Characteristics of fetal anticonvulsant syndrome associated autistic disorder
Abstract
The aim of this study was to evaluate the clinical features and frequency of autistic disorder or Asperger syndrome (AS; according to Diagnostic and Statistical Manual of Mental Disorders, 4th edition [DSM-IV] criteria) in children exposed to anticonvulsant medication in utero. During a 20-year study period, 626 children were born in Aberdeen to mothers taking antiepileptic drugs (AEDs). The study examined long-term effects of prenatal exposure to AEDs in 260 children (122 males, 138 females). Of these, 26 (16 males) were reported by parents to have social or behavioural difficulties. Eleven children (6 males, 5 females) fulfilled the DSM-IV criteria for autistic disorder and one (female) fulfilled the DSM-IV criteria for AS. These children comprised 4.6% of the exposed children studied, and 1.9% of all exposed children born during the study period. Mean age of these children at diagnosis was 5 years 4 months (SD 2y 11mo) and 9 years 10 months (SD 3y 10mo) at the time of this study. Other children from the group of 26 had difficulties in areas of speech and language development and social communication but did not meet the criteria for an autism spectrum disorder (ASD). Sodium valproate was the drug most commonly associated with autistic disorder, five of 56 (8.9%) of the study children exposed to sodium valproate alone had either autistic disorder or AS. It was concluded that prenatal exposure to anticonvulsant medication is a risk factor for the development of an ASD. Fetal anticonvulsant syndrome associated autistic disorder is characterized by an even sex ratio, absence of regression or skill loss, and language delay in the absence of global delay.
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There is well-documented support for prenatal valproic acid exposure as a cause of autistic disorder.
“For example, there is well-documented support for prenatal valproic acid exposure as a cause of AD [281].”
From Consensus Paper: Pathological Role of the Cerebellum in Autism (2012) · cites this paper as [281]
Children exposed in utero to valproate have an 8-fold increased risk of ASD.
“Children exposed in utero to valproate have 8-fold increased risk to have ASD.90”
From Autism risk factors: genes, environment, and gene-environment interactions (2012) · cites this paper as [90]
Prenatal exposure to valproate is a recognized risk factor for ASD, especially in the first trimester of pregnancy.
“Prenatal exposure to valproate is a recognized risk factor for ASD, especially in the first trimester of pregnancy.”
From Autism risk factors: genes, environment, and gene-environment interactions (2012) · cites this paper as [90]
Cites
Diagnostic and Statistical Manual of Mental Disorders
Williams, J. B. W., & First, M. B. (2013) · Oxford University Press eBooks · doi:10.1093/acrefore/9780199975839.013.104 · Cited by 109,841 · see citing works
Self-citationMendelson, G. (1995) · Australian & New Zealand Journal of Psychiatry · doi:10.3109/00048679509064964 · Cited by 2,592 · see citing works
Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells
Göttlicher, M., Minucci, S., Zhu, P., Krämer, O. H., Schimpf, A., Giavara, S., Sleeman, J. P., Coco, F. L., Nervi, C., Pelicci, P. G., et al. (2001) · The EMBO Journal · doi:10.1093/emboj/20.24.6969 · Cited by 1,889 · see citing works
Phiel, C. J., Zhang, F., Huang, E. Y., Guenther, M. G., Lazar, M. A., & Klein, P. S. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m101287200 · Cited by 1,758 · see citing works
Pervasive Developmental Disorders in preschool children
Chakrabarti, S. (2001) · JAMA · doi:10.1001/jama.285.24.3093 · Cited by 1,132 · see citing works
The epidemiology of autism: a review
FOMBONNE, E. (1999) · Psychological Medicine · doi:10.1017/s0033291799008508 · Cited by 981 · see citing works
Evidence from Turner's syndrome of an imprinted X-linked locus affecting cognitive function
Skuse, D. H., James, R. S., Bishop, D. V. M., Coppin, B., Dalton, P., Aamodt-Leeper, G., Bacarese-Hamilton, M., Creswell, C., McGurk, R., & Jacobs, P. A. (1997) · Nature · doi:10.1038/42706 · Cited by 747 · see citing works
A clinical study of 57 children with fetal anticonvulsant syndromes
Moore, S. J., Turnpenny, P., Quinn, A., Glover, S., Lloyd, D. J., Montgomery, T., & Dean, J. C. S. (2000) · Journal of Medical Genetics · doi:10.1136/jmg.37.7.489 · Cited by 562 · see citing works
