Prenatal Publicity to Valproic Acid Linked to Elevated Threat for Autism, ADHD

Prenatal publicity to valproate has been related to an elevated threat (10%) for a broad vary of congenital malformations together with neural tube defects, in addition to hostile neurodevelopmental sequelae, together with decrease IQ and developmental delays in offspring. A number of research have proven that publicity to valproic acid (Depakote) could also be related to elevated threat of autism spectrum problems or autistic traits and/or attentional issues.

A brand new research examines the affiliation between prenatal publicity to antiepileptic medicine (AEDs) and threat for autism spectrum problems (ASD) and a focus deficit/hyperactivity dysfunction (ADHD) within the youngsters of ladies with epilepsy.  On this research, Wiggs and colleagues use knowledge from the Swedish medical register to review threat for ASD and ADHD in a gaggle of 14,614 youngsters born to moms with epilepsy between 1996 and 2011 and adopted up by way of 2013.  On this cohort, about 23% of the moms used an anticonvulsant in the course of the first trimester of being pregnant, mostly carbamazepine (9.7%), lamotrigine (6.8%), and valproic acid (n=699 or 4.8%).  

Youngsters with ASD had been recognized utilizing ICD-10 diagnoses within the medical file and people with ADHD had been recognized utilizing ICD-10 diagnoses or the redemption of a prescription for an ADHD remedy.

Valproate Publicity Related to Elevated Threat for ASD and ADHD

After adjusting for potential confounding variables, together with parental psychiatric historical past and seizure severity, they noticed that using valproic acid was related to a 2.3-fold elevated threat for ASD (hazard ratio [HR] 2.30, 95% CI 1.53-3.47) and a 1.7-fold elevated threat for ADHD (HR 1.74, 95% CI 1.28-2.38) in comparison with youngsters whose moms didn’t use AEDs.  Use of carbamazepine (n=1,417, 9.7%) was related to an elevated threat of ASD; nonetheless, the danger was considerably attenuated after adjusting for confounders (HR=1.42, 95%CI=1.00-2.02) and additional restriction to monotherapy (HR=1.26, 95%CI=0.88-1.79). 

Use of lamotrigine was not related to threat for ASD (HR=0.66, 95%CI=0.27-1.58) or ADHD (HR=1.00, 95%CI=0.59-1.69). 

The strengths of the research embrace the truth that this was a big, population-based research with a comparatively lengthy follow-up interval of as much as 17 years.  Given the dimensions of the pattern the authors had been in a position to alter for a lot of doubtlessly confounding threat elements for autism together with maternal and paternal age at conception, parental psychiatric historical past, gestational age, start weight, intercourse, and parity. Nevertheless, limitations of the research embrace insufficient details about different doubtlessly confounding elements, together with perinatal folate supplementation, using alcohol or illicit medicine throughout being pregnant, and doable missed psychiatric diagnoses within the sufferers.

Findings are According to Earlier Research

The noticed improve in threat for ASD on this research was considerably decrease than that noticed in a Danish research together with 508 youngsters uncovered to valproate.  Within the Danish cohort, absolutely the threat was 4.42% for autism spectrum dysfunction (adjusted HR, 2.9, 95% CI, 1.7-4.9), and absolutely the threat was 2.50% for childhood autism (adjusted HR 5.2, 95% CI, 2.7-10.0). Nevertheless, when the evaluation was restricted solely to the 6584 youngsters born to ladies with epilepsy, the danger for autism spectrum dysfunction  fell, with and adjusted HR 1.7 (95% CI 0.9-3.2), which has similarities to that noticed within the present  research.

The truth that the danger for ASD seems to be increased amongst youngsters born to moms with out epilepsy — presumably most of those ladies had bipolar dysfunction — means that there could also be an interplay between genetic elements and environmental exposures which magnifies the danger for worse neurodevelopmental outcomes.  

Earlier research have additionally documented an elevated threat of ADHD in youngsters uncovered to valproate in utero.  As a result of ADHD is each underdiagnosed and overdiagnosed, it could be tough to glean correct knowledge on its prevalence from the medical file.  Moreover, one may argue that the danger may be underestimated as half of the kids had been adopted solely to the age of 9 years, and ADHD, significantly milder circumstances, is commonly not recognized till youngsters are older.    

Avoiding Valproic Acid In Ladies of Childbearing Age

A number of research have documented that prenatal publicity to valproate has been related to an elevated threat (10%) of a broad vary of congenital malformations together with neural tube defects, in addition to hostile neurodevelopmental sequelae.  Provided that 50% of pregnancies are unplanned in the USA, it’s questionable if valproic acid can be utilized safely in ladies of chilbearing age.

We urge clinicians to stick to the next suggestions set forth by the European Medical Company concerning using valproic acid in ladies of childbearing age:


Ruta Nonacs, MD PhD


Christensen J, Grønborg TK, Sørensen MJ, Schendel D, Parner ET, Pedersen LH, Vestergaard M. Prenatal valproate publicity and threat of autism spectrum problems and childhood autism. JAMA. 2013: 24;309(16): 1696-703.

Christensen J, Pedersen LH, Solar Y.Affiliation of Prenatal Publicity to Valproate and Different Antiepileptic Medication With Threat for Consideration-Deficit/Hyperactivity Dysfunction in Offspring.  JAMA Netw Open 2019.

Wiggs KK, Rickert ME, Sujan AC, Quinn PD, Larsson H, Lichtenstein P, Oberg AS, D’Onofrio BM.  Antiseizure remedy use throughout being pregnant and threat of ASD and ADHD in youngsters.  Neurology. 2020 Dec 15;95(24):e3232-e3240.





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