Effects of a Multiple Sclerosis Relapse Therapy With Methylprednisolone (MP) During Pregnancy on Offspring Cognitive Function, Stress Sensitivity, Behaviour and Functional and Structural Brain Development

Introduction: Multiple Sclerosis (MS) affects 1 in 1,000 people in industrialised countries, mainly women of childbearing age. To prevent MS relapses, most patients receive disease-modifying therapies (DMTs). However, most DMTs - with the exception of interferons and glatiramer acetate - are not approved during pregnancy. Consequently, DMTs are regularly discontinued during pregnancy with a subsequently increased risk of relapses. Thus, relapses during pregnancy are a common phenomenon. The average relapse rate per year in pregnant MS patients not taking DMTs during the 1st and 2nd trimester is nearly identical to the pre-partum period after which it significantly declines during the 3rd Trimester. The German Neurologic Society estimates that approximately 25% of all pregnant women with MS will suffer a relapse during their pregnancy period(s).

It is generally recommended by European and US guidelines to treat MS relapses during pregnancy with the synthetic glucocorticoid (GC) methylprednisolone (MP), which is thought to be harmless for the unborn. However, regardless of the undoubtedly positive effects of GCs for MS relapse treatment, there is considerable doubt as to whether synthetic GCs are as low in side effects for the child as MS guidelines assume. The fetus develops in the presence of very low GC levels because it is unable to produce cortisol until the end of pregnancy and about 90% of maternal cortisol is being inactivated by the placental enzyme 11ß-HSD2. In contrast to maternal cortisol, synthetic GCs are no substrate for the placental enzyme 11ß-HSD2 and, thus, pass the placenta without being inactivated. Once within the fetal circulation, GCs interfere with the development of the fetal central nervous system (CNS). The effects of synthetic GCs on fetal development and health and disease in later life as well as the mechanisms mediating these effects are best characterised for betamethasone exposure to induce fetal lung maturation in babies threatening premature labour as this treatment is used in nearly 10% of all pregnancies. In various studies excess exposure to synthetic GCs is associated with reduced birth weight, altered fetal brain development e.g., by direct effect on neuro- and gliogenesis via anti-proliferative effects on neural stem/progenitor cells, and persisting functional changes of the stress axis with its two arms, the hypothalamus-pituitary-adrenal axis (HPAA) and the autonomic nervous system (ANS). Supraphysiological GC concentrations are also thought to reset the set point of the negative feedback regulation of the fetal HPAA which results in an increase of HPAA activity in later life. Increased HPAA activity has been associated with increased stress sensitivity and a number of behavioural changes and neuropsychiatric disorders including anxiety, depressive-like disorders, and attention deficit hyperactivity disorder (ADHD). The relationship between adverse environmental influences during critical periods of fetal life, such as exposure to excess GC, and offspring health in later life is the basis of the 'Fetal Programming' hypothesis.

A predecessor study of the investigators' work group tested the hypothesis that fetal betamethasone treatment impairs structural and functional brain development as well as stress sensitivity leading to disturbances in overall neurocognitive performance and behaviour in later life. It is noteworthy, that the dosage of betamethasone (2 x 12mg, 24h apart) was approximately 300-fold lower than the dosage used to treat MS relapses (1000mg over 3-5 days). As a major study outcome, the investigators noticed detrimental effects of prenatal betamethasone exposure on general cognitive ability at the age of 8 - 9 years. Intelligence quotient (IQ)-scores in children who were prenatally exposed to betamethasone were on average 10.5 points lower than in controls, with a large effect size of d = 0.68. Even though IQ-scores of betamethasone-exposed children were still within the expected population range, the investigators assume that this difference is clinically relevant and impedes future life success of the participants. In addition, children exposed to betamethasone showed a significant increase in ADHD related symptoms on the International Classification of Diseases (ICD)-10-based rating scale, the Diagnostik-System für psychische Störungen nach ICD-10 und DSM-5 für Kinder und Jugendliche-III, with a medium effect size of d = 0.51. Electroencephalographic (EEG) analysis showed that BM-exposed children had a higher spectral edge frequency at rest and during stress suggesting a reduced overall neuroelectric relaxation capacity. Heart Rate Variability (HRV) analysis revealed a resetting of the ANS in betamethasone-exposed children.

Objectives: The primary goal of this study is to examine the general cognitive ability as a marker of brain development of children of MS patients who received MP to treat an MS relapse during pregnancy. The secondary goals are to determine the effects of MP administered during pregnancy on offspring structural and functional brain development and neuropsychiatric and behavioural performance. Stress sensitivity and epigenetic changes of GC receptor function will be measured to determine underlying mechanisms.

The study is based on the following hypotheses: