The science of uncertainty guides fetal-neonatal neurology principles and practice: diagnostic-prognostic opportunities and challenges

Abstract

Fetal-neonatal neurologists (FNNs) consider diagnostic, therapeutic, and prognostic decisions strengthened by interdisciplinary collaborations. Bio-social perspectives of the woman's health influence evaluations of maternal-placental-fetal (MPF) triad, neonate, and child. A dual cognitive process integrates "fast thinking-slow thinking" to reach shared decisions that minimize bias and maintain trust. Assessing the science of uncertainty with uncertainties in science improves diagnostic choices across the developmental-aging continuum. Three case vignettes highlight challenges that illustrate this approach. The first maternal-fetal dyad involved a woman who had been recommended to terminate her pregnancy based on an incorrect diagnosis of an encephalocele. A meningocele was subsequently identified when she sought a second opinion with normal outcome for her child. The second vignette involved two pregnancies during which fetal cardiac rhabdomyoma was identified, suggesting tuberous sclerosis complex (TSC). One woman sought an out-of-state termination without confirmation using fetal brain MRI or postmortem examination. The second woman requested pregnancy care with postnatal evaluations. Her adult child experiences challenges associated with TSC sequelae. The third vignette involved a prenatal diagnosis of an open neural tube defect with arthrogryposis multiplex congenita. The family requested prenatal surgical closure of the defect at another institution at their personal expense despite receiving a grave prognosis. The subsequent Management of Myelomeningocele Study (MOMS) would not have recommended this procedure. Their adult child requires medical care for global developmental delay, intractable epilepsy, and autism. These three evaluations involved uncertainties requiring shared clinical decisions among all stakeholders. Falsely negative or misleading positive interpretation of results reduced chances for optimal outcomes. FNN diagnostic skills require an understanding of dynamic gene-environment interactions affecting reproductive followed by pregnancy exposomes that influence the MPF triad health with fetal neuroplasticity consequences. Toxic stressor interplay can impair the neural exposome, expressed as anomalous and/or destructive fetal brain lesions. Functional improvements or permanent sequelae may be expressed across the lifespan. Equitable and compassionate healthcare for women and families require shared decisions that preserve pregnancy health, guided by person-specific racial-ethnic, religious, and bio-social perspectives. Applying developmental origins theory to neurologic principles and practice supports a brain health capital strategy for all persons across each generation.

Keywords: fetal-neonatal neurology; gene-environment interactions; maternal-placental-fetal triad; neural exposome; science of uncertainty; shared clinical decisions prevailing family values diagnostic; social determinants of health; therapeutic.

Figure 1

Functional approach to study the exposome across the lifespan: A top-down approach uses molecular epidemiology studies focused on biologic response profiles with xenobiotic exposures using “omics” technologies on host biospecimens. This approach generates hypotheses regarding exposure-disease and exposure-response relationships without necessarily capturing direct measures of exposure. Applying the bottom-up approach, comprehensive data on environmental exposures are collected through surveys, sensors, or trace chemical analyses of biospecimens to generate hypotheses on effects without necessarily investigating a specific effect. A functional exposomics study bridges these two approaches, comprised of the biologically active exposures to the individual and with specific evaluations to assess associations between environmental exposures and biological effects as a function of advancing age (81).

Figure 2

Prenatal adverse exposures to the maternal-placental-fetal triad such as maternal stress, drug use, exposure to environmental toxins, and hypoxia, among other disease pathways more likely collectively influence long-term neurologic structure and function. Current research suggests that three prominent placental disease mechanisms, maternal immune activation, ischemic placental syndrome, and the fetal inflammatory response mediate the relationships between exposures and effects on the fetal brain with long-term abnormal neurologic outcomes (61).

Figure 3

Schematic diagram summarizing structural and functional changes in the in vivo fetal brain associated with prenatal exposures. Quantitative neuroimaging modalities depicted utilize volumetric, spectroscopic, and connectivity modalities to depict altered fetal brain. Examples of toxic stressor interplay based on multiple research studies are cited in this review (61). Examples include the following: (A) drugs, (B) environmental toxins, (C) maternal infection, (D) maternal overweight or malnutrition, (E) placental insufficiency, (F) hypoxia, and (G) maternal stress. AP, anteroposterior; B, bilateral; BOLD, blood oxygen level-dependent; CAL, calcarine; CGM, cortical gray matter; CHD, congenital. Heart disease; Cho, choline; Cr, creatine; CMV, cytomegalovirus; COL, collateral; CRB, cerebellum; DGM, deep gray matter; DM, diabetes mellitus; fc, functional connectivity; FGR, fetal growth restriction; fMRI, functional magnetic resonance imaging; FRO, frontal; GA, gestational age; GM, gray matter; HIP, hippocampus; HLHS, hypoplastic left heart syndrome; INS, insula; L, left; NAA, N-acetylaspartate; OCC, occipital; PAR, parietal; PCC, posterior cingulate cortex; PFC, prefrontal cortex; SES, socioeconomic status; SMG, supramarginal gyrus; SVP, single-ventricle physiology; TBV, total brain volume; TEMP, temporal; TGA, transposition of the great arteries; WM, white matter.

Figure 4

This figure provides the definition of a brain health capital strategy, as well as explanations of three sub-components that comprise brain capital, i.e., brain health, brain economy, and brain skills (42).