Treatment algorithm for the use of psychopharmacological agents in individuals prenatally exposed to alcohol and/or with diagnosis of fetal alcohol spectrum disorder (FASD).

Back to table of contents Previous article Next article Clinical & ResearchFull AccessPatients With Prenatal Alcohol Exposure Frequently Misdiagnosed, Face Multiple ChallengesMansfield Mela, M.B.B.S., M.Sc.Psych.Mansfield MelaSearch for more papers by this author, M.B.B.S., M.Sc.Psych.Published Online:22 Dec 2022https://doi.org/10.1176/appi.pn.2023.01.1.12AbstractThere is a high prevalence of diagnosable mental disorders in youth and adults who were exposed prenatally to alcohol. More than 80% of those identified in studies as adversely affected by prenatal alcohol exposure were misdiagnosed with other mental diagnoses.iStock/nattrassMultiple organs of the fetus are at risk of damage from the teratogenic effects of alcohol crossing the placenta. Disorders of the skin and endocrine, renal, and cardiac systems are overrepresented among those affected by prenatal alcohol exposure (PAE).The trajectory and long-term outcomes of those with PAE were initially shrouded in mystery. Practitioners in the field then adopted the term invisible disorder for the consequences of PAE. According to the DSM-5, the diagnostic terms fetal alcohol spectrum disorder (FASD) or neurodevelopmental disorder associated with prenatal alcohol exposure (ND-PAE) describe the combined challenges and strengths common in people whose mothers consumed sufficient alcohol at the threshold known to be associated with adverse neurobehavioral effects. Individuals diagnosed with ND-PAE suffer primarily from cognitive and intellectual deficits, including the areas of learning and memory, language, attention, executive functioning, and adaptive and social functioning.Emanating from these primary cognitive deficits are more debilitating secondary disabilities such as psychiatric and behavioral disorders. Characteristically, these individuals present with irritability, impulsivity, poor awareness of risk, and poor communicative functioning. Comorbid conditions include mood, anxiety, substance use, and trauma-related disorders.Rigors of Diagnosis?Early confirmation of FASD/ND-PAE is a protective factor across the lifespan. Multiple schemes for diagnosis endorse a multidisciplinary team approach to identify the clinical features for a FASD/ND-PAE diagnosis. Diagnosis depends on the presence of and threshold criteria for neuropsychological deficits, facial dysmorphic features, growth restriction associated with PAE, and confirmation of alcohol exposure during gestation. Complicating the diagnosis of PAE in children, youth, and adults is the high prevalence (40% to 90%) of diagnosable mental disorders, making it difficult to differentiate the effects of alcohol exposure only. More than 80% of those identified in studies as adversely affected by PAE had previously been labeled with other mental diagnoses. Due to a deficiency in training curricula, the best chance for trainees (especially medical students) to see individuals with PAE is a rotation with a neonatologist interested in dysmorphology.PAE interacts with biosocial factors to produce disease. These genetic, nutritional, and socioeconomic factors combine with childhood adversity to inform the health trajectory of many individuals with PAE. While genetically high rates of mental disorders are common in individuals with PAE, social challenges—namely, substance use disorders, criminality, social exclusion, school failure, unemployment, and suicidality—tend to plague these patients at rates higher than that found in the general population.Role of Clinicians and New Interventions to Streamline TherapyBecause of the inherent gap in clinicians’ knowledge and expertise to diagnose those with PAE, they need a guide to raise their awareness of the complex presentation of FASD/ND-PAE. Clinical blind spots are, therefore, not due to ignorance or a source of blame. Because many patients go undiagnosed, clinical vignettes and other practical clinical strategies for detection and intervention are essential for clinicians.PAE predisposes to brain-based abnormal functioning and bodily defects. Gaps in care and delay in diagnosis are the recognized factors that are associated with negative outcomes in the trajectory of those with PAE. Mislabeling is a consequence of such negative outcomes. As no organ is spared, multiple complaints and symptoms are present in those diagnosed with the consequences of PAE. Multiple factors like shame, guilt, fear of losing offspring, poor memory, and death of the mother limit the information on PAE, which leads to a plethora of diagnoses in PAE patients. Consequently, multiple medications are prescribed to target the many symptoms usually not conceptualized to align with the unifying explanation of PAE. Research depicts the patients as unnecessarily overmedicated, prone to experiencing side effects, and highly dysfunctional. In some studies, the average number of psychotropic medications taken by those with PAE compared with neurotypical patients was three to four times and more.To address this disparity and source of inadequate care, a psychotropic medication algorithm was developed to aid prescribing. The neurocognitive and behavioral manifestations can be divided into four clusters (hyperarousal, affect dysregulation, hyperactive/cognitive, and cognitive inflexibility); different classes of psychotropic medications target each cluster. The algorithm provides psychotropic medication options to help streamline decisions; the risk-benefit ratio of rational pharmacology supports prescription and reduces polypharmacy, a well-intended and necessary outcome.There are specific evidence-based interventions that enhance mood regulation and improve cognition and math skills (see second resource noted at the end of this article). Other treatments target competence in communication, social skills, and self-awareness for socialization and safety and may include traditional group sessions but also individualized programs since learning in a group interferes with skills acquisition.ConclusionFASD/ND-PAE is a multifaceted, lifelong disorder. Early diagnosis and treatment are critical to ensure the best clinical and social outcomes. Because FASD/ND-PAE is not central in medical curricula, clinicians must now take an inquisitive approach to diagnose people affected by prenatal alcohol exposure. Exercising attentive and rigorous efforts to prevent misdiagnosis offer individuals the best chance to receiving appropriate supports early in life. Optimal functioning of individuals instead of labels should be each clinician’s goal and focus in supporting those diagnosed with FASD/ND-PAE. ■“Treatment Algorithm for the Use of Psychopharmacological Agents in Individuals Prenatally Exposed to Alcohol and/or With Diagnosis of Fetal Alcohol Spectrum Disorder (FASD)”“FASDs: Treatments”Mansfield Mela, M.B.B.S., M.Sc.Psych., is director of the Centre for Forensic Behavioral Science and Justice Studies and the diagnostic research lead of the Canada Fetal Alcohol Spectrum Disorder Research Network. He is the author of Prenatal Alcohol Exposure: A Clinician’s Guide from APA Publishing. APA members may purchase the book at a discount. ISSUES NewArchived

