white matter and in the centrum semiovale while significant decreases were observed in the cerebellum, pons, and thalamus with advancing gestational age . In the clinical setting, ADC values were reported to be decreased in specific brain regions of hydrocephalic  and CMV-infected fetuses .
Fetal brain maturation visualized with diffusion weighted imaging. Left: normal fetus, 26 weeks GA, Right: normal fetus, 32 weeks GA, diffusion weighted imaging in the axial plane. Note the change in signal intensity with maturation and decrease in the amount of unrestricted water
Maturational changes in regional apparent diffusion coefficient of the fetal brain. Diffusion weighted imaging (DWI) was performed in 48 non-sedated third trimester fetuses with normal structural MRI results. ADC was measured in white matter (frontal, parietal, temporal, and occipital lobes)
2.5.4 Magnetic Resonance Spectroscopy
Several groups have demonstrated the ability to obtain useful information on fetal metabolism using H1 spectroscopy (e.g., [37, 55, 56]). Short TEs (~35 ms) are used to detect metabolites such as glutamine, glutamate, glucose, taurine, and lipids, while longer TEs (~140 ms) are useful in the detection of N-acetylaspartate (NAA, considered to be a neuronal marker), choline (Cho, a marker of membrane formation), and creatine (Cr, a marker of mitochondrial activity). Lactate, a marker of anaerobic metabolic, can be detected as well. The relatively long imaging time and large voxel size required for MRS limit the widespread use of this technique in clinical fetal imaging (Fig. 2.13).
H1 MRS of the fetal brain: Maturational changes and effects of motion. Top: normal fetus, 26 weeks GA. The choline (Cho) peak is very high (3.36 ppm) and NAA is relatively low. Middle: a 31-week GA fetus imaged because of reduced intrauterine motility reported by the mother. Baseline is low and peaks are sharp. Choline is still high (2.48 ppm) but lower than in the younger fetus. Bottom: MRS of 35-week-old fetus showing blurring due to fetal movement. NAA is increased relative to the younger fetuses. Location of voxel is shown on the left
Development of the normal fetal brain in utero using MRS has been studied by a number of groups. The size of the voxel necessary to acquire reliable information limits the possibility of regional measurements, so these studies mostly reflect whole brain maturation. With this caveat, levels of choline (Cho), creatine (Cr), myo-inositol (myo-ins), and N-acetylaspartate (NAA) have been more recently measured in utero in fetuses in the age range of 22–41 weeks [28, 29, 99]. Brain maturation was most clearly reflected by increasing levels of the neuronal marker NAA, with a parallel decrease in choline. In clinical populations, Limperopoulos and colleagues found significantly slower increase in the NAA:choline ratio in fetuses with congenital heart disorder. Predictors of lower NAA:choline included diagnosis, absence of antegrade aortic arch flow, and evidence of cerebral lactate . A study of fetuses with intrauterine growth restriction (IUGR, [2, 12, 84]) detected a lactate peak in the brain of the most severely affected IUGR fetus, which was consistent with low oxygen content and high lactic acid concentration in umbilical blood obtained at delivery.
2.5.5 Diffusion Tensor Imaging (DTI) of Fetal Brain Connectivity
DTI is a relatively new technique, only recently applied to fetal imaging ([44, 49, 52, 54, 69, 71, 81, 86, 97]; Fig. 2.14). It may be used to map and characterize the 3D diffusion of water as a function of spatial location. The diffusion tensor describes the magnitude, the degree of anisotropy, and the orientation of diffusion anisotropy. Estimates of white matter connectivity patterns in the brain from white matter tractography may be obtained using the diffusion anisotropy and the principal diffusion directions. The technique is also highly sensitive to changes at the cellular and microstructural level [81, 86]. Unfortunately, DTI presents an even bigger challenge for in utero fetal imaging relative to other techniques since acquisition times are longer and therefore studies are more susceptible to motion artifacts. Consequently, only a few recent studies provide quantitative data from in utero studies of neuronal pathways. As an example, Kasprian et al.  examined a group of fetuses ranging in age from 18 to 37 weeks and reported that only in 40 % of examined fetuses, DTI measurements were robust enough to successfully calculate and visualize bilateral, craniocaudally oriented (mainly sensorimotor), and callosal trajectories in utero. However, the successful studies resulted in a wealth of quantitative information on fiber lengths, ADC, fractional anisotropy, and eigenvalues at different anatomically defined areas with high potential utility in understanding the etiology of neuropsychiatric disorders (e.g., ).
