What can fetal neurosonography reveal about the future of an unborn child?

Clinically apparent birth defects affect 3–4 % of all live births and are responsible for 20 % of infant deaths [1]. Furthermore, slight structural anomalies of the central nervous system (CNS) that are present at birth may only lead to a noticeable delay in neurological development after several years. Since congenital malformations can be attributed to various genetic and non-genetic causes, both imaging techniques and genetic analysis methods are important for prenatal diagnosis. Prenatal neurosonography is currently the method of choice when malformations of the fetal CNS are suspected, with MRI only being used as a secondary method with precise indications [2] [3]. Advances in ultrasound technology and specifically, the transvaginal approach, have greatly improved image resolution and now allow detailed visualization of fetal anatomy as early as the first trimester of pregnancy. 3 D/4 D ultrasound and, more recently, integrated uses of artificial intelligence (AI) were introduced to enhance the diagnostic yield of fetal neurosonography [4] [5] [6] [7] [8] [9] [10]. Meanwhile even the AI-supported sonographic analysis of fetal behavior is being discussed for the detection of early neurodevelopmental irregularities [11]. In many countries around the world, pregnant women have access to basic and advanced ultrasound examinations from the first trimester onwards, including assessment of fetal brain development and detection of abnormalities [3] [12] [13] [14]. If necessary, targeted fetal neurosonography can be performed by specialized experts, which includes a more detailed assessment of abnormal findings, e. g., searching for malformations of the cerebral cortex, diagnosing defects of the corpus callosum, and thoroughly characterizing open spinal dysraphism [4] [15] [16] [17]. In the event of abnormal findings, it is the responsibility of the attending physician to advise the parents. This often includes recommending MRI and genetic testing in order to increase diagnostic certainty and, if necessary, offer appropriate treatment [12] [13] [18] [19].

In many European countries, abortion after the first trimester is restricted to cases where there are severe, untreatable malformations/diseases of the fetus affecting central organs such as the brain (e. g., encephalocele) and associated with severely limited viability or extreme suffering. This underscores the relevance of prenatal ultrasound examinations in the first trimester, as pregnant women in these countries can more easily terminate their pregnancies during this period in accordance with legal provisions. The increase in the number and quality of prenatal ultrasound examinations over the past 2 decades has not led to a rise in the overall number of abortions in Germany [20]. However, a possible increase in selective abortions, for example as a result of conspicuous findings in fetal ultrasound, is hardly visible in the official statistics. A recent retrospective Austrian study found an increase of the number of abortions with and without feticide due to fetal structural anomalies at a single tertiary care referral center between 2007 and 2020 [18]. The most significant structural malformations leading to termination of pregnancy were brain abnormalities and spinal dysraphism, which were diagnosed at a median gestational age of approximately 21 weeks [18] [21], accounting for up to 43 % of legal abortions [18] [22] [23] [24]. On the other hand, there are reports of abortions even in cases of mild anomalies, such as isolated malformations of cortical development (MCD), partial agenesis of corpus callosum, or isolated vermis hypoplasia [25] [26] [27] [28], which may underscore the role of expectant parental fears regarding the prospect of even mild neurological developmental disorders in their child [29]. Furthermore, the possibility of false-positive or overinterpreted ultrasound findings must be taken into account in this context [22] [26] [30], even though these can usually be corrected by subsequent neurosonography and/or MRI examination. Future developments could counteract a trend toward abortion, especially in cases with minor abnormal neurosonographic findings ([Table 1]) [25] [26] [27] [28] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42].

Table 1 New developments and requirements for reducing the frequency of abortions in cases of abnormal fetal neurosonographic findings.

Developments/demands	Exemplary US findings	References
Improved knowledge of long-term neurological outcomes for certain abnormal findings	Isolated vermal hypoplasia	[27]
	Isolated malformation of cortical development	[26]
	Partial agenesis of corpus callosum	[25]
	Focal brain lesion/dysgenesis	[31]
	Intracranial hemorrhage	[32] [33]
Improved prenatal surgical therapy	Spinal dysraphism	[34]
	Hydrocephalus1	[35]
Improved understanding of the relationship between exome/genome sequencing results and neurological development	Ventriculomegaly	[36]
	Malformation of cortical development	[28]
	Agenesis of corpus callosum	[37]
Novel gene therapies2	Tuberous sclerosis	[38] [39] [40]
Optimal early rehabilitation, support, inclusion, and care through specialized centers	Spinal dysraphism with or without brain alteration	[41] [42]

¹ Direct fetal surgery specifically targeting isolated hydrocephalus is currently not recommended due to limited evidence and potential procedural risks (unlike fetal surgery for spinal dysraphism)
² Prenatal gene therapies are currently not available for diseases of the central nervous system