Background and objective Individuals with Fetal Alcohol Spectrum Disorder (FASD) tend to be prescribed a high number of psycho-tropic medications to treat high rates of comorbid psychiatric disorders. A lack of guidance regarding best practices for prescribing psychotropic medications to individuals with FASD probably accounts for this reliance on polypharmacy. The objective of this study is to describe the types of medications prescribed to individuals with prenatal alcohol exposure, comparing rates between individuals diagnosed with FASD and individuals without FASD as well as how medications are prescribed based on age, sex, and comorbid psychiatric disorders. Material and methods Data were drawn from Canada's national FASD database. This database includes information collected during an FASD assessment related to diagnostic outcomes, secondary challenges, and medical and mental health information. Descriptive statistics were calculated for four diagnostic groups (FASD with sentinel facial features [FASD + SFF], FASD without sentinel facial features [FASD - SFF], at risk for FASD [“at risk”], and no FASD). Group demographics were compared using Chi-Square, Fisher's Exact Test, and ANOVA, as appropriate. Differences in the proportion of individuals between these four diagnostic groups were calculated using each of the following six classes of psychotropic medications—antipsychotics, antidepressants/anxiolytic, anticonvulsants/mood stabilizers, stimulants, melatonin, and others—using ANOVA. Considering just the individuals with FASD by combining the FASD + SFF and FASD - SFF groups, independent sample tests were used to compare differences in the proportion of males and females prescribed different medications. Chi-Square and Fisher's Exact Test were used to compare the proportion of individuals using psychotropic medications, according to category, within the FASD group based on the presence or absence of 13 comorbid psychiatric disorders. Results The overall sample included 2349 participants (mean value = 18.1 years, SD = 10.3). The sample included 1453 participants with an FASD diagnosis (n = 218, FASD + SFF, mean = 23.7 years, SD = 15.8, and n = 1235, FASD - SFF, mean = 19.5 years, SD = 10.0 years) and 896 participants who were assessed but did not receive an FASD diagnosis (n = 653, no FASD, mean = 16.1 years and n = 261, “at risk” for FASD, mean = 12.2 years). The FASD groups had a significantly higher rates of anxiety disorders, depressive disorders, and the presence of at least one comorbid psychiatric disorder compared to the no FASD and the “at risk” groups. Both FASD groups had a higher proportion of individuals taking antipsychotic and antidepressant/anxiolytic medications compared to the no FASD and “at risk” groups. Females with FASD were more often prescribed antidepressants/anxiolytics compared to males with FASD, while males with FASD were more often prescribed stimulants than females with FASD. The prevalence of antidepressants/anxiolytics, stimulants, and melatonin use by individuals with FASD differed across the lifespan. The prevalence of the prescription of six medication categories was found to differ according to psychiatric disorder. Conclusion Compared to individuals assessed as not fulfilling criteria for FASD, those with FASD had higher rates of psychiatric disorders and were prescribed significantly more antidepressants/anxiolytics and antipsychotics. The class and rate of prescriptions may support efforts in devising treatment guidelines for a complex disorder with known high comorbidity such as FASD.

