Fetal Brain Growth in the Early Second Trimester

DISCUSSION

Advancements in MR imaging technology have expanded the clinical applications of fetal MR imaging, enabling the acquisition of diagnostic images in the early second trimester. This study aimed to address the scarcity of data on in vivo fetal brain development in pregnancies between the 12th and 20th weeks' GA by performing a retrospective analysis of brain growth in subjects whose subsequent neuroradiologic studies confirmed normality. Our results demonstrate rapid growth of all intracranial structures with distinct trajectories for individual regions. Awareness of normative and relative volumetry of structures can inform the interpretation of fetal MRIs and contribute to understanding the selective vulnerability and physiopathology of abnormalities that could arise at these early developmental stages.

Most MR imaging literature pertaining to fetal brain development in the early second trimester is based on ex vivo studies.^{10⇓⇓⇓-14} The absolute volumetric estimates for the cerebellum and total brain volume from our study align with those reported by Zhan et al¹⁰ and Xu et al.¹¹ The analysis performed by Zhan et al used submillimeter acquisitions at 7T in conjunction with atlasing techniques. In addition to having similar growth trajectories, their approach enabled them to identify a clear anterior-to-posterior gradient in these developmental changes.¹⁰ Xu et al also used submillimeter acquisitions at 7T to study cerebellar growth, and while the trends they reported are consistent with our observations, their work delved deeper into the regional patterns of individual cerebellar lobules.¹¹ Most important, our study is the only one that has addressed these challenges using in vivo MR imaging, demonstrating the feasibility of this approach and facilitating translation. Furthermore, the use of in vivo data minimizes the effects of biases related to tissue damage, swelling, and tissue preparation that are inherent in ex vivo analyses.¹⁵

The supratentorial brain was the dominant compartment, and it also displayed the highest growth rate. At 12 weeks, it constituted about one-third of the intracranial volume, which increased to nearly one-half by the 19 weeks. Active neuronal proliferation and migration, the formation of the subplate, and the rapid expansion of the latter likely drive this exuberant growth.¹⁶ As these processes halt or slow down, growth does the same, leading to a more modest growth rate reported later in pregnancy by Machado-Rivas et al.⁷ Despite moderately high rates of growth, the brainstem and cerebellum were outpaced by the supratentorial brain, which resulted in a slight decrease in their relative percentage of intracranial volume between the 12th and 19th weeks. At later GAs, the rate of growth of the supratentorial brain decreases and the cerebellum becomes the fastest-growing compartment.^7,17

The ventricles constitute a dominant structure in early pregnancy, accounting for nearly one-quarter of intracranial volume at 12 weeks. Ventricular growth is slow, a finding previously corroborated by sonography and fetal MR imaging studies across a wide range of GAs.^7,18 It is crucial to note that this slow growth results in a substantial decrease in the proportion of intracranial volume of the ventricles with advancing GA. The expansion of the extra-axial CSF emerged as another key finding in our analysis. Its growth rate was second only to that of the supratentorial parenchyma, reaching almost 40% of intracranial volume by 19 weeks' GA. The role of the extra-axial CSF as a marker of normal neurologic development is often underestimated. For instance, an increase in volume has been reported in cases of congenital heart disease, and a reduced volume is a hallmark of open neural tube defects.^19,20

Fetal neuroimaging in pregnancies of <20 weeks' GA, though uncommon, is an area of increasing interest. The desire to counsel families as early as possible, monitor vulnerable pregnancies, and triage patients for a growing number of fetal interventions has fueled this trend. One relatively common indication in our cohort was the characterization of abdominal wall defects. While not the primary malformation, the neurologic well-being of these fetuses is a pivotal point in counseling because multiorgan system malformations necessitate specialized counseling, particularly in regard to the potential for genetic or syndromic etiologies. Monochorionic diamniotic twins represent another vulnerable population; these fetuses are at risk of unbalanced vascular and placental sharing (eg, twin-twin transfusion syndrome) and resultant complications, have a high risk of cerebrovascular events, and frequently are eligible for fetoscopic interventions.^16,21 Last, sociopolitical factors, such as the evolving legal landscape surrounding pregnancy termination, could serve as an incentive to image fetuses at an earlier GA to provide prognostic information. The availability of normative volumetric data can enhance the interpretation of imaging findings in these early pregnancies.

The limitations of this study include its retrospective nature, which may introduce bias, and the relatively small sample size of 31 subjects. The exclusion of 20 subjects due to low image quality underscores the challenges of acquiring high-quality images during the early second trimester. The segmentations used for analysis were based on 2D images rather than 3D reconstructed volumes. Although previous work has pioneered the use of super-resolved 3D volumes for fetal images, these tools are not available for the GA range analyzed in this study. Consequently, the reported volumes of structures in the fetal brain might be underestimated or overestimated compared with a 3D volume estimation. Future studies with larger sample sizes, prospective designs, and improved image analysis pipelines may help refine and expand the normative data generated in this study.