Visualization of developing fiber tracts using diffusion tensor imaging. A 33-week GA normal fetus. DTI was acquired using a single-shot echoplanar spin echo sequence with the following parameters: TE/TR 105 ms/8900 ms, 50 contiguous slices, 2.2-mm thickness; matrix 128 × 128; FOV 256 × 256 mm2. Diffusion gradients were encoded in seven directions with b values of 1000 s/mm2 and an additional image with no diffusion gradient (b = 0 s/mm2). Three sets of DTI data were acquired for average and the total DTI acquisition time was 5 min 47 s. Image shows 3D fiber tracts projected onto the fetal brain. Note the corticopontine/corticospinal projection fiber (red) genu and the corpus callosum fibers (blue). Courtesy of Gabriele Masselli, MD; Sapienza University, Rome, Italy
2.5.6 Functional MRI
MRI allows for the noninvasive imaging of regional activation and functional connectivity. The feasibility of studying fetal brain activity with functional magnetic resonance imaging  (fMRI, or BOLD (blood oxygen level-dependent) MRI) was demonstrated by Hykin et al.  just before the turn of the century, reporting on fetal brain responses to maternal speech. This was followed by additional studies reporting the detection of responses to various acoustic [23, 47, 48, 70] and visual  stimuli, which were detected between 33 and 34 weeks of gestation. Functional connectivity (FC) at rest was subsequently demonstrated in the fetal brain [89, 103] in fetuses from 20 to 36 gestational weeks of age, documenting the presence of bilateral fetal brain FC as well as regional and age-related variation in the strength of FC between homologous cortical brain regions, which increased with advancing gestational age. Sorensen et al.  examined the BOLD response in the fetus and placenta following maternal hyperoxia, demonstrating an increased oxygenation in a number of fetal organs and in the placenta while oxygenation of the fetal brain remained constant. These studies together with findings from other modalities like fetal EEG and MEG  are truly revolutionary since unlike information on maturation of brain morphology and microstructure/chemistry which can be obtained postmortem, the development of function can only be studied in vivo.
2.5.7 Summary: Future Directions
The adaptation of quantitative MRI techniques to fetal brain imaging in utero is truly revolutionary, embodying the potential to transform this area of basic and clinical research and practice from the subjective, qualitative, and arbitrarily dichotomous identification of “lesions” and “abnormalities” to the much richer and promising domain of objective, continuous measurements of salient parameters reflecting different morphological, microstructural, and biochemical aspects of fetal maturation. It is fair to say that if fetal MRI is in its infancy, quantitative fetal MRI is in its embryonic developmental stage, undergoing an explosive phase of method development, fine-tuning, and validation (e.g., [61, 100]). Consequently, the majority of the published work reviewed here reflects information gathered from relatively small cohorts of normal fetuses scanned during the third trimester and the relatively smaller number of studies of pathological samples to date offer very limited or no postnatal follow-up. Further improvements in methodology and safety are needed before these studies can be extended to earlier fetal ages, affording a comprehensive view of fetal development in utero. The progressive accumulation of normative databases and extended postnatal follow-up are essential prerequisites for the future use of quantitative MRI in the diagnosis, prognosis, and prenatal treatment of developmental disorders.