Considering Prenatal Alcohol Exposure in a Developmental Origins of Health and Disease Framework.

Sleep problems in children with fetal alcohol spectrum disorders (FASD) are reportedly common but not well characterized. Objectives were to: (1) assess sleep concerns in children with FASD using a caregiver-report survey, the Children's Sleep Habits Questionnaire (CSHQ); (2) compare CSHQ results with those of previously reported community sample; and (3) describe pilot polysomnography findings in children with FASD. Children with FASD were recruited from a behavioral intervention study, and participating caregivers completed the CSHQ. CSHQ results were compared with the original data from a previously published community sample of similar age. Participants with FASD and elevated CSHQ scores were offered overnight polysomnography. Thirty-three children with FASD (4.1-12.1 years) were enrolled; 85% of children with FASD scored above the clinical cutoff Total Score of 41, reflecting marked sleep disturbance. Elevated subdomain scores occurred primarily in areas concerning for pediatric insomnia. Those with comorbid ADHD had elevated CSHQ on additional subdomains with no difference in Total Scores. Compared with the community sample, children with FASD had higher Total Scores on the CSHQ (52 vs. 39, p < 0.001). Polysomnography, completed in 5 subjects, revealed mild sleep disordered breathing and fragmented sleep with elevated non-respiratory arousal indices. Clinically significant sleep problems are present in children with FASD on both subjective and objective measures. Further investigation is needed to better describe these sleep disturbances and their impact on overall health and daytime neurobehavioral problems in this clinical population.

Fetal alcohol spectrum disorders: Mechanisms, diagnosis, treatment, and prevention.

We examined the effects of moderate prenatal alcohol exposure and/or prenatal stress exposure on (D1 R) binding in a non human primate model. The dopamine D1 R is involved in executive function, and it may play a role in cognitive behavioral deficits associated with prenatal alcohol and/or stress exposure. Little is known, however, about the effects of prenatal alcohol and/or stress exposure on the D1 R. We expected that prenatal insults would lead to alterations in D1 R binding in prefrontal cortex (PFC) and striatum in adulthood. Rhesus macaque females were randomly assigned to moderate alcohol exposure and/or mild prenatal stress as well as a control condition during pregnancy. Thirty-eight offspring were raised identically and studied as adults by noninvasive in vivo neuroimaging using positron emission tomography with the D1 antagonist radiotracer [(11) C]SCH 23390. Radiotracer binding in PFC and striatum was evaluated by 2 (alcohol)×2 (stress)×2 (sex) analysis of variance. In PFC, a significant alcohol×sex interaction was observed with prenatal alcohol exposure leading to increased [(11) C]SCH 23390 binding in male monkeys. No main effect of prenatal alcohol or prenatal stress exposure was observed. These results suggest that prenatal alcohol exposure results in long-term increases in prefrontal dopamine D1 R binding in males. This may help explain gender differences in the prevalence of neurodevelopmental disorders consequent to prenatal alcohol exposure.

Another Step Forward in Relating Facial and Brain Dysmorphologies Associated with Prenatal Alcohol Exposure

Assessment of the cerebellar neurotoxic effects of nicotine in prenatal alcohol exposure in rats