Self-citationFetal valproate syndrome and autism: additional evidence of an association
Williams, G., King, J. O., Cunningham, M. L., Stephan, M., Kerr, B. A., & Hersh, J. H. (2001) · Developmental Medicine & Child Neurology · doi:10.1017/s001216220100038x · Cited by 422 · see citing works
Samrén, E. B., van Duijn, C. M., Koch, S., Hiilesmaa, V. K., Klepel, H., Bardy, A. H., Mannagetta, G. B., Deichl, A. W., Gaily, E., Granström, I. L., et al. (1997) · Epilepsia · doi:10.1111/j.1528-1157.1997.tb01480.x · Cited by 406 · see citing works
Congenital malformations due to antiepileptic drugs
Kaneko, S., Battino, D., Andermann, E., Wada, K., Kan, R., Takeda, A., Nakane, Y., Ogawa, Y., AVANZINI, G., Fumarola, C., et al. (1999) · Epilepsy Research · doi:10.1016/s0920-1211(98)00084-9 · Cited by 374 · see citing works
Fetal Valproate Syndrome: Clinical and Neuro‐developmental Features in Two Sibling Pairs
Christianson, A. L., Chester, N., & Kromberg, J. G. R. (1994) · Developmental Medicine & Child Neurology · doi:10.1111/j.1469-8749.1994.tb11858.x · Cited by 340 · see citing works
Skuse, D. H. (2000) · Pediatric Research · doi:10.1203/00006450-200001000-00006 · Cited by 285 · see citing works
Additional educational needs in children born to mothers with epilepsy
Adab, N. (2001) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp.70.1.15 · Cited by 283 · see citing works
(1989) · American Journal of Psychiatry · doi:10.1176/ajp.146.8.1032 · Cited by 255 · cited 1× · see citing works
“…the risk of recurrence to 554 Developmental Medicine & Child Neurology 2005, 47: 551–555 subsequent female children when the first female child has an ASD, recurrence rates for siblings have been variously calculated as ranging from 4.5 to 14.5% (Ritvo et al. 1989, VeenstraVanderweele et al. 2003).”
BackgroundInfluentialLong term health and neurodevelopment in children exposed to antiepileptic drugs before birth
Dean, J., Hailey, H., Moore, S. J., Lloyd, D. J., Turnpenny, P. D., & Little, J. (2002) · Journal of Medical Genetics · doi:10.1136/jmg.39.4.251 · Cited by 253 · see citing works
Self-citationPopulation based, prospective study of the care of women with epilepsy in pregnancy
Fairgrieve, S. (2000) · BMJ · doi:10.1136/bmj.321.7262.674 · Cited by 193 · see citing works
A male with fetal valproate syndrome and autism
Williams, P. G., & Hersh, J. H. (1997) · Developmental Medicine & Child Neurology · doi:10.1111/j.1469-8749.1997.tb07500.x · Cited by 182 · see citing works
SPECIFIC COGNITIVE DYSFUNCTION IN CHILDREN WITH EPILEPTIC MOTHERS
Gaily, E. K., Kantola‐Sorsa, E., & Granström, M. (1990) · Developmental Medicine & Child Neurology · doi:10.1111/j.1469-8749.1990.tb16959.x · Cited by 123 · see citing works
Genetics of Childhood Disorders: XLVI. Autism, Part 5: Genetics of Autism
Veenstra-VanderWeele, J. M., & Cook, E. H. (2003) · Journal of the American Academy of Child & Adolescent Psychiatry · doi:10.1097/00004583-200301000-00018 · Cited by 75 · see citing works
Foetal valproate syndrome and autism: additional evidence of an association
Bescoby-Chambers, N. J. C., Forster, P., & Bates, G. (2001) · Developmental Medicine & Child Neurology · doi:10.1017/s0012162201211542 · Cited by 40 · see citing works
Flagged first, then by citations
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Newschaffer, C. J., Croen, L. A., Daniels, J., Giarelli, E., Grether, J. K., Levy, S. E., Mandell, D. S., Miller, L. A., Pinto-Martin, J., Reaven, J., et al. (2007) · Annual Review of Public Health · doi:10.1146/annurev.publhealth.28.021406.144007 · Cited by 1,228 · see citing works
Autism spectrum disorder: Definition, epidemiology, causes, and clinical evaluation
Hodges, H., Fealko, C., & Soares, N. (2020) · Translational Pediatrics · doi:10.21037/tp.2019.09.09 · Cited by 1,127 · see citing works
Autism risk factors: genes, environment, and gene-environment interactions
Chaste, P., & Leboyer, M. (2012) · Dialogues in Clinical Neuroscience · doi:10.31887/dcns.2012.14.3/pchaste · Cited by 807 · see citing works
Consensus Paper: Pathological Role of the Cerebellum in Autism
Fatemi, S. H., Aldinger, K. A., Ashwood, P., Bauman, M. L., Blaha, C. D., Blatt, G. J., Chauhan, A., Chauhan, V., Dager, S. R., Dickson, P. E., et al. (2012) · The Cerebellum · doi:10.1007/s12311-012-0355-9 · Cited by 723 · see citing works
Valproic acid in pregnancy: how much are we endangering the embryo and fetus?
