1. Trofinetide (Daybue) for Rett syndrome. Med Lett Drugs Ther. 2024; 66(1706): e115-e6.

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2. Agha Gholizadeh M, Behjati F, Ghasemi Firouzabadi S, Heidari E, Razmara E, Almadani N, Sharifi Zarchi A, Garshasbi M. Novel splicing variant and gonadal mosaicism in DYRK1A gene identified by whole-genome sequencing in multiplex autism spectrum disorder families. Neurogenetics. 2024.

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition with considerable genetic heterogeneity. The disorder is clinically diagnosed based on DSM-5 criteria, featuring deficits in social communication and interaction, along with restricted and repetitive behaviours. Here, we performed whole-genome sequencing (WGS) on four individuals with ASD from two multiplex families (MPX), where more than one individual is affected, to identify potential single nucleotide variants (SNVs) and structural variants (SVs) in coding and non-coding regions. A rigorous bioinformatics pipeline was employed for variant detection, followed by segregation analysis. Our investigation revealed an unreported splicing variant in the DYRK1A gene (c.-77 + 2T > C; IVS1 + 2T > C; NM_001396.5), in heterozygote form in two affected children in one of the families (family B), which was absent in the healthy parents and siblings. This finding suggests the presence of gonadal mosaicism in one of the parents, representing the first documented instance of such inheritance for a variant in the DYRK1A gene associated with ASD. Furthermore, we identified a 50 bp deletion in intron 9 of the DLG2 gene in two affected patients from the same family, confirmed by PCR and Sanger sequencing. In Family A, we identified potential candidate variants associated with ASD shared by the two patients. These findings enhance our understanding of the genetic landscape of ASD, particularly in MPX families, and highlight the utility of WGS in uncovering novel genetic contributions to neurodevelopmental disorders.

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3. Agius MM, Stansfield J, Murray J. A comparison of differing organizational formats for teaching requesting skills to children with autism. Augment Altern Commun. 2024: 1-12.

The selection of high-tech AAC for children diagnosed with autism spectrum disorder can be a challenging process due to the vast array of options available. One of the decisions that clinicians need to make involves how vocabulary will be organized on the display. This study aimed to compare a visual scene display (VSD) with a grid display using a multiple-probe design across participants with an embedded adapted alternating treatment design. Four young children with autism spectrum disorder who were beginning communicators were recruited and taught to request preferred items using two display formats: VSD and grid layout on a mainstream tablet with an AAC app. Two of the participants achieved criterion with both displays, the other two participants failed to achieve criterion in either display. For all participants, progress was similar in both displays. The results are discussed through the lens of each participant’s characteristics with suggestions for clinical decision-making.

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4. Bazelmans T, Arthur R, Pasco G, Shephard E, Milosavljevic B, Ali JB, Pickles A, Johnson MH, Jones EJH, Charman T. Mid-childhood autism sibling recurrence in infants with a family history of autism. Autism Res. 2024.

Autism sibling recurrence in prospective infant family history studies is ~20% at 3 years but systematic follow-up to mid-childhood is rare. In population and clinical cohorts autism is not recognized in some children until school-age or later. One hundred and fifty-nine infants with an older sibling with autism underwent research diagnostic assessments at 3 years and mid-childhood (6 to 12 years (mean 9)). We report the autism sibling recurrence rate in mid-childhood and compare developmental and behavioral profiles at mid-childhood and 3 years in those with earlier versus later recognized autism, and those who had, or had not, received a community autism diagnosis. The autism recurrence rate in this sample in mid-childhood was 37.1%, 95% CI [29.9%, 44.9%] and higher in boys than girls. Around half of those diagnosed with autism in mid-childhood had not received a diagnosis at 3 years. Later, diagnosis was more common in girls than boys. While some had sub-threshold symptoms at 3, in others late diagnosis followed a largely typical early presentation. Sibling recurrence based on community clinical diagnosis was 24.5%, 95% CI [18.4%, 31.9%]. Those who also had a community diagnosis tended to be older, have lower adaptive function and higher autism and inattention symptoms. Notwithstanding limitations of a single site study, modest sample size and limits to generalisability, autism sibling recurrence in family history infants may be higher in mid-childhood than in studies reporting diagnostic outcome at 3 years. Findings have implications for families and clinical services, and for prospective family history studies.