Prenatal tobacco exposure (PTE) and prenatal alcohol exposure (PAE) have been associated with an increased risk of delayed neurodevelopment in children as well as differential newborn DNA methylation (DNAm). However, the biological mechanisms connecting PTE and PAE, DNAm, and neurodevelopment are largely unknown. Here we aim to determine whether differential DNAm mediates the association between PTE and PAE and neurodevelopment at 6 (N = 112) and 24 months (N = 184) in children from the South African Drakenstein Child Health Study. PTE and PAE were assessed antenatally using urine cotinine measurements and the ASSIST questionnaire, respectively. Cord blood DNAm was measured using the EPIC and 450 K BeadChips. Neurodevelopment (cognitive, language, motor, adaptive behavior, socioemotional) was measured using the Bayley Scales of Infant and Toddler Development, Third Edition. We constructed methylation risk scores (MRS) for PTE and PAE and conducted causal mediation analysis (CMA) with these MRS as mediators. Next, we conducted a high-dimensional mediation analysis to identify individual CpG sites as potential mediators, followed by a CMA to estimate the average causal mediation effects (ACME) and total effect (TE). PTE and PAE were associated with neurodevelopment at 6 but not at 24 months. PTE MRS reached a prediction accuracy (R2) of 0.23 but did not significantly mediate the association between PTE and neurodevelopment. PAE MRS was not predictive of PAE (R2 = 0.006). For PTE, 31 CpG sites and eight CpG sites were identified as significant mediators (ACME and TE P < 0.05) for the cognitive and motor domains at 6 months, respectively. For PAE, 16 CpG sites and 1 CpG site were significant mediators for the motor and adaptive behavior domains at 6 months, respectively. Several of the associated genes, including MAD1L1, CAMTA1, and ALDH1A2 have been implicated in neurodevelopmental delay, suggesting that differential DNAm may partly explain the biological mechanisms underlying the relationship between PTE and PAE and child neurodevelopment.

Moderate to heavy levels of prenatal alcohol exposure have been associated with alterations in child behavior, but limited data are available on adverse effects after low levels of exposure. The objective of this study was to evaluate the dose-response effect of prenatal alcohol exposure for adverse child behavior outcomes at 6 to 7 years of age. Beginning in 1986, women attending the urban university-based maternity clinic were routinely screened at their first prenatal visit for alcohol and drug use by trained research assistants from the Fetal Alcohol Research Center. All women reporting alcohol consumption at conception of at least 0.5 oz absolute alcohol/day and a 5% random sample of lower level drinkers and abstainers were invited to participate to be able to identify the associations between alcohol intake and child development. Maternal alcohol, cigarette, and illicit drug use were prospectively assessed during pregnancy and postnatally. The independent variable in this study, prenatal alcohol exposure, was computed as the average absolute alcohol intake (oz) per day across pregnancy. At each prenatal visit, mothers were interviewed about alcohol use during the previous 2 weeks. Quantities and types of alcohol consumed were converted to fluid ounces of absolute alcohol and averaged across visits to generate a summary measure of alcohol exposure throughout pregnancy. Alcohol was initially used as a dichotomous variable comparing children with no prenatal alcohol exposure to children with any exposure. To evaluate the effects of different levels of exposure, the average absolute alcohol intake was relatively arbitrarily categorized into no, low (>0 but <0.3 fl oz of absolute alcohol/day), and moderate/heavy (>/=0.3 fl oz of absolute alcohol/day) for the purpose of this study. Six years later, 665 families were contacted. Ninety-four percent agreed to testing. Exclusions included children who missed multiple test appointments, had major congenital malformations (other than fetal alcohol syndrome), possessed an IQ >2 standard deviations from the sample mean, or had incomplete data. The Achenbach Child Behavior Checklist (CBCL) was used to assess child behavior. The CBCL is a parent questionnaire applicable to children ages 4 to 16 years. It is widely used in the clinical assessment of children's behavior problems and has been extensively used in research. Eight syndrome scales are further grouped into Externalizing or undercontrolled (Aggressive and Delinquent) behavior and Internalizing or overcontrolled (Anxious/Depressed, Somatic Complaints, and Withdrawn) behaviors. Three syndromes (Social, Thought, and Attention Problems) fit neither group. Higher scores are associated with more problem behaviors. Research assistants who were trained and blinded to exposure status independently interviewed the child and caretaker. Data were collected on a broad range of control variables known to influence childhood behavior and/or to be associated with prenatal alcohol exposure. These included perinatal factors of maternal age, education, cigarette, cocaine, and other substances of abuse and the gestational age of the baby. Postnatal factors studied included maternal psychopathology, continuing alcohol and drug use, family structure, socioeconomic status, children's whole blood lead level, and exposure to violence. Data were collected only from black women as there was inadequate representation of other racial groups. Statistical analyses were performed using the SPSS statistical package. Frequency distribution, cross-tabulation, odds ratio, and chi(2) tests were used for analyzing categorical data. Continuous data were analyzed using t tests, analyses of variance (ANOVAs) with posthoc tests, and regression analysis. Testing was available for 501 parent-children dyads. Almost one fourth of the women denied alcohol use during pregnancy. Low levels of alcohol use were reported in 63.8% and moderate/heavy use in 13% of pregnancies. Increasing prenatal alcohol exposure was associated with lower birth weight and gestational age, higher lead levels, higher maternal age, and lower education level, prenatal exposure to cocaine and smoking, custody changes, lower socioeconomic status, and paternal drinking and drug use at the time of pregnancy. Children with any prenatal alcohol exposure were more likely to have higher CBCL scores on Externalizing (Aggressive and Delinquent) and Internalizing (Anxious/Depressed and Withdrawn) syndrome scales and the Total Problem Score. The odds ratio of scoring in the clinical range for Delinquent behavior was 3.2 (1.3-7.6) in children with any prenatal exposure to alcohol compared with nonexposed controls. The threshold dose was evaluated with the 3 prenatal alcohol exposure groups. One-way ANOVA revealed a significant between group difference for Externalizing (Aggressive and Delinquent) and the Total Problem Score. (ABSTRACT TRUNCATED)