Anderson AL, Thomason ME (2013) Functional plasticity before the cradle: a review of neural functional imaging in the human fetus. Neurosci Biobehav Rev 37:2220–2232PubMed
Azpurua H, Alvarado A, Mayobre F, Salom T, Copel JA, Guevara-Zuloaga F (2008) Metabolic assessment of the brain using proton magnetic resonance spectroscopy in a growth-restricted human fetus: case report. Am J Perinatol 25:305–309PubMed
Baker PN, Johnson IR, Harvey PR, Gowland PA, Mansfield P (1994) A three-year follow-up of children imaged in utero with echo-planar magnetic resonance. Am J Obstet Gynecol 170:32–33PubMed
Baldoli C, Righini A, Parazzini C, Scotti G, Triulzi F (2002) Demonstration of acute ischemic lesions in the fetal brain by diffusion magnetic resonance imaging. Ann Neurol 52:243–246PubMed
Baysinger CL (2010) Imaging during pregnancy. Anesth Analg 110:863–867PubMed
Bonel H, Frei KA, Raio L, Meyer-Wittkopf M, Remonda L, Wiest R (2008) Prospective navigator-echo-based real-time triggering of fetal head movement for the reduction of artifacts. Eur Radiol 18:822–829PubMed
Boyer AC, Goncalves LF, Lee W, Shetty A, Holman A, Yeo L, Romero R (2013) Magnetic resonance diffusion-weighted imaging: reproducibility of regional apparent diffusion coefficients for the normal fetal brain. Ultrasound Obstet Gynecol 41:190–197PubMedCentralPubMed
Bui T, Daire JL, Chalard F, Zaccaria I, Alberti C, Elmaleh M, Garel C, Luton D, Blanc N, Sebag G (2006) Microstructural development of human brain assessed in utero by diffusion tensor imaging. Pediatr Radiol 36:1133–1140PubMed
Busse RF, Riederer SJ, Fletcher JG, Bharucha AE, Brandt KR (2000) Interactive fast spin-echo imaging. Magn Reson Med 44:339–348PubMed
Cannie M, De Keyzer F, Meersschaert J, Jani J, Lewi L, Deprest J, Dymarkowski S, Demaerel PA (2007) Diffusion-weighted template for gestational age-related apparent diffusion coefficient values in the developing fetal brain. Ultrasound Obstet Gynecol 30:318–324PubMed
Cartry C, Viallon V, Hornoy P, Adamsbaum C (2010) Diffusion-weighted MR imaging of the normal fetal brain: marker of fetal brain maturation. J Radiol 91:561–566PubMed
Cetin I, Barberis B, Brusati V, Brighina E, Mandia L, Arighi A, Radaelli T, Biondetti P, Bresolin N, Pardi G, Rango M (2011) Lactate detection in the brain of growth-restricted fetuses with magnetic resonance spectroscopy. Am J Obstet Gynecol 205(350):e1–e7PubMed
Chung HW, Chen CY, Zimmerman RA, Lee KW, Lee CC, Chin SC (2000) T2-Weighted fast MR imaging with true FISP versus HASTE: comparative efficacy in the evaluation of normal fetal brain maturation. AJR Am J Roentgenol 175:1375–1380PubMed
Clements H, Duncan KR, Fielding K, Gowland PA, Johnson IR, Baker PN (2000) Infants exposed to MRI in utero have a normal paediatric assessment at 9 months of age. Br J Radiol 73:190–194PubMed
Clouchoux C, Du Plessis AJ, Bouyssi-Kobar M, Tworetzky W, Mcelhinney DB, Brown DW, Gholipour A, Kudelski D, Warfield SK, Mccarter RJ, Robertson RL Jr, Evans AC, Newburger JW, Limperopoulos C (2013) Delayed cortical development in fetuses with complex congenital heart disease. Cereb Cortex 23:2932–2943PubMed
Clouchoux C, Kudelski D, Gholipour A, Warfield SK, Viseur S, Bouyssi-Kobar M, Mari JL, Evans AC, Du Plessis AJ, Limperopoulos C (2012) Quantitative in vivo MRI measurement of cortical development in the fetus. Brain Struct Funct 217:127–139PubMed
Corbett-DETIG J, Habas PA, Scott JA, Kim K, Rajagopalan V, Mcquillen PS, Barkovich AJ, Glenn OA, Studholme C (2011) 3D global and regional patterns of human fetal subplate growth determined in utero. Brain Struct Funct 215:255–263PubMedCentralPubMed
