The Biomarkers of Neurological Disease in Utero Study

BACKGROUND There are approximately 50 million people with epilepsy worldwide, with approximately 3-5 births per thousand to women with epilepsy; in the United Kingdom (UK) there are 2500 births per year to women with epilepsy. The teratogenic effects of anti-epileptic drugs (AEDs) on the fetus is a major public health concern. In 2016 UK national prescribing data showed around 18,000 women of child-bearing age were taking Sodium Valproate. for which current evidence suggests has the most potent teratogenic effects of all AEDs. The Medicines and Healthcare Products Regulatory Agency (MHRA) has formulated a specific prevention programme aimed at reducing the rates of valproate-associated teratogenicity. Longitudinal studies of fetal AED exposure show increased rates of congenital malformations, abnormal motor development, lower intelligence quotient, and poorer educational attainment. However, to date there is a major lack of research on the underlying neuroanatomical basis for such alterations in cognitive function, whether pre or post-natal.

Early exposure to neuromodulatory drugs likely induces abnormalities in structural brain development, neuromotor behaviour, and functional networks. Fetal MRI presents a novel multimodal approach for interrogating the effects of pathological exposures, identify biomarkers, define onset of abnormalities, and the dose response. This may aiding risk stratification, identify candidates for earlier intervention, and improve neurodevelopmental outcomes.

There are limited strategies available to the clinician to assess the risk to the fetus' brain health. Current guidance recommends Ultrasound Scan (USS) to screen for physical defects. However, USS is limited in its ability to comprehensively understand brain development. Fetal MRI presents an advance that is of clinical utility to neurologists, psychiatrists and obstetricians who routinely prescribe AEDs for a range of neurobiological conditions. Advances in fetal MRI have identified biomarkers for disease that may guide clinical management, and offers the potential of a multi-dimensional characterisation of the developing nervous system by analysing brain structure, neuronal networks, expression of metabolites and behavioural analysis, which may also provide the basis for long-term adverse outcomes. A small unpublished case series from the Chief Investigator's doctoral study elucidated several promising features of fetal MRI : (i) MRI confirms USS findings and can improve the characterisation of brain structure; (ii) longitudinal in utero imaging is feasible and sometimes necessary; (iii) brain anomalies are present and may be attributable to exposure to AEDs; (iv) clinical management of pregnancies and the postnatal period is directly impacted by fetal MRI.

This study will undertake a pilot study using fetal MRI on 20 pregnant women with the aim of developing a tool to further characterise in utero brain development. This is a pilot study which will include 2 cohorts: women with epilepsy taking AEDs (WWE) (N=10), and age-matched healthy pregnant controls (HC) with no known neurological disorder (N=10).

RESEARCH QUESTIONS The aim of this study is to investigate the adverse neurological effects on a fetus exposed to Anti-Epileptic Drugs.