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5. Doherty M, Foley KR, Schloss J. Complementary and Alternative Medicine for Autism – A Systematic Review. J Autism Dev Disord. 2024.

Complementary and Alternative Medicine (CAM) is a therapeutic option currently used by autistic people with continued interest and uptake. There remains limited evidence regarding the efficacy of CAM use in autism. The aim of this systematic review is to comprehensively review published clinical trials to explore the efficacy of CAM in autism. A systematic literature review of available research published from June 2013 to March 2023 was conducted. Our literature search identified 1826 eligible citations, and duplications removed (n = 694) with 102 articles eligible for title/abstract screening. After full text review, 39 studies were included. The results of this systematic review identified that for autistic people, vitamin and mineral supplements may only be of benefit if there is a deficiency. The results also found that the main interventions used were dietary interventions and nutraceuticals, including targeted supplements, vitamins and minerals, omega 3 s and prebiotics, probiotics and digestive enzymes. The evidence does not support some of the most frequently utilised dietary interventions, such as a Gluten Free Casein Free (GFCF) diet, and the use of targeted nutraceutical supplements may be of benefit, but more conclusive research is still required to direct safe and effective treatment.

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6. Ghaffar A, Akhter T, Strømme P, Misceo D, Khan A, Frengen E, Umair M, Isidor B, Cogné B, Khan AA, Bruel AL, Sorlin A, Kuentz P, Chiaverini C, Innes AM, Zech M, Baláž M, Havrankova P, Jech R, Ahmed ZM, Riazuddin S, Riazuddin S. Variants of NAV3, a neuronal morphogenesis protein, cause intellectual disability, developmental delay, and microcephaly. Commun Biol. 2024; 7(1): 831.

Microtubule associated proteins (MAPs) are widely expressed in the central nervous system, and have established roles in cell proliferation, myelination, neurite formation, axon specification, outgrowth, dendrite, and synapse formation. We report eleven individuals from seven families harboring predicted pathogenic biallelic, de novo, and heterozygous variants in the NAV3 gene, which encodes the microtubule positive tip protein neuron navigator 3 (NAV3). All affected individuals have intellectual disability (ID), microcephaly, skeletal deformities, ocular anomalies, and behavioral issues. In mouse brain, Nav3 is expressed throughout the nervous system, with more prominent signatures in postmitotic, excitatory, inhibiting, and sensory neurons. When overexpressed in HEK293T and COS7 cells, pathogenic variants impaired NAV3 ability to stabilize microtubules. Further, knocking-down nav3 in zebrafish led to severe morphological defects, microcephaly, impaired neuronal growth, and behavioral impairment, which were rescued with co-injection of WT NAV3 mRNA and not by transcripts encoding the pathogenic variants. Our findings establish the role of NAV3 in neurodevelopmental disorders, and reveal its involvement in neuronal morphogenesis, and neuromuscular responses.

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7. Hou W, Cheng R, Zhao Z, Liao H, Li J. Atypical and variable attention patterns reveal reduced contextual priors in children with autism spectrum disorder. Autism Res. 2024.

