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Stefan Franz Nemec, Medical University Vienna, Department of Radiology, Division of Neuroradiology and Musculoskeletal Radiology, Waehringer Guertel 18-20, Vienna A-1090 Austria. E-mail: firstname.lastname@example.org
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Prenatal magnetic resonance imaging (MRI) has become an important adjunct to fetal ultrasonography (US) for the in utero diagnosis of anomalies between 18 gestational weeks (GW) and term.[1, 2] Recently improved MR techniques have increased the spectrum of new potential uses for fetal MRI beyond the detection of central nervous system (CNS) and pulmonary abnormalities.[3, 4] Overall, the application of fetal MRI should be considered in the context of the expertise and availability, coverage of expenses, and national regulations for pregnancy termination.
Congenital musculoskeletal disorders and malformations may occur in isolation or may be associated with other anomalies and syndromes, and a specific prenatal diagnosis is vital for genetic counseling, prognostication, and management. These abnormalities may be focal or may be generalized disorders related to poor fetal outcome. However, even focal anomalies, such as hypoplastic thumbs, may be associated with a genetic disease, for example, Townes–Brocks syndrome, which also includes cardiac, renal, and anorectal abnormalities.
Detailed examination of the limbs is not listed in the guidelines of the American Institute of Ultrasound in Medicine for standard sonography (American Institute of Ultrasound in Medicine), but limb evaluation has been emphasized as a critical component by several US imaging studies.[9-14] Prenatal US, although subject to some limitations, is currently regarded as the method of choice for long bone measurement, for diagnosing distal limb abnormalities, and for assessing skeletal dysplasias in utero. Thus, US, including two-dimensional or three-dimensional (3D) visualization, is the primary fetal imaging modality and the predominant technique for the evaluation of the fetal musculoskeletal system. It provides a safe and relatively inexpensive procedure, allows real-time imaging, and is readily available. Although, the recent technical development has extended the use of MRI for the diagnosis of a variety of diseases apart from the CNS, it will be the topic of future research to determine how this additional exam may affect the perinatal management.
In contrast to a number of US investigations, there exists only preliminary literature about the application of MRI for the evaluation of musculoskeletal abnormalities.[16, 17] In addition to T2-weighted (w) imaging being the ‘all-in-one device’ for prenatal MRI,[2, 18, 19] this article will comment on the role of techniques such as echo planar imaging (EPI), thick-slab T2-w, and dynamic steady-state free precession sequences in fetal musculoskeletal imaging (Tables 1-4). We will demonstrate the impact of an MRI diagnosis by reviewing the author's preliminary experience with this subject and by summarizing the initial data in the recent literature.
• Movement of extremities, head, and body; swallowing; diaphragm excursions
• Akinesia (fetal akinesia deformation sequence)
• Fetal bulk motion
Repetition time: 3.14 ms; echo time: 1.57 ms; field-of-view: 320 mm; matrix: 176×110 mm; slice thickness: 30 mm; flip angle: 60°; 4–6 frames per second; up to 8 repetitions; duration: 34 s
Although the first publications about EPI (Table 2) in the fetal environment reach back to the very beginnings of prenatal MRI,[20, 21] the actual application of this technique is limited to just a few fetal musculoskeletal imaging studies.[17, 22] In prenatal MRI, EPI is able to demonstrate osseous structures in correlation with the gestational age, and thus, the degree of ossification of the fetal skeleton[2, 17, 19] (Figures 1 and 2). To date, it is the only modality able to visualize the fetal bones before 27 GW, which is not possible using only standard T2-w sequences.[2, 17, 19] On the basis of the gestational age, the diaphyses of the fetal ossifying bones are characterized by distinct MR signal hypointensity and the cartilaginous epiphyses by hyperintensity.[2, 19] EPI enables the visualization of the morphological changes of the growing epi-metaphyseal region of the long bones (Figure 3), in addition to fetal US, which demonstrates ossification centers as hyper-echogenic areas from 9 weeks onward. A major limitation of EPI is, however, the low spatial resolution and minor soft tissue contrast in internal organs other than the musculoskeletal system.
Thick-slab T2-w imaging (Table 3) creates a three-dimensional-like visualization with notable T2-w contrast of the whole fetus on one image, even in advanced gestation, because of the large field-of-view. Thick-slab T2-w imaging is acquired as one image in less than 1 s, which is not influenced by fetal motion, or as radial stacks that can be rotated on a viewing workstation. As a result, this technique allows determination of fetal proportions and the positioning of the extremities, in addition to a conventional stack of MR slices (Figure 4). Fetal proportions may be altered because of asymmetrical intrauterine growth restriction (IUGR) or in skeletal dysplasias. Thick-slab T2-w sequences may be particularly suited to delineate abnormalities such as clubfeet, arthrogryphosis, or extremity shortening in mesomelia or rhizomelia, by depicting the shape and position of the whole limb on one image[2, 16-19] (Figure 4). Thick-slab T2-w imaging may be also well-suited for assessing the integrity of the fetal surface contours, including the muscle mass, and the completeness of limbs, and of a regular body wall. Moreover, thick-slab T2-w imaging may be useful for capturing the most obvious abnormal findings on one image. Because of the aforementioned scanning time, thick-slab T2-w imaging is less time-consuming compared with post-processed 3D reconstructions based upon two-dimensional MR raw data.
