Development of the Fetal Vermis: New Biometry Reference Data and Comparison of 3 Diagnostic Modalities–3D Ultrasound, 2D Ultrasound, and MR Imaging

BACKGROUND AND PURPOSE: Normal biometry of the fetal posterior fossa rules out most major anomalies of the cerebellum and vermis. Our aim was to provide new reference data of the fetal vermis in 4 biometric parameters by using 3 imaging modalities, 2D ultrasound, 3D ultrasound, and MR imaging, and to assess the relation among these modalities. MATERIALS AND METHODS: A retrospective study was conducted between June 2011 and June 2013. Three different imaging modalities were used to measure vermis biometry: 2D ultrasound, 3D ultrasound, and MR imaging. The vermian parameters evaluated were the maximum superoinferior diameter, maximum anteroposterior diameter, the perimeter, and the surface area. Statistical analysis was performed to calculate centiles for gestational age and to assess the agreement among the 3 imaging modalities. RESULTS: The number of fetuses in the study group was 193, 172, and 151 for 2D ultrasound, 3D ultrasound, and MR imaging, respectively. The mean and median gestational ages were 29.1 weeks, 29.5 weeks (range, 21–35 weeks); 28.2 weeks, 29.05 weeks (range, 21–35 weeks); and 32.1 weeks, 32.6 weeks (range, 27–35 weeks) for 2D ultrasound, 3D ultrasound, and MR imaging, respectively. In all 3 modalities, the biometric measurements of the vermis have shown a linear growth with gestational age. For all 4 biometric parameters, the lowest results were those measured by MR imaging, while the highest results were measured by 3D ultrasound. The inter- and intraobserver agreement was excellent for all measures and all imaging modalities. Limits of agreement were considered acceptable for clinical purposes for all parameters, with excellent or substantial agreement defined by the intraclass correlation coefficient. CONCLUSIONS: Imaging technique–specific reference data should be used for the assessment of the fetal vermis in pregnancy.

I maging of the fetal posterior fossa is considered a routine part of the fetal sonographic examination. Normal sonographic biometry and normal morphology of the posterior fossa rule out most major anomalies of the fetal cerebellum and vermis. 1 However, in case of an abnormal posterior fossa, evaluation of the vermian biometry and morphology is of paramount im-portance, considering the wide clinical spectrum of this imaging finding. 2 Fetal posterior fossa anomalies range from benign asymptomatic conditions to severe abnormalities associated with neurologic impairment. [3][4][5][6] The most frequent of these anomalies, Blakes pouch cyst, vermian hypoplasia, and Dandy-Walker malformation, have a similar imaging appearance 7,8 but different vermian biometry and, therefore, different prognoses. 9 Many anomalies of the posterior fossa can be depicted with sonography alone. 10 Although the standard axial imaging planes may detect most anomalies of the posterior fossa, the diagnosis of the exact type of abnormality might be challenging because a clear visualization of the midsagittal plane is essential. Subtle changes in the morphology of the vermis are hidden by this axial view, and this feature can lead to false-positive diagnoses of vermian pathologies. 11,12 Our group has proposed using the transabdominal sagittal plane for visualization of the fetal vermis, 13 while Malinger et al 14 reported their experience with the transvaginal approach. Vinals et al 15 used volume contrast imaging (VCI) on plane C to construct nomograms for the normal fetal vermis. Our group used this same VCI on plane C technique to compare normal and abnormal fetal vermis measurements, and we concluded that the 3D sonographic technique has many advantages in the detection of posterior fossa anomalies. 16 It allows off-line evaluation and reconstruction of images, even with abnormal angles when the midsagittal plane is difficult to obtain.
MR imaging is a well-known complementary tool in the prenatal diagnosis of fetal brain abnormalities. The challenges described above in achieving a good visualization of the midsagittal plane in prenatal sonography led to frequent use of this tool to assess, more accurately, the structures of the posterior fossa and improve prenatal diagnosis.
Various nomograms have been developed to establish normal biometric measures of the fetal vermis by using ultrasound (US) or MR imaging. [17][18][19] None of these nomograms provided data regarding all 4 vermian biometric parameters. Moreover, there were no comparisons among all 3 imaging modalities. 20 The aims of our study were the following: to provide normal reference biometric data of the fetal vermis in 4 biometric parameters for 3 imaging modalities, to evaluate the reproducibility of the vermian biometry, and to compare the measurements obtained by 2D sonography, 3D sonography, and MR imaging.