Daffos F, Forestier F, Mac Aleese J, Aufrant C, Mandelbrot L, Cabanis EA, Iba-Zizen MT, Alfonso JM, Tamraz J (1988) Fetal curarization for prenatal magnetic resonance imaging. Prenat Diagn 8:312–314PubMed
Damodaram MS, Story L, Eixarch E, Patkee P, Patel A, Kumar S, Rutherford M (2012) Foetal volumetry using magnetic resonance imaging in intrauterine growth restriction. Early Hum Dev 88(Suppl 1):S35–S40PubMed
De Wilde JP, Rivers AW, Price DL (2005) A review of the current use of magnetic resonance imaging in pregnancy and safety implications for the fetus. Prog Biophys Mol Biol 87:335–353PubMed
Erdem G, Celik O, Hascalik S, Karakas HM, Alkan A, Firat AK (2007) Diffusion-weighted imaging evaluation of subtle cerebral microstructural changes in intrauterine fetal hydrocephalus. Magn Reson Imaging 25:1417–1422PubMed
Fulford J, Vadeyar SH, Dodampahala SH, Moore RJ, Young P, Baker PN, James DK, Gowland PA (2003) Fetal brain activity in response to a visual stimulus. Hum Brain Mapp 20:239–245PubMed
Fulford J, Vadeyar SH, Dodampahala SH, Ong S, Moore RJ, Baker PN, James DK, Gowland P (2004) Fetal brain activity and hemodynamic response to a vibroacoustic stimulus. Hum Brain Mapp 22:116–121PubMed
Garel C, Chantrel E, Elmaleh M, Brisse H, Sebag G (2003) Fetal MRI: normal gestational landmarks for cerebral biometry, gyration and myelination. Childs Nerv Syst 19:422–425PubMed
Garel C, Sebag G, Brisse H, Elmaleh M, Oury JF, Hassan M (1996) Magnetic resonance imaging of the fetus. Contribution to antenatal diagnosis. Presse Med 25:452–456PubMed
Gholipour A, Estroff JA, Barnewolt CE, Connolly SA, Warfield SK (2011) Fetal brain volumetry through MRI volumetric reconstruction and segmentation. Int J Comput Assist Radiol Surg 6:329–339PubMedCentralPubMed
Girard N, Gire C, Sigaudy S, Porcu G, D’ercole C, Figarella-Branger D, Raybaud C, Confort-Gouny S (2003) MR imaging of acquired fetal brain disorders. Childs Nerv Syst 19:490–500PubMed
Girard N, Fogliarini C, Viola A, Confort-Gouny S, Fur YL, Viout P, Chapon F, Levrier O, Cozzone P (2006) MRS of normal and impaired fetal brain development. Eur J Radiol 57:217–225PubMed
Girard N, Gouny SC, Viola A, Le Fur Y, Viout P, Chaumoitre K, D’ercole C, Gire C, Figarella-Branger D, Cozzone PJ (2006) Assessment of normal fetal brain maturation in utero by proton magnetic resonance spectroscopy. Magn Reson Med 56:768–775PubMed
Gong QY, Roberts N, Garden AS, Whitehouse GH (1998) Fetal and fetal brain volume estimation in the third trimester of human pregnancy using gradient echo MR imaging. Magn Reson Imaging 16:235–240PubMed
Griffiths PD, Jarvis D, Mcquillan H, Williams F, Paley M, Armitage P (2013) MRI of the foetal brain using a rapid 3D steady-state sequence. Br J Radiol 86:20130168PubMedCentralPubMed
Grossman R, Hoffman C, Mardor Y, Biegon A (2006) Quantitative MRI measurements of human fetal brain development in utero. Neuroimage 33:463–470PubMed
Habas PA, Kim K, Corbett-Detig JM, Rousseau F, Glenn OA, Barkovich AJ, Studholme C (2010) A spatiotemporal atlas of MR intensity, tissue probability and shape of the fetal brain with application to segmentation. Neuroimage 53:460–470PubMedCentralPubMed
Habas PA, Kim K, Rousseau F, Glenn OA, Barkovich AJ, Studholme C (2010) Atlas-based segmentation of developing tissues in the human brain with quantitative validation in young fetuses. Hum Brain Mapp 31:1348–1358PubMedCentralPubMed
Habas PA, Scott JA, Roosta A, Rajagopalan V, Kim K, Rousseau F, Barkovich AJ, Glenn OA, Studholme C (2012) Early folding patterns and asymmetries of the normal human brain detected from in utero MRI. Cereb Cortex 22:13–25PubMedCentralPubMed
