Prenatal risk factors, inflammation, and effects of treatment in neurodevelopmental disorders

<jats:p>&lt;p dir="ltr"&gt;Neurodevelopmental disorders (NDDs), including attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and intellectual disability (ID), are early-onset conditions that often co-occur and persist into adulthood. Although NDDs are highly heritable disorders, early developmental periods, particularly the prenatal and early postnatal stages, are increasingly recognised as critical windows during which environmental exposures may exert lasting effects on brain maturation and mental health.&lt;/p&gt;&lt;p dir="ltr"&gt;This thesis is divided into two parts. Studies I-II investigated prenatal and early postnatal risk factors for offspring NDDs, while accounting for maternal psychiatric disorders. Maternal immune activation (MIA) and autoimmune (ADs) or autoinflammatory disorders (AIDs) have been linked to higher risks of neurodevelopmental outcomes in offspring. However, previous studies have largely focused on selected maternal conditions or specific offspring outcomes, limiting understanding of the broader impact of maternal immune dysregulation on neurodevelopment. Antidepressant use during pregnancy has increased substantially over recent decades, yet its effects on offspring neurodevelopment remain unclear, particularly with respect to antidepressant type and timing of exposure.&lt;/p&gt;&lt;p dir="ltr"&gt;Study I investigated the effects of prenatal and early postpartum antidepressant exposure on offspring psychiatric and neurodevelopmental risks using a nationwide cohort of all 1,107,802 live births in Finland (1996-2014), followed until 2021. Cox proportional hazards models were used to estimate associations between the five most commonly used antidepressants, stratified by exposure timing, and offspring outcomes. Exposure during both early and mid-to-late pregnancy was associated with mildly increased risks of several NDDs across medications. When exposure was restricted to early pregnancy, only serotonin- norepinephrine reuptake inhibitors (SNRI) venlafaxine was associated with increased risk. Among antidepressants initiated during mid-to-late pregnancy, only the selective serotonin reuptake inhibitors (SSRIs) citalopram was associated with higher offspring risk, while all SSRIs were associated with lower Apgar scores. Postpartum noradrenergic and specific serotonergic antidepressant (NaSSa) mirtazapine exposure was associated with lower risks of several psychiatric diagnoses, whereas SSRIs escitalopram and sertraline were associated with increased risks of intellectual disability.&lt;/p&gt;&lt;p dir="ltr"&gt;Study II evaluated in utero exposure to various maternal ADs and AIDs using the same Finnish cohort. Cox regression analyses indicated that when categorised by the primary affected body system, offspring mental diagnoses were predominantly associated with maternal connective tissue and endocrine AD/AIDS. Although most effect sizes were modest, a striking &gt;2-fold risk was identified for ASD in mothers with autoimmune thyroiditis, and for other behavioural or emotional disorders (mainly nonorganic enuresis, encopresis, and feeding disorder) in mothers with pernicious anaemia.&lt;/p&gt;&lt;p dir="ltr"&gt;Studies III-V examined inflammatory mechanisms and treatment-related effects in ADHD. Gastrointestinal symptoms are frequently reported in individuals with ADHD and may be linked to intestinal inflammation and poor gut microbiota. Methylphenidate (MPH), the most commonly prescribed psychostimulant for ADHD, has also been associated with gastrointestinal side effects, microbiota alterations, and increased circulating inflammatory markers. A synbiotic, which combines beneficial bacteria with growth-supporting dietary fibres, has been shown to improve gut microbiota composition and reduce psychiatric symptoms and plasma inflammatory markers in individuals with ADHD. In addition, MPH has been linked to potential cardiovascular risks in recent epidemiological studies. However, the observational nature of these studies precludes causal inference, and the biological mechanisms underlying these associations remain poorly understood.