Dynamic MRI scans (Table 4) are crucial for the evaluation of extremity abnormalities and movement disorders. As part of a whole-body protocol, the application of dynamic sequences with four to seven images per second allows real-time demonstration of fetal movements of the extremities, gross fetal motions, and swallowing and diaphragmatic motions[2, 19] (Video S1). Thus, in addition to standard US evaluation of fetal movements,[24, 25] MRI can also indicate the presence, reduction, or absence of fetal movements involving the extremities, trunk, and head.[2, 16, 17, 19] From a practical point of view, dynamic scans are also essential to otherwise diagnose rapidly moving fetuses, which cannot be visualized by static MR sequences because of marked motion artifacts. In contrast to US, which represents a true real-time technique, until now there have been no diagnostic standards for MRI to assess the qualitative aspects of fetal movement based upon modified US recommendations.[24, 25] Consequently, the diagnosis of movement reduction on dynamic MRI studies may be limited, so the scans should be repeated several times at 5, 10, 15, 20, 25, and 35 min during the whole examination. Adapted US criteria, such as reduced amplitude and speed, or number of participating body parts, may be used to determine specific or generalized disorders of fetal motion. The fixed nature of contractures can be visualized as the absence of changes in the extremity position during the course of the MRI study. Moreover, dynamic MRI studies should be evaluated in combination with the fetal anatomy, because temporary variants of malpositioning in advanced gestation or oligohydramnios may mimic the appearance of true joint contractures. Focal limb abnormalities, such as clubfeet or hand abnormalities, may be more obvious in motion when using dynamic MRI. Fetal akinesia, an absence of motion, in combination with decreased muscle mass, abnormal muscular fat deposition, and polyhydramnios, could indicate a (neuro)muscular disease. In addition, lung hypoplasia and facial abnormalities could suggest a fetal akinesia, which is termed the fetal akinesia deformation sequence (FADS).[16, 26] In such circumstances, CNS anomalies should also be considered as underlying conditions in fetal akinesia.
SKULL AND OSSEOUS FACIAL STRUCTURES
Abnormalities of the skull include changes in the size, shape, and bone density, and skull defects and fetal skull neoplasms, such as hemangiomas.[27, 28] Although case reports have demonstrated the MRI diagnosis of craniosynostosis and cloverleaf skull deformity in Apert syndrome, US is usually the standard procedure for assessing the size and shape of the fetal head/skull. In particular, for the diagnosis of fetal migration disorders resulting in malformations such as microcephaly, MRI appears to demonstrate better results than US. Macrocephaly may result from a skeletal dysplasia, a specific syndrome, or from increased intracranial pressure. Skeletal dysplasias, such as osteogenesis imperfecta or hypophosphatasia, may also present with a decrease in the osseous density of the skull, which may be detected by MRI as signal attenuation on EPI sequences. In addition, most prenatal-onset skeletal dysplasias demonstrate a relative disproportion of the skeletal measurements when compared with those of the cranium. MRI may also detect associated brain abnormalities in skeletal dysplasias that occur rarely. Encephaloceles should be examined with special attention to their content. Symmetrically enlarged parietal foramina may also be seen on fetal MRI.
On MRI, the skull base and cranio-cervical junction should be examined with attention to the width and content of the foramen magnum, and particularly for cerebellar herniation, which is a feature of Chiari malformations. The degree of ossification of the skull base may be altered in various skeletal dysplasias. With regard to the middle cranial fossa, the fluid-filled inner ear structures can be delineated from 18 GW onward.[2, 36]
Two-dimensional US and 3D US enable the visualization of cleft lip and the anterior palate, and micrognathia and retrognathia.[37, 38] The US assessment of the posterior palate, however, may be difficult because of osseous artifacts. In comparison, T2-w MRI demonstrates the posterior palate consistently, and MRI provides better detection and classification of clefts of the primary and secondary palate than ultrasound alone (Figure 5). In contrast, the MRI diagnosis of isolated cleft lip, without other involvement, may be difficult because of partial volume averaging. The diagnosis of micrognathia can influence the prenatal and postnatal outcomes of affected individuals because of its association with additional abnormalities. Maxillary and mandibular teeth buds may be also recognized on T2-w images.
