Introduction
The measurement of a range of anatomical structures is an integral part of the ante-natal assessment of the fetus using ultrasonography (USS). This includes assessment of the fetal head size by way of bi-parietal diameter (BPD), occipito-frontal diameter (OFD) and/or head circumference. There are several published growth charts of normative data, to which USS measurements can be compared [
1‐
3]. Head size is also assessed if a fetus is referred for MR imaging due to suspected abnormalities. The published reference values from MR imaging data are limited however, due to a narrow range of gestational ages or small sample sizes [
4‐
7]. USS charts are therefore used as a reference for MR, highlighting the need for further studies.
It is possible to measure some linear brain dimensions (as opposed to skull) on USS but this is not routinely carried out in clinical practice, so skull measurements are frequently used as a surrogate indicator of brain size. That approach is unreliable because growth of the fetal skull is influenced by factors other than growth of the brain per se. For example, it is well established that increased volume and pressure in the cerebral ventricles (fetal hydrocephalus) is usually accompanied by increased skull size because the individual bones of the fetal calvarium are unfused [
8]. Linear measurements of the skull may be useful up to a point but it seems intuitively correct that accurate measurement of the intracranial contents will improve the diagnosis of fetal neuro-pathologies. As such, the design and trialing of methods that allow accurate and reproducible measurement of the volumes of intracranial structures is a worthwhile research goal.
There are several ways to divide the intracranial contents anatomically and a frequently used model describes three compartments: the cerebrospinal fluid (CSF) containing ventricular volume (VV), brain parenchymal volume (BPV) and the extra-axial volume (EAV) containing both CSF and vascular structures. These three volumes summated constitute the total intracranial volume (TICV). It is now possible to acquire data in individual fetuses using ultrafast three-dimensional (3D) MR imaging [
9‐
13] that permits the volume of these compartments to be measured after post-processing. This development could be important for accurate diagnosis because different types of fetal neuropathology are expected to affect the compartments in different ways. The first stage in this process is to describe normality.
In this paper, we provide normative MR data for linear head measurements and for the volumes of the intracranial compartments for second and third trimester fetuses between 18 and 37 gestational weeks (gw).
Discussion
We have presented normative data of the skull and intracranial contents from a large cohort (
n = 200) of control fetuses and individualised data on the intracranial and compartmental volumes between 18 and 37gw. Our approach to measuring intracranial volumes utilises 3D volume MR data with good anatomical resolution and good tissue contrast between CSF and brain. The images are manually segmented, which is time intensive. The recent development of automated methods makes the routine measurement of fetal brain volumes a realistic possibility in clinical practice, enabling the estimation of volumes in shorter time scales with minimal user input [
21‐
24]. However, these methods are guided by templates that require a priori knowledge of normality and have yet to be applied when the normal structure of the brain parenchyma is altered by a pathological process.
Ideally, a study such as this would be supported by comparison with actual, known values but this is not possible when the target is a normal fetus in utero. We were also unable to formally compare our data to that of other MR studies as data is rarely presented in tabulated format [
25‐
27], or the anatomical boundaries for measurements differ [
25,
28,
29] alternatively data is limited to a narrow gestational age range [
25,
26,
30]. However, estimations of data from the graphs presented by Tilea et al [
4], Kyriakopoulou et al [
6] and Conte [
7] do indicate similar values for BPD and OFD. Review of the results from studies by Kyriakopoulou et al [
6] and Gholipour et al [
31] also appear to show a good match to our volumetric data.
We were unable to do a within-fetus comparison of USS and MR measurements of BPD or OFD as the time elapse between USS and MR imaging was too long. We have, however, compared our results of BPD and OFD with published results using USS [
1] specifically skull measurements made the same way as our method (outer table to outer table of the skull). There was exceptional correlation between the two techniques although there was a tendency for iuMR to measure slightly larger BPD (mean difference 2.36 mm) and smaller OFD (mean difference − 1.49 mm) when compared with USS. We have not been able to compare our intracranial compartmental volume results with data from USS because such data does not exist.