Hawkes RC, Holland GN, Moore WS, Worthington BS (1980) Nuclear magnetic resonance (NMR) tomography of the brain: a preliminary clinical assessment with demonstration of pathology. J Comput Assist Tomogr 4:577–586PubMed
Heerschap A, Kok RD, Van Den Berg PP (2003) Antenatal proton MR spectroscopy of the human brain in vivo. Childs Nerv Syst 19:418–421PubMed
Hoffmann C, Grossman R, Bokov I, Lipitz S, Biegon A (2010) Effect of cytomegalovirus infection on temporal lobe development in utero: quantitative MRI studies. Eur Neuropsychopharmacol 20:848–854PubMed
Hoffmann C, Weisz B, Lipitz S, Yaniv G, Katorza E, Bergman D, Biegon A (2014) Regional apparent diffusion coefficient values in 3rd trimester fetal brain. Neuroradiology 56:561–567PubMed
Hogan BA, Brown CJ, Brown JA (2008) Cecal volvulus in pregnancy: report of a case and review of the safety and utility of medical diagnostic imaging in the assessment of the acute abdomen during pregnancy. Emerg Radiol 15:127–131PubMed
Holland GN, Hawkes RC, Moore WS (1980) Nuclear magnetic resonance (NMR) tomography of the brain: coronal and sagittal sections. J Comput Assist Tomogr 4:429–433PubMed
Hu HH, Hung CI, Wu YT, Chen HY, Hsieh JC, Guo WY (2011) Regional quantification of developing human cortical shape with a three-dimensional surface-based magnetic resonance imaging analysis in utero. Eur J Neurosci 34:1310–1319
Huppi PS (2011) Cortical development in the fetus and the newborn: advanced MR techniques. Top Magn Reson Imaging 22:33–38PubMed
Huppi PS, Dubois J (2006) Diffusion tensor imaging of brain development. Semin Fetal Neonatal Med 11:489–497PubMed
Hykin J, Moore R, Duncan K, Clare S, Baker P, Johnson I, Bowtell R, Mansfield P, Gowland P (1999) Fetal brain activity demonstrated by functional magnetic resonance imaging. Lancet 354:645–646PubMed
Jansz MS, Seed M, Van Amerom JF, Wong D, Grosse-Wortmann L, Yoo SJ, Macgowan CK (2010) Metric optimized gating for fetal cardiac MRI. Magn Reson Med 64:1304–1314PubMed
Jardri R, Houfflin-Debarge V, Delion P, Pruvo JP, Thomas P, Pins D (2012) Assessing fetal response to maternal speech using a noninvasive functional brain imaging technique. Int J Dev Neurosci 30:159–161PubMed
Jardri R, Pins D, Houfflin-Debarge V, Chaffiotte C, Rocourt N, Pruvo JP, Steinling M, Delion P, Thomas P (2008) Fetal cortical activation to sound at 33 weeks of gestation: a functional MRI study. Neuroimage 42:10–18PubMed
Jiang S, Xue H, Counsell S, Anjari M, Allsop J, Rutherford M, Rueckert D, Hajnal JV (2009) Diffusion tensor imaging (DTI) of the brain in moving subjects: application to in-utero fetal and ex-utero studies. Magn Reson Med 62:645–655PubMed
Johnson IR, Stehling MK, Blamire AM, Coxon RJ, Howseman AM, Chapman B, Ordidge RJ, Mansfield P, Symonds EM, Worthington BS et al (1990) Study of internal structure of the human fetus in utero by echo-planar magnetic resonance imaging. Am J Obstet Gynecol 163:601–607PubMed
Kanal E, Shellock FG, Talagala L (1990) Safety considerations in MR imaging. Radiology 176:593–606PubMed
Kasprian G, Brugger PC, Weber M, Krssak M, Krampl E, Herold C, Prayer D (2008) In utero tractography of fetal white matter development. Neuroimage 43:213–224PubMed
Kim K, Habas PA, Rousseau F, Glenn OA, Barkovich AJ, Studholme C (2010) Intersection based motion correction of multislice MRI for 3-D in utero fetal brain image formation. IEEE Trans Med Imaging 29:146–158PubMedCentralPubMed
Kim K, Habas PA, Rousseau F, Glenn OA, Barkovich AJ, Studholme C (2010) Reconstruction of a geometrically correct diffusion tensor image of a moving human fetal brain. Proc Med Imag: Image Proc. 7623:I:1–I:9