Population
A retrospective study was conducted between June 2011 and June 2013.
All sonographic examinations were performed during routine pregnancy follow-up and were in addition to the standard axial views. MR imaging examinations were performed due to increased risk of suspected cerebral pathology, including suspected infectious fetopathy, suspected sonographic cerebral abnormality, positive family history, a previous pregnancy with CNS abnormality, decreased fetal movements, polyhydramnios, and extracranial anomalies such as club foot, cleft lip, and/or palate. However, there was no evidence of intracranial abnormalities.
The inclusion criteria for the 3 groups were the following: singleton pregnancy, good dating, estimated fetal weight within the 10th to 90th percentiles, normal obstetric course (no evidence of intrauterine growth restriction or macrosomia or pregnancy-related hypertensive disorders or gestational diabetes mellitus), absence of maternal disease (healthy women without any background illness such as hypercoagulability state, hypertension, diabetes, or other systemic disease), clinically normal fetus at birth (normal Apgar scores at birth, normal neonate physical examination findings), and no known neurologic family history. A detailed sonographic scan was performed to rule out fetal malformations. Only 1 measurement was used for each patient with each gestational week in each imaging technique.       The measurements of vermian parameters were performed according to the following anatomic landmarks: 1) The maximum superoinferior (SI) diameter, the greatest height of the vermis, which is generally parallel to the axis of the brain stem; 2) maximum anteroposterior (AP) diameter from the peak of the fourth ventricle, the fastigium, to the maximal AP diameter; 3) perimeter, the track line that follows vermian fissures; and 4) surface area, the same peripheral line that calculates surface area. All 4 parameters of the fetal vermis were measured at the same landmarks for each technique (Fig 1).
For each study group, all measurements were performed by a single operator. To evaluate the reproducibility of measurements, an arbitrary sample of 50 fetuses was evaluated twice by the first operator and then by a second operator. Each operator was unaware of the results obtained by the other.