Accumulating evidence suggests that individuals with autism spectrum disorder (ASD) show impairments in using contextual priors to predict others’ actions and make intention inference. Yet less is known about whether and how children with ASD acquire contextual priors during action observation and how contextual priors relate to their action prediction and intention inference. To form proper contextual priors, individuals need to observe the social scenes in a reliable manner and focus on socially relevant information. By employing a data-driven scan path method and areas of interest (AOI)-based analysis, the current study investigated how contextual priors would relate to action prediction and intention understanding in 4-to-9-year-old children with ASD (N = 56) and typically developing (TD) children (N = 50) during free viewing of dynamic social scenes with different intentions. Results showed that children with ASD exhibited higher intra-subject variability when scanning social scenes and reduced attention to socially relevant areas. Moreover, children with high-level action prediction and intention understanding showed lower intra-subject variability and increased attention to socially relevant areas. These findings suggest that altered fixation patterns might restrain children with ASD from acquiring proper contextual priors, which has cascading downstream effects on their action prediction and intention understanding.

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8. Ilen L, Delavari F, Feller C, Zanoletti O, Sandi C, Schneider M. Diurnal cortisol profiles in autistic adolescents and young adults: Associations with social difficulties and internalizing mental health symptoms. Autism Res. 2024.

Several autism-related characteristics, such as social difficulties, may contribute to high perceived stress and increased exposure to stressful life events in some autistic individuals. Repeated exposure to stress might lead to the dysfunction of the hypothalamic-pituitary-adrenocortical-axis and be a vulnerability factor for developing mental health difficulties. Previous studies show contradictory findings on salivary cortisol in autism. In the current study, we investigated diurnal cortisol profiles in autistic adolescents and young adults, as well as their associations with social difficulties, stress exposure, and mental health symptoms. Autistic (n = 48, M(age) = 17.6) and nonautistic (n = 51, M(age) = 18.4) participants collected salivary cortisol at home six times a day for 2 days. Social difficulties, exposure to stressful life events/bullying, and mental health symptoms were assessed with questionnaires and clinical interviews. Similar diurnal cortisol slopes (DCS) and cortisol awakening responses were observed between the groups, but autistic participants showed higher total cortisol output (AUC(G), area under the curve with respect to ground) during the day (b = 19.09, p = 0.009). In the autistic group, more severe social difficulties were associated with flatter DCS (b = 0.01, p = 0.007). Finally, cortisol alterations were associated with self-reported mental health symptoms, especially in autistic females in analyses uncorrected for multiple comparisons. In conclusion, our results do not indicate autism-related group-level alterations in most diurnal cortisol measures, but autistic youth showed higher total cortisol (AUC(G)) compared with nonautistic peers. More detailed investigation of interindividual variability in cortisol profiles within autistic people might give us important insights into vulnerability to developing stress-related mental health difficulties.

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9. Isenstein EL, Freedman EG, Molholm S, Foxe JJ. Somatosensory temporal sensitivity in adults on the autism spectrum: A high-density electrophysiological mapping study using the mismatch negativity (MMN) sensory memory paradigm. Autism Res. 2024.

Atypical reactivity to somatosensory inputs is common in autism spectrum disorder and carries considerable impact on downstream social communication and quality of life. While behavioral and survey work have established differences in the perception of somatosensory information, little has been done to elucidate the underlying neurophysiological processes that drive these characteristics. Here, we implemented a duration-based somatosensory mismatch negativity (MMN) paradigm to examine the role of temporal sensitivity and sensory memory in the processing of vibrotactile information in autistic (n = 30) and neurotypical (n = 30) adults. To capture the variability in responses between groups across a range of duration discrepancies, we compared the electrophysiological responses to frequent standard vibrations (100 ms) and four infrequent deviant vibrations (115, 130, 145, and 160 ms). The same stimuli were used in a follow-up behavioral task to determine active detection of the infrequent vibrations. We found no differences between the two groups with regard to discrimination between standard and deviant vibrations, demonstrating comparable neurologic and behavioral temporal somatosensory perception. However, exploratory analyses yielded subtle differences in amplitude at the N1 and P220 time points. Together, these results indicate that the temporal mechanisms of somatosensory discrimination are conserved in adults on the autism spectrum, though more general somatosensory processing may be affected. We discuss these findings in the broader context of the MMN literature in autism, as well as the potential role of cortical maturity in somatosensory mechanisms.