The assessment of the fetal face is important in cases of skeletal dysplasias, complex malformations, and syndromic disorders. An abnormal facial profile is usually best depicted on sagittal T2-w imaging. Glabellar bossing, a flattened nasal bridge, and micrognathia may be found in some disorders. Abnormalities that may involve the nose, orbits, and also bulbar abnormalities, may be associated with midline anomalies such as holoprosencephaly. In case of abnormal tooth anlagen, for instance, a single median incisor may be also identified.
THORAX AND SPINE
Because a small thorax and lung hypoplasia can be a major life-limiting feature of some skeletal dysplasias and generalized muscular disorders, such as a fetal akinesia deformation sequence, lung assessment is critical to determine the appropriate in utero management. US and MRI are both able to visualize the thorax shape and lung abnormalities.[3, 41] A chest-to-abdominal circumference ratio of <0.6 is strongly suggestive of lethality. More important, the volume of the lungs can be determined with MR volumetry, and normal lung maturation is also characterized by high T2-w signal intensities.
Congenital scoliosis because of improper vertebral formation and/or segmentation, is the most frequent congenital deformity of the spine[42, 43] MRI may be helpful in distinguishing isolated cases from those with associated malformations (Figure 6). Spinal dysraphism or neural tube defects encompass a diverse group of spinal anomalies in which MRI is a complementary tool to further elucidate spine abnormalities, and associated CNS and non-CNS anomalies that may have an influence on prognosis[44-46] (Figure 7). The type of spinal dysraphism can be better evaluated on MRI than on US, because MRI provides exact delineation of the cord and the interface between the cerebrospinal fluid and the extradural space[44-46] (Figure 7). T1-w imaging can be used to assess the fatty component in lipomyelomeningoceles and the blood content. At the same time, EPI is useful for evaluating the ossified vertebral bodies. Moreover, MRI may be helpful in identifying associated gastrointestinal and urologic anomalies in caudal regression syndrome, and possibly, also in cloacal malformations. The prognosis of spinal dysraphism is influenced by the level and the type of the lesion, the presence of associated anomalies, ventriculomegaly, and the type of closure. The accurate prenatal diagnosis of open and closed spinal dysraphism becomes critical in providing appropriate counseling and perinatal management that may include termination of pregnancy, fetal surgery, and/or caesarean section, with immediate postnatal surgery. T2-w images with a slice thickness of 3 mm are most useful in assessing spinal and associated intracranial anomalies. Multiplanar images of the brain should be obtained for the evaluation of hindbrain herniation, and for associated anomalies, such as callosal agenesis.
LONG BONES AND EXTREMITIES
The ossification of the clavicles and mandible occurs at 8 weeks; ossification of the appendicular skeleton, the ileum, and scapula by 12 weeks; and the metacarpals and metatarsals by 12 to 16 weeks.[12, 23] Secondary ossification centers are demonstrated at US and MRI from 29 weeks onward (Figure 3). The fetal skeleton is readily visualized by two-dimensional ultrasound by 14 weeks, and femoral and humeral measurements are considered to be part of any basic midtrimester US exam.[10, 23] Femoral or humeral length measurements lower than the 5th percentile or two standard deviations below the mean in the second trimester may suggest the presence of a generalized skeletal disorder. Abnormal bone length may be also observed in addition to other abnormal growth parameters, and placental abnormalities in IUGR can be also evaluated by fetal MRI.
Ultrasonography is the method of choice for measuring long bones and observing subtle findings that involve the hands and feet, which are particularly well-suited for 3D US.[13, 49] In addition to US, abnormalities of the hands and feet can also be observed using conventional two-dimensional T2-w imaging, and at 3D T2-w thick-slab imaging and on reconstructed images (Figures 4 and 8). The spectrum of malformations varies from subtle finger deformities to the complete absence of limbs. Hand malformations can be classified according to the predominant anomaly: abnormal alignment (e.g. clenched hand); thumb anomalies; abnormal echogenicity (abnormal calcifications); or an abnormal number of components (e.g. polydactyly or ectrodactyly) (Figure 8). Limb malformations may be isolated or associated with a monogenic or chromosomal syndrome.
Initial details concerning the development of the epiphysis, and disorders of ossification, have been noted through the use of EPI sequences.[2, 17] (Figures 3 and 9). Because of similarities to human fetuses, the MRI appearance of pig femur specimens at different gestational ages, including changes of the intercondylar notch and epiphyseal ossification center, and in the signal intensity and shape of the bone marrow, have been described. Recent improvements in sequence technology have overcome the prior deficiencies of conventional T2-w imaging, but the MR stages of normal human bone development are currently under investigation and need to be defined in detail.