&lt;/p&gt;&lt;p dir="ltr"&gt;Study III examines the therapeutic potential of this synbiotic and its components on intestinal inflammation and peripheral biomarkers in a dextran sulfate sodium-induced colitis mouse model in both sexes. Compared to placebo, the complete multispecies synbiotic (Synbio1) uniquely restores clinical scores to levels comparable to healthy controls. Both Synbio1 and Synbio3 treatments resulted in notable improvement of inflammation in the colon. Synbio1 additionally increased plasma IL-17A, VEGF-D, and TNFRSF11B levels, which were associated with better clinical conditions or less severe colonic inflammation. Most beneficial effects appeared more pronounced in female mice.&lt;/p&gt;&lt;p dir="ltr"&gt;Study IV explored the clinical associations between plasma immune activity markers and ADHD symptoms/comorbid traits in an ADHD cohort (49 children, 105 adults) and matched controls (4 children, 57 adults). In children with ADHD, plasma CXCL1 levels positively correlated with ADHD symptom severity scores.&lt;/p&gt;&lt;p dir="ltr"&gt;Among adults with ADHD, elevated levels of CXCL1 and IL-12/IL-23p40 were associated with greater comorbid autistic symptoms, while higher IL-2Ra and IL- 12/IL-23p40 levels correlated with more severe insomnia symptoms. However, no significant differences in these marker levels were observed between adults with ADHD and healthy controls.&lt;/p&gt;&lt;p dir="ltr"&gt;Study V investigated the effects of MPH on human brain microvascular endothelial cells (HBECs) and human aortic endothelial cells (HAECs) at therapeutic and supratherapeutic concentrations, complemented by plasma endothelial marker validation in ADHD patients (87 children, 102 adults) and controls (4 children, 44 adults). Acute exposure (24h) to therapeutic concentrations of MPH altered the expression of multiple endothelial function- related genes and significantly increased the secretion of von Willebrand factor (vWF) and tissue plasminogen activator. In clinical samples, children receiving MPH exhibited significantly higher vWF levels than medication-naïve counterparts, an effect not observed in adults. Supratherapeutic concentrations (50UM and/or 100uM) further decreased Claudin-5 expression and compromised endothelial barrier integrity.&lt;/p&gt;&lt;p dir="ltr"&gt;Overall, the findings of this thesis may contribute to informed decision-making in maternity care regarding antidepressant use and maternal autoimmune or autoinflammatory disorders in relation to offspring neurodevelopmental risk, the development of synbiotic-based adjunctive therapies for ADHD, and biological support for previous epidemiological findings suggesting adverse vascular effects of methylphenidate.&lt;/p&gt;&lt;h3 dir="ltr"&gt;List of scientific papers&lt;/h3&gt;&lt;p dir="ltr"&gt;I. &lt;b&gt;Wenjie Cai&lt;/b&gt;, Martin Lundberg, Ida AK Nilsson, Martin Schalling, Mika Gissler, Catharina Lavebratt. Association of prenatal exposure to antidepressants with risk of offspring psychiatric and neurodevelopmental disorders. [Submitted]&lt;/p&gt;&lt;p dir="ltr"&gt;II. Elin Skott, &lt;b&gt;Wenjie Cai&lt;/b&gt;, Miranda Stiernborg, Anna Fogdell-Hahn, MaiBritt Giacobini, Mika Gissler, Samson Nivins, Catharina Lavebratt. Associations of prenatal exposure to maternal autoimmune disorders with a wide spectrum of psychiatric and neurodevelopmental disorders in offspring - a nationwide cohort study. Human reproduction open, 2026 Apr 26;2026(2):hoag026. &lt;a href="https://doi.org/10.1093/hropen/hoag026" target="_blank" rel="noreferrer"&gt;https://doi.org/10.1093/hropen/hoag026&lt;/a&gt;&lt;/p&gt;&lt;p dir="ltr"&gt;III. &lt;b&gt;Wenjie Cai&lt;/b&gt;, Kateryna Pierzynowska, Miranda Stiernborg, Jingjing Xu, Ida Ak Nilsson, Ulla Svensson, Philippe A Melas, Catharina Lavebratt. Multispecies synbiotics alleviate dextran sulfate sodium (DSS)- induced colitis: Effects on clinical scores, intestinal pathology, and plasma biomarkers in male and female mice. Clinical nutrition ESPEN, 2024 Oct;63:74-83. &lt;a href="https://doi.org/10.1016/j.clnesp.2024.06.011" target="_blank" rel="noreferrer"&gt;https://doi.org/10.1016/j.clnesp.2024.06.011&lt;/a&gt;&lt;/p&gt;&lt;p dir="ltr"&gt;IV. &lt;b&gt;Wenjie Cai&lt;/b&gt;*, Liu L. Yang*, Elin Skott, Miranda Stiernborg, MaiBritt Giacobini, Catharina Lavebratt. Characterising the association of proinflammatory mediators with symptoms and comorbid traits in ADHD. [Manuscript]&lt;/p&gt;&lt;p dir="ltr"&gt;* Equal contribution.&lt;/p&gt;&lt;p dir="ltr"&gt;V. &lt;b&gt;Wenjie Cai&lt;/b&gt;, MaiBritt Giacobini, Cecilia Österholm, Catharina Lavebratt. Effects of methylphenidate on the human vascular endothelium. Translational Psychiatry. 2026 Jul 17;16(1):369. &lt;a href="https://doi.org/10.1038/s41398-026-04237-6" target="_blank" rel="noreferrer"&gt;https://doi.org/10.1038/s41398-026-04237-6&lt;/a&gt;&lt;/p&gt;</jats:p>