There have been significant advances in assessment processes and diagnostic criteria since the effects of prenatal alcohol exposure were first described in the medical literature (Lemoine, Harrouseau, & Borteyru, 1968; Ulleland, Wennberg, Igo, & Smith, 1970) and the terminology of fetal alcohol syndrome was first applied (Jones & Smith, 1973). However, a key issue that continues to plague the fetal alcohol spectrum disorder (FASD) field is a lack of agreement regarding terminology, and criteria for describing and diagnosing FASD. A recent study by Coles, Bandoli, Kable, del Campo, Suttie, and Chambers (2023) undertook a retrospective comparison of three of the most commonly used FASD diagnostic systems in North America to determine the degree of association among these systems. The study by Coles and colleagues concluded that “…more reliable methods for diagnosis should be a goal for the future. To continue without improving consistency in our approach to this problem is to contribute to confusion about the reliability and validity of this diagnosis, which does a disservice to all those who are concerned about the care of affected individuals.” Coles and colleagues describe how the question of the relative accuracy of the three diagnostic systems compared in their study cannot be resolved and they call for “a more empirically based diagnostic schema.” The study by Coles and colleagues provides us with an important opportunity to reflect on the past, current, and future approaches to developing diagnostic criteria and consider how the FASD field can successfully come together to advance a more empirically based diagnostic system. Depending on the diagnostic approach and terminology you ascribe to, FASD is a condition or FASDs are a group of conditions that arise from prenatal exposure to alcohol. While there is somewhat of a consensus on the broad features considered as part of the diagnosis (i.e., facial dysmorphology, neurodevelopmental impairments, and plus or minus consideration of growth restriction), there continues to be variation in how these features are considered and conceptualized to inform diagnostic outcomes. Alongside the fact that there continues to be a lack of agreement regarding the descriptors used to refer to FASD, with various diagnostic terminologies currently in use around the world (e.g., FASD with three facial features, fetal alcohol syndrome, partial fetal alcohol syndrome, FASD with less than three facial features, alcohol-related neurodevelopmental disorder, static encephalopathy alcohol exposed, and neurobehavioral disorder alcohol exposed). Coles et al. (2023) highlight that FASD continues to be under-identified and that while there may be multiple reasons for under-identification, variability in diagnostic methods is likely a contributing factor. Given the heterogeneous nature of prenatal alcohol exposure effects, it makes sense that describing and defining an associated condition or group of conditions has been a significant challenge. I commend the work of all the researchers in the FASD field, who over many years have worked diligently to improve diagnosis and awareness of FASD and improve the quality of life for individuals living with FASD and their families. The challenges we face both within our field of research and in the wider research world provides motivation for us to strengthen collaborative efforts, to maximize research opportunities and ultimately, the real-world impacts we can achieve for individuals living with FASD and their families. Although a current obstacle to broad collaboration in the FASD field regarding the topic of diagnosis that needs to be acknowledged is the disparities in the established research groups. This was highlighted in a recent study I was involved with that undertook an international survey of FASD specialist diagnostic clinics to explore barriers and facilitators to developing a unified approach to FASD diagnosis (Reid et al., 2022). The vast majority of respondents (90.9%; n = 50) believed that a unified approach to diagnosis would be possible. However, one of the top barriers described by participants to such an approach was “personal preference/ego.” Therefore, collaborating to advance an empirically based diagnostic system will require all of us to put aside our personal preferences and egos and carefully consider the best available evidence to improve diagnostic approaches for individuals living with FASD. The FASD field is of course not alone in experiencing challenges coming to consensus regarding diagnostic criteria. All conditions without objective tests or biomarkers that rely on symptom-based diagnostic criteria have faced and continue to face similar challenges. As researchers and clinicians, how we can contribute to moving forward in the face of these challenges is through utilizing the best available evidence to inform clinical decision-making. Using the best available evidence involves systematic evidence reviews of all the available evidence and implementing the best available methods for developing and presenting evidence summaries. A method that has been used widely in the creation of clinical practice guidelines is the GRADE approach (Schünemann, Brożek, Guyatt, & Oxman, 2013), which provides a transparent framework for developing and reporting evidence summaries and a structured approach to the development of clinical practice recommendations. Systematic reviews and meta-analyses combined with the GRADE approach could support the development of an empirically based set of FASD diagnostic criteria. Notably, numerous researchers (e.g., First, 2017; Kendler & Solomon, 2016) have highlighted that the Diagnostic and Statistical Manual (DSM) has not consistently incorporated systematic evidence reviews, placing the DSM out of step with the wider medical field, which emphasizes the importance of systematic reviews and meta-analyses as “a manifestation of the evidence-based medicine movement” (First, 2017, p. 1). Consequently, utilizing systematic reviews and structured evidence-based decision-making processes could have widespread implications for improving the development of diagnostic criteria beyond the FASD field. Relevant to this discussion is the distinction that has been made regarding consensus-based and evidence-based guidelines. Djulbegovic and Guyatt (2019) suggest that “making a distinction between evidence-based and consensus-based guidelines is both misguided and misleading because both require consensus. The crucial difference between evidence-based medicine and non-evidence-based medicine methods is that the former necessitates that judgments are consistent with the underlying evidence, whereas the latter do not (p. 3).” This is helpful to consider, as if we could come to consensus about the current best available evidence, this could inform a core set of diagnostic criteria. Of course, there will be gaps in the available evidence, but taking a systematic approach to reviewing the evidence and identifying the gaps would facilitate a targeted and collaborative approach to addressing the research gaps and lead to continuous quality improvement of the core criteria. The body of evidence and core set of criteria could then inform the development of national clinical practice guidelines, which will invariably differ, due to contextual differences across countries that need to be considered when developing recommendations, for example, cultural considerations, existing differences in health and disability support systems, and local patient values and preferences. The recent work of Coles et al. (2023) has provided the opportunity for a renewed call to action to improve the way FASD diagnostic criteria are developed and inform future research opportunities. Trends in the wider medical field advocate for the use of evidence-based approaches in the development of diagnostic criteria and clinical practice guidelines. A significant opportunity exists for the FASD field to work together and utilize the best available evidence to advance an empirically based approach to FASD diagnosis. Open access publishing facilitated by The University of Queensland, as part of the Wiley - The University of Queensland agreement via the Council of Australian University Librarians. The authors declare no conflict of interest.