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10. Iverson JM, Britsch ER, Schneider JL, Plate SN, Focaroli V, Taffoni F, Keller F. Reaching While Learning to Sit: Capturing the Kinematics of Co-Developing Skills at Home. Dev Psychobiol. 2024; 66(6): e22527.

This study examined the co-development of infant reaching and postural control across the transition to arms-free sitting at home. We observed infants with typical likelihood (TL; n = 24) and elevated likelihood (EL; n = 20) for autism at four biweekly sessions spanning the transition to arms-free sitting (infant age = 4.5-8 months at first session). At each session, infants sat on a pressure-sensitive mat with external support or independently, wore magneto-inertial sensors on both wrists, and reached for toys presented at midline. Analyses focused on characterizing and comparing control of sitting during reaching actions and standard kinematic metrics of reaching during Supported versus Independent Sitting. Although EL infants achieved arms-free sitting later than TL peers, there were no group differences on any measures. Across sessions, infants’ control of the sitting posture during concurrent reaching movements improved in both contexts, though they were less stable as they reached when sitting independently compared to when sitting with support. A similar effect was apparent in the kinematics of reaches, with overall improvement over time, but evidence of poorer control in Independent relative to Supported Sitting. Taken together, these findings underscore the mutually influential and dynamic relations between emerging skills and well-established behaviors.

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11. Massaguer-Bardaji B, Grau-Touriño A, Gómez-Hinojosa T. [Differences in self-harm among adolescents and young adults with autism spectrum disorder: a gender-based approach]. Rev Neurol. 2024; 79(2): 35-40.

INTRODUCTION: Self-harm in children and young people with autism spectrum disorder (ASD) poses risks to their physical well-being, negatively impacts their quality of life and that of their families, and presents challenges to their integration into school and social environments. This study aimed to investigate possible differences in terms of gender between adolescents and young adults with autism admitted to the neurodevelopmental unit of ITA Argentona due to non-suicidal self-harming behaviour. PATIENTS AND METHODS: A sample of 50 patients with ASD, whose ages ranged from 14 to 27 years, who were treated in the ITA Argentona neurodevelopmental unit. The methodology adopted consisted of a non-causal correlational cross-sectional study, for which the Autism Diagnostic Observation Schedule, second edition, and the Autism Diagnostic Interview-Revised were administered, as well as the Inventory of Statements About Self-injury. RESULTS: The results obtained revealed significant and positive correlations between sex and certain types of self-harm (burning, pulling hair and carving) and the motivations or functions that the participants report for engaging in non-suicidal self-harm. CONCLUSIONS: Although the study concluded that there is no substantially greater likelihood of one sex in particular engaging non-suicidal self-harm, significant differences were identified in terms of the specific types of self-harm, and the motivations or functions associated with these non-suicidal self-harming behaviours.

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12. Ozgur EG, Balci S. Might the fungus candida albicans a risk factor for autism? A meta-analysis study. Afr Health Sci. 2023; 23(4): 230-5.

OBJECTIVE: Due to the high increase in rate of autism, it has gained great importance to determine the etiology of autism spectrum disorder. The purpose of our study was to assess the role of Candida albicans as a risk factor to cause autism behavior. METHODS: We searched Scopus, PubMed, Web of Science and PsycINFO for articles up to December, 2021. The studies involving children diagnosed with autism spectrum disorder were included. Children’ outcomes were selected as Candida albicans (positive) and Candida albicans (negative). Odds ratios were reported using fixed-effect and random-effect meta-analysis. The heterogeneity was assessed by the Chi-square test and Higgins’ I(2) test. The publication bias was examined via funnel plot and Hegger’s test. RESULTS: Our meta-analysis was conducted based on 254 diagnosed with Autism Spectrum Disease cases and 161 healthy cases from 4 studies. Compared to the healthy cases, the odds of presence of Candida albicans (OR=7.21; 95% CI: 3.75-13.85; p<0.001) were higher in those diagnosed with autism spectrum disorder. CONCLUSION: This study as a whole showed that children diagnosed with autism spectrum disorder have higher frequency of the presence of the fungus Candida albicans. Therefore, Candida albicans may be an etiological factor for the autistic behavior in children.