Kok RD, Steegers-Theunissen RP, Eskes TK, Heerschap A, Van Den Berg PP (2003) Decreased relative brain tissue levels of inositol in fetal hydrocephalus. Am J Obstet Gynecol 188:978–980PubMed
Kok RD, Van Den Berg PP, Van Den Bergh AJ, Nijland R, Heerschap A (2002) Maturation of the human fetal brain as observed by 1H MR spectroscopy. Magn Reson Med 48:611–616PubMed
Kubik-Huch RA, Huisman TA, Wisser J, Gottstein-Aalame N, Debatin JF, Seifert B, Ladd ME, Stallmach T, Marincek B (2000) Ultrafast MR imaging of the fetus. AJR Am J Roentgenol 174:1599–1606PubMed
Lauterbur PC (1989) Image formation by induced local interactions. Examples employing nuclear magnetic resonance 1973. Clin Orthop Relat Res 244:3–6
Levine D, Zuo C, Faro CB, Chen Q (2001) Potential heating effect in the gravid uterus during MR HASTE imaging. J Magn Reson Imaging 13:856–861PubMed
Limperopoulos C, Tworetzky W, Mcelhinney DB, Newburger JW, Brown DW, Robertson RL Jr, Guizard N, Mcgrath E, Geva J, Annese D, Dunbar-Masterson C, Trainor B, Laussen PC, Du Plessis AJ (2010) Brain volume and metabolism in fetuses with congenital heart disease: evaluation with quantitative magnetic resonance imaging and spectroscopy. Circulation 121:26–33PubMedCentralPubMed
Liu J, Glenn OA, Xu D (2014) Fast, free-breathing, in vivo fetal imaging using time-resolved 3D MRI technique: preliminary results. Quant Imaging Med Surg 4:123–128PubMedCentralPubMed
Magin RL, Lee JK, Klintsova A, Carnes KI, Dunn F (2000) Biological effects of long-duration, high-field (4 T) MRI on growth and development in the mouse. J Magn Reson Imaging 12:140–149PubMed
Malamateniou C, Malik SJ, Counsell SJ, Allsop JM, Mcguinness AK, Hayat T, Broadhouse K, Nunes RG, Ederies AM, Hajnal JV, Rutherford MA (2013) Motion-compensation techniques in neonatal and fetal MR imaging. AJNR Am J Neuroradiol 34:1124–1136PubMed
Manganaro L, Perrone A, Savelli S, Di Maurizio M, Maggi C, Ballesio L, Porfiri LM, De Felice C, Marinoni E, Marini M (2007) Evaluation of normal brain development by prenatal MR imaging. Radiol Med 112:444–455PubMed
Mansfield P, Maudsley AA (1977) Medical imaging by NMR. Br J Radiol 50:188–194PubMed
Mansfield P, Stehling MK, Ordidge RJ, Coxon R, Chapman B, Blamire A, Gibbs P, Johnson IR, Symonds EM, Worthington BS et al (1990) Echo planar imaging of the human fetus in utero at 0.5 T. Br J Radiol 63:833–841PubMed
Mccarthy SM, Filly RA, Stark DD, Hricak H, Brant-Zawadzki MN, Callen PW, Higgins CB (1985) Obstetrical magnetic resonance imaging: fetal anatomy. Radiology 154:427–432PubMed
Michel SC, Rake A, Keller TM, Huch R, Konig V, Seifert B, Marincek B, Kubik-Huch RA (2003) Original report. Fetal cardiographic monitoring during 1.5-T MR imaging. AJR Am J Roentgenol 180:1159–1164PubMed
Mitter C, Kasprian G, Brugger PC, Prayer D (2011) Three-dimensional visualization of fetal white-matter pathways in utero. Ultrasound Obstet Gynecol 37:252–253PubMed
Moore RJ, Vadeyar S, Fulford J, Tyler DJ, Gribben C, Baker PN, James D, Gowland PA (2001) Antenatal determination of fetal brain activity in response to an acoustic stimulus using functional magnetic resonance imaging. Hum Brain Mapp 12:94–99PubMed
Mukherjee P, Mckinstry RC (2006) Diffusion tensor imaging and tractography of human brain development. Neuroimaging Clin N Am 16:19–43, viiPubMed
Myers C, Duncan KR, Gowland PA, Johnson IR, Baker PN (1998) Failure to detect intrauterine growth restriction following in utero exposure to MRI. Br J Radiol 71:549–551PubMed
Nemec SF, Brugger PC, Nemec U, Bettelheim D, Kasprian G, Amann G, Rimoin DL, Graham JM Jr, Prayer D (2012) Situs anomalies on prenatal MRI. Eur J Radiol 81:e495–e501PubMed