The combined impact of prenatal alcohol exposure (PAE) and prenatal tobacco exposure (PTE) on white-matter integrity in pre-adolescence is poorly understood. We aimed to explore white-matter integrity in children aged 8- to 12-years with PAE and/or PTE versus those without (controls, CON). Here, 410 children (CON: n=84; PAE: n=94; PTE: n=67; PAE+PTE: n=165) underwent diffusion tensor MRI as part of the Safe Passage Study, a cohort based in Cape Town, South Africa. Linear regression modeling was used to investigate the main and interaction effects of PAE and PTE. There were disordinal PAE×PTE interactions on right-cerebral-peduncle mean, axial, and radial diffusivity: Individuals with PAE and PTE had higher mean and axial diffusivity than those with either exposure on its own, but similar to those with neither. In children with PAE, there were associations with altered axial diffusivity among those exposed during the first trimester and mean, axial, and radial diffusivity in those exposed during the second trimester in commissural, association, and projection tracts. Further, there were PTE associations with fractional anisotropy and radial diffusivity in projection tracts among those exposed mainly during the second trimester. These results support previous research in children with PAE and add to the PTE literature, highlighting potentially lasting impact on axonal and myelin microstructural development, which are important for motor, sensory, cognitive, and behavioral functions. Our results suggest sensitivity to the timing of exposure of PAE and PTE, particularly during the first and second trimesters of pregnancy.