There are anatomical, pathophysiological and neuroimaging advantages to considering the intra-cranial contents as a number of separate compartments distinguished by their contents—brain tissue and CSF. The CSF-containing structures are usefully ascribed to either the ventricular or the extra-axial CSF compartment, both of which are in continuity via the foramina of Magendie and Luschka of the fourth ventricle. The extra-axial CSF compartment, specifically the sub-arachnoid space, also contains some of the larger intracranial vascular structures, although it is usually impossible to differentiate the vascular component from the larger CSF-containing parts on iuMR imaging so they are measured together, unless abnormal. In this paper, we describe three definable and measurable intracranial compartments (VV, BPV and EAV), which, when summated, constitute the TICV.
The TICV and skull dimensions in older children and adults are fixed at any time point because of the rigid nature of the skull after fusion of the fontanelles and cranial sutures. In that situation, the Monroe-Kellie doctrine [
32] explains that an increase in volume in one sub-compartment must be accommodated by reductions in the volume of the other sub-compartments or produce raised intracranial pressure. Alternatively, loss of volume from one compartment in an adult must be accompanied by increased volume in one or both of the other compartments or result in reduced intracranial pressure. The situation in the fetus is different because the bones of the calvarium are unfused. This introduces compliance into the system so that increase in volume of intracranial compartment(s) can occur without raising intracranial pressure (within limits). For example, increased pressure and volume of the cerebral ventricles (hydrocephalus) is likely to cause increased TICV and skull dimensions. Using the reverse argument, it is predicted that interference with growth of the fetal brain (a destructive process for example) or reduction in CSF pressure are likely to result in a reduced skull size/TICV when compared to chronologically matched controls.
For these reasons, measurement of skull size is an integral part of the USS assessment of the fetus as any major deviation from normative values on a single study, or a substantial change in the skull size on serial studies, may indicate brain pathology. From the preceding discussion, however, it becomes obvious that that argument is too simplistic because the brain is not the only intracranial structure. A fetus with microcephaly is highly likely to have a small brain, by necessity, but it is not true that a fetus with skull dimensions in the normal range must have a normal sized brain. A disproportionately small brain, in relation to skull size, is known as micrencephaly and often indicates acquired brain pathology. Reduced brain volume is usually accompanied by increased CSF volume, either VV and/or EAV, which maintains the skull dimensions. This distinction is often difficult to make on USS because of poor visualisation of the EAV in particular and is one of the major theoretical advantages of iuMR imaging.
Knowledge of the volumes of the intracranial sub-compartments may assist the differential diagnosis provided by visual assessment of iuMR studies but the methods are still exploratory and formal studies are required to determine the clinical utility of the information provided by volumetric data. The potential of the technique however is shown in the case studies presented in the
online supplemental material.
A major strength of this study is the inclusion of 200 fetuses across a wide gestational age range with a minimum of six fetuses for nearly all ages. This has enabled the reliable calculation of centiles for intracranial volumes for gestations 19–36 weeks. Values for 18 and 37 weeks were excluded for the calculation of centiles because we had limited numbers of measurements at these gestations (4 and 3 respectively). The prospective study design and stringent inclusion criteria also allowed a high degree of certainty that the fetuses included were normal. Additionally, fetuses with a family history of abnormalities were also excluded. This is in contrast to other studies whose normative data is derived from fetuses who were either referred for MR imaging due to siblings with abnormalities, had suspected brain abnormality on USS that were subsequently excluded on MR imaging or have a normal brain examination but an abnormality affecting another anatomical area [
6,
13,
30]. These cannot be considered a truly normal population, although one study [
6] carried out postnatal assessments of the children studied to confirm the data reported was drawn from a normal population. A limitation of this study is that we did not have postnatal imaging or neurodevelopment outcomes for any of the children who had been studied as normal fetuses are not routinely assessed postnatally in the UK. However, previous research has shown that the false positive and false negative rate for detecting abnormalities by prenatal MR is very low [
14]. In future studies, we intend to correlate the results with an assessment of outcome. This will also allow comparisons of male and female populations.
A further limitation of our method is the time required for manual segmentation (between 2 and 6 h) which restricts its application routinely in clinical practice. Whilst there has been a great deal of effort to develop automated segmentation methods by several groups [
13,
22‐
26,
28,
33] user input is required to increase precision and there has yet to be a proven clinical utility.
In summary, we have described normative values for a range of cranial and intracranial dimensions in control fetuses between 18 and 37gw. We stress, however, that the software used for creating the 3D datasets (3D Slicer) does not have CE-marking and cannot be used as a clinical tool at present.
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