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13. Rafi’i MR, Ja’afar MH, Abd Wahil MS, Md Hanif SA. Urine manganese, cadmium, lead, arsenic, and selenium among autism spectrum disorder children in Kuala Lumpur. PeerJ. 2024; 12: e17660.

BACKGROUND: The development of autism spectrum disorder (ASD) may stem from exposure to environmental pollutants such as heavy metals. The primary objective of this study is to determine the role of heavy metals of concern such as manganese (Mn), cadmium (Cd), lead (Pb), arsenic (As), and essential trace element selenium (Se) among ASD children in Kuala Lumpur, Malaysia. METHOD: A total of 155 preschoolers in Kuala Lumpur between the ages 3 to 6 participated in an unmatched case-control study, comprising ASD children (n = 81) recruited from an early intervention program for autism, and 74 children without autism who were recruited from public preschools. Urine samples were collected at home, delivered to the study site, and transported to the environmental lab within 24 hours. Inductively coupled plasma mass spectrometry (ICP-MS) was applied to measure the concentration of heavy metals in the samples. Data were analysed using bivariate statistical tests (Chi-square and T-test) and logistic regression models. RESULT: This study demonstrated that Cd, Pb, and As urine levels were significantly greater in children without autism relative to those affected with ASD (p < 0.05). No significant difference was in the levels of Se (p = 0.659) and Mn (p = 0.875) between children with ASD and the control group. The majority of children in both groups have urine As, Pb, and Cd values lower than 15.1 µg/dL, 1.0 µg/dL, and 1.0 µg/dL, respectively which are the minimal risk values for noncarcinogenic detrimental human health effect due to the heavy metal's exposure . Factors associated with having an ASD child included being a firstborn, male, and higher parental education levels (adjusted odds ratios (aOR) > 1, p < 0.05). CONCLUSION: Preschoolers in this study demonstrated low levels of heavy metals in their urine samples, which was relatively lower in ASD children compared to the healthy matched controls. These findings may arise from the diminished capacity to excrete heavy metals, especially among ASD children, thereby causing further accumulation of heavy metals in the body. These findings, including the factors associated with having an ASD child, may be considered by healthcare professionals involved in child development care, for early ASD detection. Further assessment of heavy metals among ASD children in the country and interventional studies to develop effective methods of addressing exposure to heavy metals will be beneficial for future reference.

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14. Su Q, Wong OWH, Lu W, Wan Y, Zhang L, Xu W, Li MKT, Liu C, Cheung CP, Ching JYL, Cheong PK, Leung TF, Chan S, Leung P, Chan FKL, Ng SC. Multikingdom and functional gut microbiota markers for autism spectrum disorder. Nat Microbiol. 2024.

Associations between the gut microbiome and autism spectrum disorder (ASD) have been investigated although most studies have focused on the bacterial component of the microbiome. Whether gut archaea, fungi and viruses, or function of the gut microbiome, is altered in ASD is unclear. Here we performed metagenomic sequencing on faecal samples from 1,627 children (aged 1-13 years, 24.4% female) with or without ASD, with extensive phenotype data. Integrated analyses revealed that 14 archaea, 51 bacteria, 7 fungi, 18 viruses, 27 microbial genes and 12 metabolic pathways were altered in children with ASD. Machine learning using single-kingdom panels showed area under the curve (AUC) of 0.68 to 0.87 in differentiating children with ASD from those that are neurotypical. A panel of 31 multikingdom and functional markers showed a superior diagnostic accuracy with an AUC of 0.91, with comparable performance for males and females. Accuracy of the model was predominantly driven by the biosynthesis pathways of ubiquinol-7 or thiamine diphosphate, which were less abundant in children with ASD. Collectively, our findings highlight the potential application of multikingdom and functional gut microbiota markers as non-invasive diagnostic tools in ASD.

