The Next Frontier in Neurology Is In Utero

Advances in prenatal neuroimaging and genetic testing have resulted in an increased need for specialized fetal neurologic counseling and care. The clinical context of fetal neurologic consultation is unique in that (1) embryonic and fetal brain development occurs alonga temporal spectrum prone to a variety of trimester-specific genetic and environmental risk factors; (2) without access to the neurological examination or electroencephalography in utero, neurologic prognostication is based substantially on imaging and genetic testing when available; and (3) counseling synthesizes diagnostic and prognostic information for 2 patients (the pregnant individual and the fetus) throughout pregnancy, perinatal management, and postnatal care. As the field evolves, a gap is emerging wherein severe neurogeneticand neurometabolic disorders can be diagnosed earlier and more frequently while therapeutic tools remain limited. Experimental strategies are nonetheless quickly advancing to stem disease progression before birth. Given the magnitude of macroanatomic and microstructural brain development that occurs antenatally, in utero therapeutic intervention will soon transform neurology and change neurodevelopmental trajectories. However, ethical concern for access, safety, and social inclusion must be front and center for human trials of these revolutionary fetal therapies.

Improved diagnostic accuracy for severe fetal neurogenetic conditions places more onus on both clinicians and patients toseekearly identification and intervention. Noninvasive prenatal screening in the first trimester can detect fetal aneuploidies and parental carrier status for inherited conditions and can be performed well before structural anomalies are seen on the routine second trimester ultrasonography.¹ Amniocentesis, conducted after 16 weeks, remains the most reliable diagnostictool to test fetal cells with karyotype, chromosomal microarray, and increasingly, whole-exome and whole-genome sequencing.² Early identification of neurogenetic disorders based on fetal magnetic resonance imagingis also increasingly common. Often prompted by an abnormality on ultrasonography, fetal brain magnetic resonance imaging provides higher-resolution detail of the developing brain (eg, clarifying the degree of fetal cerebral gyrification and identifying evolving cortical malformations like polymicrogyria), helping inform diagnosis and prognosis, as well as guide etiologic workup and interpretation of genetic testing.³ With the use of advanced imaging modalities such as resting state connectivity, it will soon be possible to move beyond purely structural anatomic assessments to functional evaluation of circuit development. Multicenter collaboration is needed to better characterize the spectra of fetal presentations of numerous neurogenetic and metabolic disorders and the relationship between prenatal imagingfindings and postnatal outcomes across conditions.

With the expansion of large-scale research collaborations to refine diagnostic and prognostic accuracy, advancements in prenatal testing must balance technical capabilities with equitable implementation and data protections. Emphasis on earlier detection via genomic sequencing means a greater burden of incidental findings, increased pressure for timely results, and the possibility of unintentionally uncovering disease-risk variants that could erode protections against life insurance penalties.⁴ Given inequitable access to prenatal and follow-up health care in the United States, clinicians should be transparent about financial costs of expensive genetic testing that is not always covered by insurance as well as discrimination that may ensue for families whose genetic information would be more readily accessible. Further, the burden of uncertainty around prognosis for pathogenic variants and variants of uncertain clinical significance, especiallyfor groups underrepresented in genomic research, and the interplay of environmental or social factors that shape outcomes must also be considered.^4,5

Foreshadowing future possibilities, outcomes may soon be transformed by several cutting-edge second- and third-trimester in utero therapies in the research pipeline, adding to an arsenal that already includes in uterosurgical repairof myelomeningocele.⁶ In utero enzyme replacement therapy has been successfully used to prevent neurological deterioration of 2 human fetuses with Pompe disease.⁷ The first case of successful in utero embolization of vein of Galen malformation was recently reported.⁸ Additional experimental strategies are accumulating preclinical evidence, including intraamniotic stem cell therapy, which typically involves infusions of autologous amniotic fluid mesenchymal stem cells. Subtle efficacy is apparent in rodent models of neural tube defects, and exploration is underway for applying this technology more broadly in other fetal disorders.⁹ Donor cell options may also include heterologous donors, genetic manipulation of donor cells, and application of tissue specific multipotent cells. Similarly, in utero gene therapy for conditions like spinal muscular atrophy is on the horizon, whether through CRISPR-mediated gene editing, transgene delivery, or transient RNA-based cell- and tissue-specific manipulation. The unique profile of maternal-fetal physiology and the intrauterine milieu may be particularly amenable to gene therapy strategies, given the smaller fetal biomass, higher abundance of tissue progenitors, higher permeability of the blood-brain barrier for neural-directed therapies, and relative immune tolerance for heterologous cells and viral delivery mechanisms.⁹

As research and clinical implementation of fetal therapies evolve, so too must evaluations of safety, efficacy, and optimal therapeutic delivery tominimize toxic and off-target effects for pregnant persons and their fetuses under necessarily higher regulatory and ethical standards. Weighing benefits and risks to each therapeutic strategy, such as fetal intracranial injections of viral vectors, is not just a clinical endeavor; directly engaging the experiences of families participating in in utero clinical trials across various personal, social, and legal contexts will be crucial to understanding and counselling about acceptability of risks associated with each intervention. The potential for germline transduction is one of many longer-term concerns that may conflict with immediate patient priorities in the prenatal period.

Ultimately, expanding neurological management to the prenatal period could vastly improve outcomes, especially if the benefits are desirable and accessible to those who are currently underserved by prenatal and pediatric health care. Experimental in utero therapies to treat genetic neurodevelopmental disorders during critical periods of fetal neurogenesis aim to reduce postnatal treatment burdens for families and health care payers. However, given that prenatal care is already hindered by variable access, it is imperative that prenatal neurological therapeutic trials and treatments do not become a coercive option for pregnant persons. Without access to the full range of choices—continuing the pregnancy uninterrupted, opting for termination, or opting for experimental therapy—families are not in a position to be fully informed, weigh the entire spectrum of risks and benefits, or consent to fetal therapy The social power dynamics between clinicians and families should also reflect trustworthy and respectful care to maximize patient autonomy over decision-making. Moreover, past experience with experimental pediatric neurological therapies highlight the need to improve access, efficiently and transparently share data on emergent outcomes, and ensure direct clinician-patient engagement with social values around disability and identity.¹⁰

Fetal neurologists will play a fundamental role in participant/patient selection, family counseling, integration of risk/benefit analysis and equity considerations, and short- and long-term monitoring of neurodevelopmental outcomes of fetal therapies. The offering of in utero operative procedures, enzyme replacement therapy, stem cell delivery, and gene therapy represent the vanguard of treatment for congenital neurological disorders. On the precipice of this paradigm shift toward fetal therapies, the next frontier in neurology is before birth, demanding continued commitment to innovation and ethical care.