Interpretation
On postnatal imaging, Danzer et al. reported a lower total maturation score in CDH infants after birth (6). Along the same lines, Lucignani et al reported reduced cortical maturation in extended brain areas of CDH newborns compared to healthy controls. 25 In earlier studies based on prenatal images, fetuses with CDH had brain sulcation scores, which are indicators of prenatal brain maturation, within the normal range between 20 and 37 weeks.8, 26One study on infants who had both pre- and postnatal imaging, reported signs of brain injury (e.g. hemorrhage, white matter injury, …) on postnatal, but not on prenatal MRI . In that study , the injury score correlated with the degree of pulmonary hypoplasia, evidenced by the o/e TFLV.26 Also, there was no indication of delayed sulcation in the prenatal period in those fetuses.
Conversely, this study demonstrates that CDH fetuses have indications of atypical brain development, i.e. there was a significant delay at 28 weeks and 33 weeks of gestation. By 33 weeks the quantitative scores were in the normal range. However, quantitative scoring was performed on primary and not on secondary sulci, limiting the detection of subtle folding abnormalities. 27 The qualitativescoring system we used, allows for a thorough scoring of brain sulcation throughout a wide GA range, as it evaluates the primary formation as well as the presence of secondary and tertiary sulcation.15 We were not (yet) able to compare our morphologic findings with postnatal clinical neurobehavioral assessment. In CDH infants, 9% (4-14%) have abnormal opercularization, which translates later into language and speech abnormalities.28 In our study, grading of the operculum was significantly lower at the first time point as well as at the second time point, although only left-sided. This may, at least in theory, have functional consequences: in earlier studies scores using the same system correlated well with the Neonatal behavioral Assessment Scale 29, albeit this was in fetuses with isolated non-severe ventriculomegaly or with late-onset growth restriction. (15, 23) On the other hand, one must take into account that any abnormality observed postnatally may as well have been acquired after birth.
The significant increase in volume of all fluid compartments at 33 weeks of gestation in CDH we observed, is in line with work of Radhakishnan et al. who reported enlarged extra-axial spaces in the third trimester.8 Because fetuses had normal biometry of the cerebral hemispheres and lacked major parenchymal abnormalities, the authors questioned the clinical relevance of these findings.(7) One other study has reported lower cognitive scores and lesser language skills in children with larger extra-axial spaces. (6)
Irrespective of the functional impact, what would cause atypical brain folding as we observed in CDH fetuses, remains unclear. One factor may be a degree of hemodynamic dysfunction. We have previously reported a decline in the middle cerebral artery peak systolic velocity, hence in brain perfusion in fetuses with CDH .5, 30 One may recognize similarities with circulatory disturbances in fetuses with congenital heart defects, which coincide with signs of abnormal brain development. In hypoplastic left heart syndrome (HLHS) a lower blood flow velocity has been associated with lower brain volume.31, 32 Furthermore, fetuses with HLHS and other congenital heart defects display delayed brain maturation in the late second and early third trimester, and again, this has been linked to abnormal hemodynamics and oxygen delivery.33 Lucigagni et al based actually support this theory to explain their recent findings of altered cortical maturation in CDH newborns.25
Abnormal extra-axial and intraventricular fluid volumes have been previously explained by a change in cardiac output in CDH caused by herniation of abdominal structures in turn leading to mild or moderate cardiac hypoplasia in left-sided CDH.34 Also cardiac compression may compromise venous return. 2634 This may in turn cause venous congestion and lead to decreased CSF resorption, 35 and an overall increase of intracranial fluid. It may be useful to assess cardiac function and hemodynamics in more detail in fetuses with CDH to study whether there is a link with brain development.