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15. Tanaka Y, Kurasawa S, Ouchi K, Oi N. Structural associations between self-perception of support and knowledge of disability characteristics of autism spectrum disorder among staff in facilities providing after-school day services. Fukushima J Med Sci. 2024.

BACKGROUND: We constructed a hypothetical model of the knowledge of autism spectrum disorder (ASD) and self-perception of support of staff working in after-school day services to clarify structural relationships. METHODS: A questionnaire survey was conducted at 194 facilities providing after-school day services in Fukushima Prefecture (October 2020), including a basic attributes questionnaire, the Literacy Scale of Characteristics of Autistic Spectrum Disorder (LS-ASD), and a staff questionnaire. We developed a hypothetical model of the relationship between self-perception and LS-ASD total scores of after-school service staff. To obtain latent variables for structural equation modeling (SEM) to confirm factor extraction and the interrelationships among variables, exploratory factor analysis was performed. SEM was used to examine the fit of the hypothetical model to the data and the relationships among variables. RESULTS: The study included 302 staff members from 58 of 194 facilities. Four factors (Factor 1, motivation; 2, self-perception of knowledge; 3, information sharing; 4, self-confidence) were extracted. The final model showed that Factor 2 had a positive direct effect (path coefficient = 0.64) and Factor 4 had a negative direct effect (path coefficient = -0.22) on LS-ASD scores. The model goodness of fit was acceptable (Goodness-of-Fit Index = 0.890; Comparative Fit Index = 0.912; Root Mean Square Error of Approximation = 0.086; Akaike’s Information Criterion = 392.7). CONCLUSION: Self-perception of knowledge contributes greatly to knowledge acquisition, while excessive confidence may hinder knowledge retention.

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16. Wang X, Qian C, Yao H. Parental Inflammatory Bowel Disease with Child Autism: A Comprehensive Review and Meta-Analysis. J Autism Dev Disord. 2024.

Inflammatory bowel disease (IBD) has been shown to be connected to a greater possibility of neurologically developed problems, such as autism spectrum disorders (ASDs). However, the proof linking parental IBD with ASD in offspring is inconclusive. Thus, we carried out a meta-analysis and comprehensive review to elucidate such linking. Prior research was identified through reviewing multiple internet-based sources, including Cochrane, Web of Knowledge, Embase, CINAHL, PubMed, and PsycINFO, from 1960 to December 2022. Pooled relative risks (RRs) and corresponding 95% confidence intervals (CIs) were determined employing random-effects models, in spite of the I(2) statistic measurement of heterogeneity. Prediction intervals (PIs) have been presented to allow for more useful inferences and to indicate the range of genuine effects that might be predicted in future scenarios. Six studies (two case-control studies and four cohort studies) involving 3,200,199 participants were incorporated into the meta-analysis. The pooled RRs of ASDs among offspring of IBD parents were 1.15 (95% CI, 0.92 to 1.45, P = 0.226; I(2) = 81.4%, P = 0.003; PI, 0.53-2.62), indicating no significant connection between parental IBD and the likelihood of ASDs in children. Type of IBD, and sex both also yielded no statistically significant results according to subgroup analysis. Our meta-analysis does not provide evidence that parental IBD is connected with the elevated likelihood of ASDs in their children. To confirm these results and understand their underlying mechanisms, additional research with larger sample sizes and improved study designs is required.

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17. Yeung MK, Bai J, Mak KL. Longitudinal changes in executive function in autism spectrum disorder: A systematic review and meta-analyses. Autism Res. 2024.