Imaging Technique and Measurements
Sonography. All patients were scanned by using a Voluson 730 Expert or a Voluson E8 (GE Medical Systems, Kretz Ultrasound, Zipf, Austria) with a transabdominal transducer of 4 -8 MHz or a 5-to 9-MHz transvaginal probe.
2D Technique. The fetal brain was scanned in a midsagittal plane by using the transfontanel approach. A true midsagittal image of the entire vermis is defined as a plane of a section that passes through the rostral and caudal convexities at the levels of the superior, middle, and inferior portion of the vermis. The fastigium should be visualized in this plane.
According to Achiron et al, 13 the midsagittal view includes the corpus callosum, the cavum septi pellucidi, and the brain stemvermis plane. At the brain stem-vermis level, attention was paid to include the rostral part of the thalamus, the midbrain, the pons, the medulla oblongata, the fourth ventricle, and the cerebellar vermis (Fig 2A).
3D Technique. After a standard 2D examination, 3D volumes were acquired for off-line computer evaluation. 10 Before we acquired the volume, the contrast of the 2D image was optimized by activating the harmonic function with high frequency, low gain, and high contrast, to enhance tissue interfaces. The 3D image was acquired during fetal rest in the absence of fetal movements, and the standard volume sweep angle was 55°. The starting image was in the axial plane at the level of the transverse cerebellar diameter. The static VCI on plane C was rebuilt, and a perfect midsagittal view was obtained. Subsequently, the volume measurements were stored, and analysis was performed off-line with 4D View, Version 7.0 software (GE Healthcare, Kretz Ultrasound).
After obtaining a measurement of the volume of the fetal brain in the axial plain, we placed the reference dot in the A reference image in the middle of the vermis. Afterward, the skull was rotated along the z-axis until the midline was horizontal, and the dot of interest was placed in the middle of the vermis in the B reference image. Finally, the skull was rotated again along the z-axis until the midline was again horizontal. The image was magnified to the maximal size available, and biometric measurements were performed (Fig 2B).
MR Imaging. Scans were obtained by using a 1.5T system (Optima; GE Healthcare). Single-shot fast spin-echo T2-weighted sequences in 3 orthogonal planes were performed with the following parameters: section thickness, 3 mm; no gap; flexible coil (8channel cardiac coil); matrix, 320/224; TE, 90 ms; and TR, 1298 ms. The FOV was determined by the size of the fetal head and was 24 cm for the smaller fetuses and up to 30 cm for the larger fetuses. T1 fast spoiled gradient-echo sequences were performed only in the axial plane with a larger FOV (400 mm); section thickness, 3 mm; gap, 0.5 mm; TR, 160 ms; TE, 2.3 ms. Then diffusionweighted sequences in the axial plane were performed with an FOV, 40 cm; b-value, 0 and 1000 ms; section thickness, 3 mm; and no gap.  The biometric parameters of the fetal vermis were measured in the midsagittal plane by using single-shot fast spin-echo T2weighted sequences (Fig 2C).

Statistical Analysis
Statistical analysis was performed with the SPSS software, Version 22.0 (IBM, Armonk, New York). Gestational age was described as mean, median, and range. Biometric measurements of the vermis are described for each gestational age as median and 5th and 95th percentiles and as mean Ϯ SD and 95% CI of the mean. Linear regression models were used to assess the relationship between gestational age and vermian biometric measurements.
Comparison among the 3 imaging modalities for each biometric measurement adjusted for gestational age was performed by using a general linear model with the Bonferroni multiple comparison test. Because MR imaging was not performed before 27 weeks' gestational age, a sensitivity analysis was added considering MR imaging, US 2D, and US 3D measurements at the gestational age of Ն27 weeks. Estimates of the intraclass correlation coefficient (ICC) were used to explore inter-and intra-agreement between the radiologists. Agreement was considered slight with ICC Յ 0.2, fair with 0.2 Ͻ ICC Յ 0.4, moderate with 0.4 Ͻ ICC Յ 0.6, substantial with 0.6 Ͻ ICC Յ 0.8, and almost perfect with ICC Ͼ 0.8.

Ethics Approval
The study was approved by the institutional review board of the Sheba Medical Center.
Biometric measurements of the vermis are described for each parameter, imaging modality, and gestational age as median and 5th and 95th percentiles (Tables 1-4) and as mean Ϯ SD and 95% CI of the mean (Fig 3 and On-line Tables 1-4). For all 3 imaging modalities, the biometric measurements of the vermis have shown a linear growth with gestational age. Results from linear regression models are presented in Table 5.
When we compared the effect of imaging technique controlled for gestational age in the general linear model, the lowest results were those measured by MR imaging, while the highest results were measured by 3D US. All the differences (Bonferroni comparison) were significant (P Ͻ .001) except AP and surface area (SA) measurements by 2D and 3D US (P ϭ .601 and .02) ( Table 6 and On-line Tables 5 and 6).

Reproducibility of Measurements
Reproducibility of measurement was excellent for all measures and all imaging modalities (Tables 7 and 8), The limits of agreement were considered acceptable for clinical purposes for all parameters, with excellent or substantial agreement defined by ICC.

DISCUSSION
The differential diagnosis of vermian pathology is quite challenging. Biometric parameters allow assessment of the integrity of the