Magnetic resonance imaging of the fetal musculature has only been recently investigated.[16, 17] On US, abnormal muscular development may be observed with focal limb abnormalities or in generalized disorders, such as arthrogryposis and FADS, spinal muscle dystrophy, or muscle dystrophy, particularly with qualitative and quantitative movement assessment.[52-54]
Normal individual muscles (with few exceptions, e.g. the diaphragm) may not be differentiated from the underlying bones, particularly after 30 GW, because of their homogenous T2-w signal hypointensity. In contrast, EPI creates a marked distinction between the extremity bones and the adjacent muscles. MRI can show the abnormal thickness and contours of the skeletal muscles, and atrophy (Figure 10). In addition, T1-w and T2-w signals may be abnormal, with increased signal intensities indicating muscular edema or fatty transformation[2, 16] (Figure 10).
COMPLEX DEFECTS OF THE MUSCULOSKELETAL SYSTEM
Abnormalities may be either isolated or may be accompanied by other defects, particularly in monogenic or chromosomal syndromes.[5, 9, 55] The prenatal diagnosis of musculoskeletal anomalies should be based on information assembled from imaging, and combined with other genetic studies. Prenatal diagnosis may serve as a valuable tool for counseling the parents regarding prognosis, natural history, and recurrence risks. The management of pregnancies with musculoskeletal disease depends mainly on three factors: the time of diagnosis, the severity of disease, and the parents' decision. When identifying a musculoskeletal abnormality, the whole fetus should be assessed in detail, particularly the CNS, to detect any visceral abnormalities. The presence or absence of specific MRI findings can help to differentiate between isolated and complex anomalies, which is a major contribution of fetal MRI.
Ultrasonography of suspected skeletal dysplasias involves systematic imaging of the long bones, thorax, hands and feet, skull, spine, and pelvis.[12, 15] Assessment of the fetus with 3D US has been shown to improve diagnostic accuracy, because additional phenotypic features not detectable at two-dimensional US may be identified. However, considering that there are over 450 recognized genetic skeletal disorders, it is hardly surprising that a precise diagnosis by prenatal US diagnosis is challenging.[12, 56, 57] Although many skeletal dysplasias can be detected by 14 weeks of gestation, prenatal diagnosis is often difficult in the absence of a relevant family history. Among the diagnostic limitations are the large number of rare skeletal dysplasias and their phenotypic variability with overlapping features, and variability in time of onset of findings. The most common predictors of lethal skeletal dysplasias include early and severe shortening of the long bones, a femur length-to-abdominal-circumference ratio of less than 0.16, and a hypoplastic thorax. However, the latter findings are not pathognomic for a specific disorder. Although in thanatophoric dysplasia and osteogenesis imperfecta typical sonographic findings account for high rates of accurate prenatal diagnosis, the overall accuracy for the diagnosis of the specific skeletal dysplasias using routine US approaches only 40% of cases, which may indicate a potential future role for MRI in these conditions. The final diagnosis will also involve postdelivery radiographs and possibly autopsy, including histologic analysis of cartilage and bone and molecular testing, as available. Recent investigations have reported the application of 3D computed tomography (CT) for the in utero diagnosis of skeletal dysplasias after 30 GW.[61, 62] Because of the associated radiation dose, which may be similar to that of conventional fetal radiography, the use and potential impact of CT is limited.[61, 62] Finally, the use of US, MRI, and potentially, 3D CT in the prenatal diagnosis of skeletal disorders may obviate the need for radiographs obtained in utero, which typically have poor resolution.
In conclusion, this current article reviews our preliminary results with fetal musculoskeletal MRI for the diagnosis of abnormalities of the skeleton and muscles in utero. US is still the most commonly used and cost effective modality in following fetal development from the early stages of gestation, and US continues to be the first-line exam for musculoskeletal issues. We have illustrated, in a limited set of clinical cases, the potential role of MRI as an adjunct exam to standard fetal US. To date, initial studies indicate that MRI has been proven to be useful for fetal spinal imaging, and for the differentiation between isolated and complex abnormalities. The MR visualization of normal and abnormal bone development and muscular disorders is suggested by this initial experience. In our institution, MRI has become a frequently used tool for various indications, including the musculoskeletal system, which may be somewhat controversial in view of the predominant role of prenatal US. Ultimately, much more research must be conducted to clarify the true clinical value of the additional MRI findings, compared with US, which might have an impact on the perinatal management.
WHAT'S ALREADY KNOWN ABOUT THIS TOPIC?
Previous studies have demonstrated that fetal MR imaging may be useful in the visualization of spinal dysraphism and in differentiating between isolated and complex skeletal deformities with associated malformations.
WHAT DOES THIS STUDY ADD?
Our preliminary insights into the prenatal MR imaging diagnosis of skeletal and muscular anomalies may potentially expand the contemporary MR indications, which are confined to the fetal central nervous system in a majority of cases.