Thalidomide or Valproate drugs being taken by the mother early during pregnancy gives rise to an increase proportion of the children with autism

This was initially simply shown as an excess statistically but the attempts to look for the reason behind it were much more difficult. It was possible to show in rodents given the thalidomide or valproate during pregnancy, that the drugs modified the production of serotonergic neurones in the developing mouse foetus’ brain. They found also that other brain compounds (e.g. monoamines, encephalins) were also affected in concentration but what caused what is unclear. However, there was little demonstration that this was actually causing the symptoms in humans or that the withdrawal of the drugs continued to allow the brain modification.

Neither valproate nor thalidomide has continued to be used in pregnancy at all unless by accident. As such this effect could not be considered to have caused the apparent increase that has been reported in the last 20 years. However, the phenomenon might be useful to create an animal model for the condition.

It is fairly clear that these cases appeared to start with signs of illness fairly early, and they were not thought of as regressive autism. Also, because of all the other side effects of the drugs the damage seen may be part of something much more complex.

Hormones: There are indications of hypertesteronism prenatally in the autistic children: this is seen on another web page.

The 2D:4D ratio of significance in understanding prenatal hormones

1) Association with thalidomide embryopathy.

Stromland K, Nordin V, Miller M, Akerstrom B, Gillberg C. Autism in thalidomide embryopathy: a population study. Dev Med Child Neurol 1994;36:351-6.

Miyazaki K, Narita N, Narita M. Maternal administration of thalidomide or valproic acid causes abnormal serotonergic neurons in the offspring: implication for pathogenesis of autism. Int J Dev Neurosci. 2005 Apr-May;23(2-3):287-97. (this work was done in rats, and looked into the chemistry of the brain)

Narita N, Kato M, Tazoe M, Miyazaki K, Narita M, Okado N. Increased monoamine concentration in the brain and blood of fetal thalidomide- and valproic acid-exposed rat: putative animal models for autism. Pediatr Res. 2002 Oct;52(4):576-9.

Rodier PM, Ingram JL, Tisdale B, Croog VJ. Linking etiologies in humans and animal models: studies of autism. Reprod Toxicol. 1997 Mar-Jun;11(2-3):417-22. Review. (reviews thalidomide association with autism)

2) Association with prenatal valproate

This is an antiepileptic drug that is in full and extensive use currently and as such some women become pregnant but are unaware of the effect of the valproate. It penetrates throughout the body and does not disappear quickly after the drug is stopped.

Schneider T, Przewłocki R. Behavioral alterations in rats prenatally exposed to valproic acid: animal model of autism. Neuropsychopharmacology. 2005 Jan;30(1):80-9.

Schneider T, Ziòłkowska B, Gieryk A, Tyminska A, Przewłocki R. Prenatal exposure to valproic acid disturbs the enkephalinergic system functioning, basal hedonic tone, and emotional responses in an animal model of autism. Psychopharmacology (Berl). 2007 Sep;193(4):547-55.

Rinaldi T, Kulangara K, Antoniello K, Markram H. Elevated NMDA receptor levels and enhanced postsynaptic long-term potentiation induced by prenatal exposure to valproic acid. Proc Natl Acad Sci U S A. 2007 Aug 14;104(33):13501-6. Epub 2007 Aug (N-methyl d-alanine receptors are involved in opioids and various others receptors)

Ingram JL, Peckham SM, Tisdale B, Rodier PM. Prenatal exposure of rats to valproic acid reproduces the cerebellar anomalies associated with autism. Neurotoxicol Teratol. 2000 May-Jun;22(3):319-24. Compared to controls, rats exposed to a single dose of 600-mg/kg sodium valproate on embryonic day 12.5 had significantly fewer Purkinje cells in the cerebellar vermis and a reduction short of significant in the hemispheres

Schneider T, Roman A, Basta-Kaim A, Kubera M, Budziszewska B, Schneider K, Przewłocki R. Gender-specific behavioral and immunological alterations in an animal model of autism induced by prenatal exposure to valproic acid. Psychoneuroendocrinology. 2008 Apr 5.