Ornoy, A. (2009) · Reproductive Toxicology · doi:10.1016/j.reprotox.2009.02.014 · Cited by 526 · see citing works
Altered gut microbiota and activity in a murine model of autism spectrum disorders
de Theije, C. G. M., Wopereis, H., Ramadan, M., van Eijndthoven, T., Lambert, J., Knol, J., Garssen, J., Kraneveld, A. D., & Oozeer, R. (2014) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2013.12.005 · Cited by 433 · see citing works
The intense world syndrome-an alternative hypothesis for autism
Markram, H. (2007) · Frontiers in Neuroscience · doi:10.3389/neuro.01.1.1.006.2007 · Cited by 394 · see citing works
The prevalence of neurodevelopmental disorders in children prenatally exposed to antiepileptic drugs
Bromley, R. L., Mawer, G. E., Briggs, M., Cheyne, C., Clayton-Smith, J., Garcia-Finana, M., Kneen, R., Lucas, S. B., Shallcross, R., Baker, G. A., et al. (2013) · Journal of Neurology, Neurosurgery & Psychiatry · doi:10.1136/jnnp-2012-304270 · Cited by 367 · see citing works
Validating γ oscillations and delayed auditory responses as translational biomarkers of autism
Gandal, M. J., Edgar, J. C., Ehrlichman, R. S., Mehta, M., Roberts, T. P. L., & Siegel, S. J. (2010) · Biological Psychiatry · doi:10.1016/j.biopsych.2010.09.031 · Cited by 314 · see citing works
ADHD and autism: differential diagnosis or overlapping traits? A selective review
Taurines, R., Schwenck, C., Westerwald, E., Sachse, M., Siniatchkin, M., & Freitag, C. (2012) · ADHD Attention Deficit and Hyperactivity Disorders · doi:10.1007/s12402-012-0086-2 · Cited by 301 · see citing works
Rinaldi, T., Kulangara, K., Antoniello, K., & Markram, H. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0704391104 · Cited by 290 · see citing works
Prenatal factors associated with autism spectrum disorder (ASD)
Ornoy, A., Weinstein-Fudim, L., & Ergaz, Z. (2015) · Reproductive Toxicology · doi:10.1016/j.reprotox.2015.05.007 · Cited by 238 · see citing works
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Grafodatskaya, D., Chung, B., Szatmari, P., & Weksberg, R. (2010) · Journal of the American Academy of Child & Adolescent Psychiatry · doi:10.1016/j.jaac.2010.05.005 · Cited by 235 · see citing works
Rinaldi, T. (2008) · Frontiers in Neural Circuits · doi:10.3389/neuro.04.004.2008 · Cited by 210 · see citing works
Hyperconnectivity of Local Neocortical Microcircuitry Induced by Prenatal Exposure to Valproic Acid
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The Autism Birth Cohort: a paradigm for gene–environment–timing research
Stoltenberg, C., Schjølberg, S., Bresnahan, M., Hornig, M., Hirtz, D., Dahl, C., Lie, K. K., Reichborn-Kjennerud, T., Schreuder, P., Alsaker, E., et al. (2010) · Molecular Psychiatry · doi:10.1038/mp.2009.143 · Cited by 119 · see citing works
Kolozsi, E., Mackenzie, R. N., Roullet, F. I., Decatanzaro, D., & Foster, J. A. (2009) · Neuroscience · doi:10.1016/j.neuroscience.2009.07.021 · Cited by 110 · see citing works
Qiu, S., Anderson, C. T., Levitt, P., & Shepherd, G. M. G. (2011) · The Journal of Neuroscience · doi:10.1523/jneurosci.6569-10.2011 · Cited by 106 · see citing works
Agmatine rescues autistic behaviors in the valproic acid-induced animal model of autism
Kim, J.-W., Seung, H., Kim, K. C., Gonzales, E. L. T., Oh, H. A., Yang, S. M., Ko, M. J., Han, S.-H., Banerjee, S., & Shin, C. Y. (2017) · Neuropharmacology · doi:10.1016/j.neuropharm.2016.09.014 · Cited by 102 · see citing works
Repeated prenatal exposure to valproic acid results in cerebellar hypoplasia and ataxia
Main, S. L., & Kulesza, R. J. (2017) · Neuroscience · doi:10.1016/j.neuroscience.2016.10.052 · Cited by 80 · see citing works
Altered morphology of motor cortex neurons in the VPA rat model of autism
Snow, W. M., Hartle, K., & Ivanco, T. L. (2008) · Developmental Psychobiology · doi:10.1002/dev.20337 · Cited by 72 · see citing works
Behavioral and Cerebellar Transmission Deficits in Mice Lacking the Autism-Linked Gene Islet Brain-2