The associations of prenatal alcohol exposure (PAE) and prenatal tobacco exposure (PTE) with adolescent neuroanatomical development are typically evaluated cross-sectionally. It is unclear whether observed effects persist throughout life or reflect different developmental trajectories. To examine whether PAE and PTE are associated with early-adolescent cortical structure and development. This cohort study included children aged 9 to 12 years who participated in the Adolescent Brain Cognitive Development (ABCD) Study's first 2 neuroimaging time points (data collected 2016-2021) at 21 US study sites. Data analysis was conducted from March 2024 to March 2025. PAE and PTE, based on caregiver reports of alcohol and tobacco use during pregnancy, both before and after pregnancy recognition. Cortical thickness (in millimeters) and cortical surface area (in millimeters squared) measured approximately 2 years apart, across 68 bilateral cortical regions. Summary scores from the Behavioral Inhibition and Behavioral Activation Scale, the Child Behavior Checklist, the Sleep Disturbances Scale for Children, and the Urgency, Perseverance, Premeditation, and Sensation Seeking Scale were collected. At baseline data collection, the 5417 youth participants (2912 [53.8%] assigned male at birth; 724 [13.4%] Black, 1048 [19.3%] Hispanic, and 3640 [67.2%] White) had a mean (SD) age of 9.9 (0.6) years; the mean (SD) age at the second appointment was 11.9 (0.6) years. Cortical thickness decreased with age. Cortical surface area either expanded or contracted with age, depending on region. PAE was not associated with cortical structure (main correlation) or development (PAE × age interaction). PTE had false discovery rate-corrected main correlations with cortical thickness in the bilateral parahippocampal and left lateral orbitofrontal cortices (eg, right parahippocampal: |rp| = 0.04; P < .001) and was associated with faster rates of cortical thinning (PTE × age interactions) in medial and anterior frontal lobe regions (eg, right rostral middle frontal: |rp| = 0.04; P < .001). Post hoc analyses on PTE's associations with cortical structure and development among children whose mother continued tobacco use after pregnancy recognition and among those whose mother did not also use alcohol had weaker effect sizes. Exploratory developmental-outcome analyses suggested that faster cortical thinning was associated with more externalizing behavior and sleep problems (eg, right pars orbitalis and externalizing behavior: |rp| = 0.04, P = .003), primarily in those with PTE. In this study, PTE was correlated with cortical thickness development. Analyzing developmental trajectories informs not only how PTE and PAE affect cortical structure (and related behavioral outcomes) but also how the cortex develops long after prenatal exposures occurred. Future analyses involving cotinine biomarkers of PTE would enhance the temporal resolution of the ABCD's PTE-related queries of tobacco use before and after learning of the pregnancy.