In particular, a well-founded database on the long-term prognosis of defined fetal CNS anomalies, either in isolation or in combination with other organ changes and genetic findings, is crucial for providing sound advice to expectant parents. Currently, the evidence base for the prognosis remains limited, especially in cases of mild to moderate changes in the fetal CNS, and the prognosis given to parents is mainly extrapolated from postnatal cohorts. However, the results of a recent systematic review of the currently small database show that approximately one-third of live-born children diagnosed with fetal MCD had normal neurological development or mild neurological developmental delay [26]. The risk and severity of associated epilepsy depend on the degree of malformation: isolated focal MCDs may cause well-treatable focal epilepsy in adolescents who otherwise show age-appropriate development, in contrast to multifocal or diffuse MCDs, which are more commonly associated with refractory epilepsy from infancy onwards [43]. In a small study of isolated cerebellar vermis hypoplasia, the results tended to be good, with normal, age-appropriate neurological development or minimal deficits in the majority of patients, especially when no genetic abnormalities were detected [27]. Also for fetal mild ventriculomegaly, there is a scarcity of long-term investigations that specifically examine minor neurodevelopmental abnormalities, such as attention deficit disorders, behavioral problems, and learning disabilities. A review of published studies showed normal neurodevelopmental outcomes reported in the majority of cases, and approximately 10 % of cases that developed a mild or severe form of neurodevelopmental impairment [44]. In isolated mild ventriculomegaly cases after a thorough ultrasound assessment, the rate of chromosomal or other genetic anomalies appeared to be very low (< 5 %). Even among surviving children with a prenatal diagnosis of apparently isolated severe ventriculomegaly, a meta-analysis found that 40 % of cases were without disability, although longer follow-up studies are needed to identify subtle anomalies and the prevalence of developmental delays [45]. Isolated periventricular pseudocysts (PVPC) were reported with normal neurological outcomes in nearly all cases [46]. To detect associated intracranial anomalies that may be missed on dedicated neurosonography, MRI is recommended; white matter abnormalities on MRI account for the majority of additional anomalies, and the neurodevelopmental outcomes of non-isolated PVPC fetuses depend on the accompanying anomaly [46]. Similarly, fetuses with isolated corpus callosum agenesis (CCA) have a better prognosis than those with additional anomalies. In a recent review of studies involving 217 fetuses with isolated CCA and no other abnormalities detected during prenatal examination, neurological development was favorable in two-thirds of cases, but disabilities occurred in a minority [46]. In particular, it was discussed that disabilities can also occur after school age and that the risk of severe cognitive impairments remains low [47].

Also the finding of fetal brain abnormalities caused by intracranial hemorrhage (ICH) leads in a relevant proportion of cases to termination of pregnancy [32] [48]. Fetuses with ICH who are born alive appear to suffer from cerebral palsy in almost one-third of cases, and in almost one-third of cases there is also severe neurological developmental delay, while 54 % of fetuses were found to have normal neurological development [32]. Recent reviews confirm the current view that the frequency of cerebral palsy and severe neurological developmental delays depends on the location and size of the hemorrhage, with the comparatively highest frequency of unfavorable outcomes occurring in supratentorial intraparenchymal hemorrhages and complicated intraventricular hemorrhages (IVH) [32] [48]. In turn, a normal (short-term) outcome was reported in 100 % of cases with small (grade I or grade II) supratentorial IVH in a meta-analysis [32], and a favorable outcome according to the Pediatric Stroke Outcome Measure (normal to moderate deficits but no loss of functions) was found in 100 % of cases with small (grade I or grade II) supratentorial IVH in a prospective, single-center observational study with follow-up at a median age of 3 years 8 months [48]. However, it should be noted that the number of cases in these studies is very small and that large-scale, ideally multicenter studies are needed to further investigate the predictive value of neurosonographic (and MRI) findings. Assessing the severity and location of the ICH, if possible using complementary fetal MRI, is important for pregnancy management, especially in countries where abortions are permitted beyond 24 weeks of gestation [32]. Genetic analysis may also be considered. On the other hand, there is a need for further validation of the indicators for a likely favorable outcome.

These examples illustrate the need for comprehensive databases containing detailed information on long-term outcomes. This could not only improve counseling for expectant parents, but also enable the targeted provision of early support, rehabilitation, and specialized care. Such an enhanced approach could make it easier for expectant parents to decide to continue with the pregnancy, even if their child is likely to have mild to moderate neurological developmental delays.

The current issue of Ultraschall in der Medizin contains articles that contribute to understanding in this field. Gottschalk et al. (in this issue) provide a comprehensive overview of intrauterine therapies resulting from fetal ultrasound diagnostics in their CME article [49]. This article also outlines the cornerstones of ultrasound diagnostics and prenatal surgery for open spinal dysraphism. The prenatal diagnosis and surgery of fetuses with myelomeningocele is an excellent example of the advances in prenatal medicine that significantly improve the neurological outcomes of these children [41] [50]. Chen et al. (in this issue) report on the relationship between prenatal neurosonography and genetic findings obtained with chromosomal microarray and trio (fetal and parental) exome sequencing in fetal MCD [28]. In particular, they could demonstrate that the most relevant ultrasound signs indicating a genetic cause were premature or aberrant appearance of sulcation, abnormal development of the Sylvian fissure, delayed achievement of cortical milestones, and intraparenchymal echogenic nodules. Sgayer et al. (in this issue) conducted a systematic review of studies on the outcomes of pregnancies with fetal cerebral lateral ventricle asymmetry without dilation [51]. The review highlights that in approximately 40 % of these cases a progression to ventriculomegaly is detected at follow-up investigation. These children had no apparent developmental delay during the first year of life, however, in subsequent years of age lower writing speed was observed. Rüegg et al. (in this issue) propose the systolic M-sign in the middle cerebral artery Doppler waveform as a novel, additional marker of cardiovascular imbalance indicating twin-to-twin transfusion syndrome [52]. Bronshtein et al. (in this issue) report the ultrasonic detection of premature fetal linear vertebral calcification, a finding requiring differentiation from congenital vertebral malformation [53].

Given the advantage of biological safety of ultrasound for fetal imaging provided its use according to the guidelines [54] [55] [56], it will remain the mainstay of prenatal imaging. It is likely that the evolving knowledge about the complex relationship between the fetal genome, the structure of the CNS depicted in ultrasound, the plasticity of the CNS, and the neurodevelopmental outcome will facilitate AI-supported individualized counseling in the near future.

Prof. Dr. med. Uwe Walter, M.D., FEAN

Conflict of Interest

The author declares that he has no conflict of interest.

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Publikationsverlauf

Artikel online veröffentlicht:
06. Oktober 2025