Individuals with an autism spectrum disorder (ASD) diagnosis show impairment in executive function (EF). However, findings are mixed regarding differences in the age effect on EF between autistic individuals and persons with typical development (TD). Questions remain regarding whether the age-related trajectories of EF in ASD are the same as or different from those in TD. To bridge this knowledge gap, we conducted a systematic review and meta-analyses of longitudinal studies that compared age-related changes in EF between ASD and TD groups (preregistration: osf.io/j5764). A literature search was conducted using PubMed, PsycINFO, and Web of Science on January 29, 2024. After screening by two independent reviewers, 14 longitudinal studies were included. Random-effects meta-analyses of studies involving a maximum total of 518 autistic and 3558 TD children and adolescents (mean baseline ages: 5.7-12.0 years) showed that ASD had significantly poorer EF than TD at both baseline and follow-up. However, there was no significant group difference in the age-related change in EF across domains, including working memory, inhibition, shifting, and planning. Robust Bayesian meta-analyses also provided substantial evidence in favor of the null hypothesis that ASD and TD groups showed similar changes over time for most EF processes. Limitations of the literature included the limited number of longitudinal studies and a narrow range of developmental stages and EF constructs analyzed across studies. Altogether, these findings suggest that autistic children and adolescents generally can improve in EF over time similarly to their neurotypical peers. This has important implications for parents and educators, encouraging appropriate EF training and intervention for autistic children and adolescents at an early stage.

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18. You W, Choi A, Lee H, Han JY, Lee JH, Shin JY. Adverse Pregnancy and Child Outcomes in Oral Retinoid-Exposed Pregnancies: A Nationwide Population-Based Study. J Korean Med Sci. 2024; 39(26): e201.

BACKGROUND: Oral retinoids are used to treat various dermatological conditions, and their use is increasing in women of childbearing age. However, there is limited knowledge on the incidence of adverse outcomes after retinoid exposure during pregnancy. We aimed to evaluate the risk of adverse outcomes associated with oral retinoid exposure during pregnancy. METHODS: We conducted a retrospective cohort study using the NHIS mother-child linked healthcare database in South Korea. We included all women who gave live birth from April 1, 2009 to December 31, 2020 and their children. The exposure was defined as having ≥ 1 prescription of isotretinoin, alitretinoin, and acitretin from one month before pregnancy to the delivery. The outcomes of interest were adverse child outcomes including major congenital malformations, low birth weight, and neurodevelopmental disorders (autism spectrum disorder and intellectual disorder), and adverse pregnancy outcomes including gestational diabetes mellitus, preeclampsia, and postpartum hemorrhage. Propensity score-based matching weights were used to control for various potential confounders. For congenital malformation, low birth weight, and adverse pregnancy outcomes, we calculated relative risk (RR) with 95% confidence interval (CI) using a generalized linear model and for neurodevelopmental disorders, we estimated hazard ratio (HR) with 95% CI using the Cox proportional hazard model. RESULTS: Of 3,894,184 pregnancies, we identified 720 pregnancies (0.02%) as the oral retinoid-exposed group. The incidence of major congenital malformation was 400.6 per 10,000 births for oral retinoid-exposed group and 357.9 per 10,000 births for unexposed group and the weighted RR was 1.10 (95% CI, 0.65-1.85) in oral retinoid-exposed group compared with unexposed group. The neurodevelopmental disorder showed a potential increased risk, with the weighted HR of 1.63 (95% CI, 0.60-4.41) for autism spectrum disorder and 1.71 (95% CI, 0.60-4.93) for the intellectual disorder, although it did not reach statistical significance. For low birth weight and adverse pregnancy outcomes, no association was observed with oral retinoid exposure during pregnancy. CONCLUSION: This study found no significantly increased risk of congenital malformations, autism spectrum disorders, and intellectual disability associated with oral retinoid exposure during pregnancy; however, given the limitations such as including only the live births and increased point estimate, potential risk cannot be fully excluded.

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