Giza, J., Urbanski, M. J., Prestori, F., Bandyopadhyay, B., Yam, A., Friedrich, V., Kelley, K., D'Angelo, E., & Goldfarb, M. (2010) · The Journal of Neuroscience · doi:10.1523/jneurosci.1161-10.2010 · Cited by 68 · see citing works
Malformation of the superior olivary complex in an animal model of autism
Lukose, R., Schmidt, E., Wolski, T. P., Murawski, N. J., & Kulesza, R. J. (2011) · Brain Research · doi:10.1016/j.brainres.2011.05.013 · Cited by 59 · see citing works
Antiepileptic drugs in women with epilepsy during pregnancy
Gedzelman, E., & Meador, K. J. (2012) · Therapeutic Advances in Drug Safety · doi:10.1177/2042098611433192 · Cited by 57 · see citing works
Olde Loohuis, N. F. M., Kole, K., Glennon, J. C., Karel, P., Van der Borg, G., Van Gemert, Y., Van den Bosch, D., Meinhardt, J., Kos, A., Shahabipour, F., et al. (2015) · Neurobiology of Disease · doi:10.1016/j.nbd.2015.05.006 · Cited by 54 · see citing works
Neurodevelopmental effects of fetal antiepileptic drug exposure
Velez-Ruiz, N. J., & Meador, K. J. (2015) · Drug Safety · doi:10.1007/s40264-015-0269-9 · Cited by 48 · see citing works
Raza, S., Harker, A., Richards, S., Kolb, B., & Gibb, R. (2015) · Behavioural Brain Research · doi:10.1016/j.bbr.2014.12.055 · Cited by 37 · see citing works
Raza, S., Himmler, B. T., Himmler, S. M., Harker, A., Kolb, B., Pellis, S. M., & Gibb, R. (2015) · Behavioural Pharmacology · doi:10.1097/fbp.0000000000000169 · Cited by 37 · see citing works
Lee, H. J., Dreyfus, C., & DiCicco‐Bloom, E. (2016) · Developmental Neurobiology · doi:10.1002/dneu.22359 · Cited by 34 · see citing works
Raznahan, A., Lee, Y., Vaituzis, C., Tran, L., Mackie, S., Tiemeier, H., Clasen, L., Lalonde, F., Greenstein, D., Pierson, R., et al. (2012) · Autism Research · doi:10.1002/aur.238 · Cited by 12 · see citing works
“In addition to arguing that HOXA1 may play a role in normal human cerebellar development, our findings raise the possibility that the tentative links that have been made between functional variation within HOXA1 signaling pathways and ASD risk [Rasalam et al., 2005] may be mediated by the capacity of HOXA1 to modify d…”
BackgroundMarí-Bauset, S., Peraita-Costa, I., Donat-Vargas, C., Llopis-González, A., Marí-Sanchis, A., Llopis-Morales, J., & Morales Suárez-Varela, M. (2022) · Autism · doi:10.1177/13623613211039950 · Cited by 10 · see citing works
- Authors
- Rasalam, A., Hailey, H., Williams, J., Moore, S., Turnpenny, P., Lloyd, D., & Dean, J.
- Affiliations
- University of Aberdeen (GB)
- Aberdeen Royal Infirmary (GB)
- Memorial University of Newfoundland (CA)
- Royal Aberdeen Children's Hospital (GB)
- Venue
- Developmental Medicine & Child Neurology
- Publisher
- Wiley
- Published
- 2005-07-14
- Volume
- 47
- Issue
- 8
- Pages
- 551-555
- ISSN
- 0012-1622 (ISSN-L)
- 1469-8749
- OpenAlex
- W2137154110
- Cited by
- 456
- References
- 21
- Citations by year
- 2026: 6 · 2025: 16 · 2024: 23 · 2023: 26 · 2022: 18 · 2021: 24 · 2020: 25 · 2019: 22 · 2018: 25 · 2017: 15 · 2016: 25 · 2015: 31 · 2014: 25 · 2013: 36 · 2012: 37
- FWCI
- 12.12
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Developmental Medicine & Child Neurology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- GlaxoSmithKline
- World Health Organization
- Topics
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmacological Effects and Toxicity Studies
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Prenatal Substance Exposure Effects
- Keywords
- autistic disorder, Asperger syndrome, antiepileptic drugs, valproic acid, autism spectrum disorder, language delay, sex ratio, age at diagnosis
- MeSH terms
- Anticonvulsants, Autistic Disorder, Child, Child, Preschool, Epilepsy, Female, Fetal Diseases, Humans, Male, Mothers, Population Surveillance, Pregnancy, Prenatal Exposure Delayed Effects, Syndrome, Prevalence, Asperger Syndrome, Diagnostic and Statistical Manual of Mental Disorders
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