Novak Z, Thurmond AS, Ross PL, Jones MK, Thornburg KL, Katzberg RW (1993) Gadolinium-DTPA transplacental transfer and distribution in fetal tissue in rabbits. Invest Radiol 28:828–830PubMed
Okazaki O, Murayama N, Masubuchi N, Nomura H, Hakusui H (1996) Placental transfer and milk secretion of gadodiamide injection in rats. Arzneimittelforschung 46:83–86PubMed
Paley MN, Morris JE, Jarvis D, Griffiths PD (2013) Fetal electrocardiogram (fECG) gated MRI. Sensors (Basel) 13:11271–11279
Pier DB, Levine D, Kataoka ML, Estroff JA, Werdich XQ, Ware J, Beeghly M, Poussaint TY, Duplessis A, Li Y, Feldman HA (2011) Magnetic resonance volumetric assessments of brains in fetuses with ventriculomegaly correlated to outcomes. J Ultrasound Med 30:595–603PubMedCentralPubMed
Poutamo J, Partanen K, Vanninen R, Vainio P, Kirkinen P (1998) MRI does not change fetal cardiotocographic parameters. Prenat Diagn 18:1149–1154PubMed
Prayer D, Barkovich AJ, Kirschner DA, Prayer LM, Roberts TP, Kucharczyk J, Moseley ME (2001) Visualization of nonstructural changes in early white matter development on diffusion-weighted MR images: evidence supporting premyelination anisotropy. AJNR Am J Neuroradiol 22:1572–1576PubMed
Prayer D, Brugger PC, Prayer L (2004) Fetal MRI: techniques and protocols. Pediatr Radiol 34:685–693PubMed
Rajagopalan V, Scott J, Habas PA, Kim K, Rousseau F, Glenn OA, Barkovich AJ, Studholme C (2010) Measures for characterizing directionality specific volume changes in TBM of brain growth. Med Image Comput Comput Assist Interv 13:339–346PubMedCentralPubMed
Rajagopalan V, Scott J, Habas PA, Kim K, Rousseau F, Glenn OA, Barkovich AJ, Studholme C (2012) Mapping directionality specific volume changes using tensor based morphometry: an application to the study of gyrogenesis and lateralization of the human fetal brain. Neuroimage 63:947–958PubMedCentralPubMed
Righini A, Bianchini E, Parazzini C, Gementi P, Ramenghi L, Baldoli C, Nicolini U, Mosca F, Triulzi F (2003) Apparent diffusion coefficient determination in normal fetal brain: a prenatal MR imaging study. AJNR Am J Neuroradiol 24:799–804PubMed
Roelants-Van Rijn AM, Groenendaal F, Stoutenbeek P, Van Der Grond J (2004) Lactate in the foetal brain: detection and implications. Acta Paediatr 93:937–940PubMed
Rofsky NM, Pizzarello DJ, Weinreb JC, Ambrosino MM, Rosenberg C (1994) Effect on fetal mouse development of exposure to MR imaging and gadopentetate dimeglumine. J Magn Reson Imaging 4:805–807PubMed
Rothenberger A, Roessner V (2006) Diffusion tensor imaging (DTI) of the corpus callosum may further elucidate development of brain lateralization. Fortschr Neurol Psychiatr 74:133–135PubMed
Rousseau F, Glenn OA, Iordanova B, Rodriguez-Carranza C, Vigneron DB, Barkovich JA, Studholme C (2006) Registration-based approach for reconstruction of high-resolution in utero fetal MR brain images. Acad Radiol 13:1072–1081PubMed
Schneider JF, Confort-Gouny S, Le Fur Y, Viout P, Bennathan M, Chapon F, Fogliarini C, Cozzone P, Girard N (2007) Diffusion-weighted imaging in normal fetal brain maturation. Eur Radiol 17:2422–2429PubMed
Schopf V, Kasprian G, Brugger PC, Prayer D (2012) Watching the fetal brain at ‘rest’. Int J Dev Neurosci 30:11–17PubMed
Scott JA, Habas PA, Kim K, Rajagopalan V, Hamzelou KS, Corbett-Detig JM, Barkovich AJ, Glenn OA, Studholme C (2011) Growth trajectories of the human fetal brain tissues estimated from 3D reconstructed in utero MRI. Int J Dev Neurosci 29:529–536PubMedCentralPubMed