Prenatal alcohol exposure (PAE) can cause lasting physical damage to the developing foetus including the brain. This brain damage can manifest as cognitive dysfunction and behavioural difficulties, which can be diagnosed as foetal alcohol spectrum disorders (FASD). FASD is thought to be common in the UK, with estimates ranging from 3.24% up to 17% of the population affected, although rates of diagnosis are much lower than this. Children with FASD are at increased risk of a range of traumatic or adverse childhood experiences, such as neglect or abuse. Studies into the longterm effects of neglect or abuse show a similar range of cognitive dysfunction and behavioural difficulties as those seen in FASD, but there is a lack of evidence on the impact of a dual exposure of PAE and trauma. This is especially necessary for clinicians, who may need to use the presence of trauma to inform and potentially exclude a diagnosis on the foetal alcohol spectrum. This aim of this thesis was to investigate the impact of childhood trauma on the cognitive and behavioural functioning of children with FASD. A wide-ranging overview of the literature on the effects of PAE and trauma as separate exposures was conducted and was followed by a systematic literature review of studies into the dual exposure of PAE and trauma. The reviews showed that only five studies had investigated the impact of both exposures, although one further study was published more recently. The literature reviews, including the one new study showed that, although there had only been a small number of studies conducted, a pattern was emerging that children with both FASD and trauma were more similar to children with just FASD than they were to children with just trauma, in terms of their cognitive and behavioural functioning. The findings of the reviews were used to develop four original studies, which advanced the evidence in this area. The studies were designed to assess the damage caused by dual exposure at four levels: neurological, cognitive, behavioural, and finally the effect of behavioural problems on other people. A neuroimaging study measured task-related blood oxygenation in the prefrontal cortex in 15 children aged 8-14 years with FASD with and without a history of trauma. A series of cognitive tasks assessed verbal, non-verbal and overall intelligence, working memory and inhibitory control in 25 children aged 8-14 years with FASD with and without a history of trauma. An informant-report survey that assessed Adverse Childhood experiences, cognitive, affective and overall empathy, behavioural strengths and difficulties, and comorbid diagnoses was completed by the carers of children aged 4-16 years with FASD. A series of semi-structured interviews was conducted with caregivers of children aged 8-14 years with FASD, with and without a history of trauma. Children with FASD had high levels of adverse childhood experiences including neglect and abuse, poor empathy, high levels of behavioural difficulties, and high levels of comorbid diagnoses, particularly attention deficit hyperactivity disorder (ADHD). They also had verbal, non-verbal and overall intelligence in the average range, and working memory and inhibitory control scores that were similar to the scores of typically developing children of the same age. Children with both FASD and a history of trauma were found not to be significantly different from children with FASD without trauma in terms of their task-related prefrontal activity, verbal, non-verbal and overall intelligence, working memory, inhibitory control, and empathy. There was a slight tendency for children with higher numbers of adverse childhood experiences to exhibit more severe behavioural difficulties, particularly conduct problems. Caregivers of children with both exposures described experiences with the same themes as those whose children had FASD without trauma. Caregivers described their children as difficult to manage, but also described many strengths and rewarding moments. Caregivers were critical of service providers including medical and educational services, social services, adoption agencies and local authorities, who lacked knowledge and understanding of FASD. This led to their children being misunderstood and offered insufficient or inappropriate services. The findings of this thesis support previous research showing that children with FASD have high levels of behavioural difficulties, poor empathy, and high levels of comorbid diagnoses. It provides the first data on levels of adverse childhood experiences in children with FASD, which are also high. The main finding of the thesis is that the impact of traumatic childhood experiences on the cognitive and behavioural functioning of children with FASD may be very subtle, especially in terms of cognitive functioning. Clinicians and other professionals should be aware that a history of neglect or abuse does not appear to be a better explanation for cognitive dysfunction or behavioural difficulties than prenatal alcohol exposure. Where children have a history of both exposures, they should primarily be treated as children with FASD, and provided appropriate support and interventions specifically designed for FASD.

The present article defines fetal alcohol spectrum disorders (FASD), describes the aetiology, prevalence, manifestations, and consequences of FASD impacting the quality of life of individuals and their families, diagnostic, intervention approaches, and emphasises prevention. Fetal Alcohol Spectrum Disorders (FASD) is an umbrella term covering a group of congenital neurodevelopmental defects and brain damage resulting from prenatal alcohol exposure (PAE). It is a continuum of bio-psycho-social impacts associated with PAE. There are multiple approaches to diagnosing and treating disorders associated with prenatal alcohol exposure during pregnancy worldwide. All persons with FASD have lifelong cognitive, social, and behavioural difficulties. Individuals with FASD present multidimensional challenges in childhood for parents and caregivers, with an impact on other family members. For this reason, families also need support from society. Evidence-based interventions need to be implemented to support individuals with FASD and their families. Addressing this issue requires a multidisciplinary professional approach. FASD is a costly issue for society, so it is reasonable to invest in significant prevention. Our qualitative research mapped the positive and negative influences on the quality of life of child with FASD and his/her caregivers/parents. We found that the negative aspects affecting the quality of life of the child with FASD and his/her caregivers/parents include: Significant manifestations of behavioural problems of the child with FASD in the school and home environment; Early traumatisation and re-traumatisation of the child with FASD; Disrupted relational bond between the caregiver/parent and the child with FASD and Negative impact of parenting a child with FASD on the mental and physical health of the caregiver/parent. We identified the following positive resources supporting the quality of life of the child with FASD and his/her caregivers/parents: Professional support as one aspect of enhancing the quality of life of the child with FASD and his/her caregivers/parents; Compensating for the learning difficulties of the child with FASD in the home environment; Consciously establishing a secure relational bond between the caregiver/parent and the child with FASD; Alternative teaching approaches to the child with FASD in school as a positive influencing factor. The topic of the quality of life of a child with FASD and his/her caregivers/parents is not sufficiently explored in the Slovak and international context. It is about the interconnected links between the child's situation with FASD himself/herself and the impact on his/her whole ecosystem (home environment, parents, siblings, school and broader community). This study presents pilot data on the quality of life of children diagnosed with FASD and their caregivers/parents in Slovakia. The research was supported by a grant Kega No. 002UK-4/2020 Supporting the child with sensory processing disorder through a multisensory environment.