Scott JA, Habas PA, Rajagopalan V, Kim K, Barkovich AJ, Glenn OA, Studholme C (2013) Volumetric and surface-based 3D MRI analyses of fetal isolated mild ventriculomegaly: brain morphometry in ventriculomegaly. Brain Struct Funct 218:645–655PubMed
Shellock FG, Kanal E (1991) Policies, guidelines, and recommendations for MR imaging safety and patient management. SMRI Safety Committee. J Magn Reson Imaging 1:97–101PubMed
Shellock FG, Kanal E (1996) Bioeffects and safety of MR procedures. In: Hasselink JR, Zlatkin MB, Edelman RR (eds) Clinical magnetic resonance imaging. Saunders, Philadelphia, p 426
Smith FW, Adam AH, Phillips WD (1983) NMR imaging in pregnancy. Lancet 1:61–62PubMed
Sorensen A, Peters D, Simonsen C, Pedersen M, Stausbol-Gron B, Christiansen OB, Lingman G, Uldbjerg N (2013) Changes in human fetal oxygenation during maternal hyperoxia as estimated by BOLD MRI. Prenat Diagn 33:141–145PubMed
Sørensen A, Peters D, Fründ E, Lingman G, Christiansen O, Uldbjerg N (2013) Changes in human placental oxygenation during maternal hyperoxia estimated by blood oxygen level-dependent magnetic resonance imaging (BOLD MRI). Ultrasound Obstet Gynecol 42:310–314PubMed
Stegemann T, Heimann M, Dusterhus P, Schulte-Markwort M (2006) Diffusion tensor imaging (DTI) and its importance for exploration of normal or pathological brain development. Fortschr Neurol Psychiatr 74:136–148PubMed
Stern MD, Kopylov U, Ben-Horin S, Apter S, Amitai MM (2014) Magnetic resonance enterography in pregnant women with Crohn’s disease: case series and literature review. BMC Gastroenterol 14:146PubMedCentralPubMed
Story L, Damodaram MS, Allsop JM, Mcguinness A, Wylezinska M, Kumar S, Rutherford MA (2011) Proton magnetic resonance spectroscopy in the fetus. Eur J Obstet Gynecol Reprod Biol 158:3–8PubMed
Studholme C (2011) Mapping fetal brain development in utero using magnetic resonance imaging: the Big Bang of brain mapping. Annu Rev Biomed Eng 13:345–368PubMedCentralPubMed
Sundgren PC, Leander P (2011) Is administration of gadolinium-based contrast media to pregnant women and small children justified? J Magn Reson Imaging 34:750–757PubMed
Thickman D, Mintz M, Mennuti M, Kressel HY (1984) MR imaging of cerebral abnormalities in utero. J Comput Assist Tomogr 8:1058–1061PubMed
Thomason ME, Dassanayake MT, Shen S, Katkuri Y, Alexis M, Anderson AL, Yeo L, Mody S, Hernandez-Andrade E, Hassan SS, Studholme C, Jeong JW, Romero R (2013) Cross-hemispheric functional connectivity in the human fetal brain. Sci Transl Med 5:173ra24PubMedCentralPubMed
Thomason ME, Thompson PM (2011) Diffusion imaging, white matter, and psychopathology. Annu Rev Clin Psychol 7:63–85PubMed
Triulzi F, Manganaro L, Volpe P (2011) Fetal magnetic resonance imaging: indications, study protocols and safety. Radiol Med 116:337–350PubMed
Wack C, Steger-Hartmann T, Mylecraine L, Hofmeister R (2012) Toxicological safety evaluation of gadobutrol. Invest Radiol 47:611–623PubMed
Williamson RA, Weiner CP, Yuh WT, Abu-Yousef MM (1989) Magnetic resonance imaging of anomalous fetuses. Obstet Gynecol 73:952–956PubMed
Yaniv G, Hoffmann C, Weisz B, Lipitz S, Katorza E, Kidron D, Bergman D, Biegon A (2014) Region selective reductions in brain apparent diffusion coefficient in CMV-infected fetuses. Ultrasound Obstet Gynecol. doi: 10.1002/uog.14737. [Epub ahead of print]
Yip YP, Capriotti C, Talagala SL, Yip JW (1994) Effects of MR exposure at 1.5 T on early embryonic development of the chick. J Magn Reson Imaging 4:742–748PubMed
Zizka J, Elias P, Hodik K, Tintera J, Juttnerova V, Belobradek Z, Klzo L (2006) Liver, meconium, haemorrhage: the value of T1-weighted images in fetal MRI. Pediatr Radiol 36:792–801PubMed