Prenatal Valproic Acid (Depakote) Publicity Will increase Threat for Neurodevelopmental Problems

Whereas we’ve got appreciable data relating to the teratogenic danger related to prenatal publicity to numerous antiepileptic medication (AEDs), we’ve got significantly much less data on the impression of publicity to AEDs on behavioral outcomes in kids.  A number of research have proven that publicity to valproic acid (Depakote) could also be related to elevated danger of autistic traits and/or attentional issues; nonetheless, we’ve got much less data on the chance of different conduct issues.  

In a nationwide population-based cohort research, researchers used information from the French Nationwide Well being Information System to look at the prevalence of neurodevelopmental issues amongst kids with prenatal publicity to AEDs.  Singleton liveborn infants (with out mind malformations) born between January 2011 and December 2014 have been adopted from start as much as December 2016. Neurodevelopmental issues (NDs) have been recognized based mostly on diagnoses of psychiatric or behavioural issues documented within the medical document and utilization of speech remedy, orthoptic (associated to eye motion issues) or psychiatric companies. 

The cohort consisted of 1,721,990 kids, 8848 of whom have been uncovered prenatally to AED monotherapy. Throughout a imply follow-up of three.6 years, 15,458 kids had a prognosis of a psychiatric or behavioural dysfunction. The chance of NDs was in contrast between kids with prenatal publicity to AED monotherapy and unexposed kids;  Cox proportional hazard regression fashions have been used to estimate adjusted hazard ratios (aHRs).

Prenatal publicity to valproic acid (VPA) was related to an elevated danger of NDs general (aHR: 3.7; 95% CI 2.8–4.9), particularly pervasive developmental issues (aHR, 4.6; 95% CI 2.9–7.5), issues of psychological improvement (aHR, 4.7; 95% CI 3.5–6.4) and psychological retardation (aHR, 5.1; 95% CI 3.1–8.5).

The chance of NDs amongst kids uncovered to VPA differed in keeping with the timing of the publicity.  Extended exposures throughout being pregnant (1st trimester and at the very least in the course of the 2nd or third trimester) have been related to greater danger, whereas publicity solely in the course of the first trimester of being pregnant was not related to an elevated danger of NDs.  As well as, they noticed a dose–response relationship between VPA publicity and danger of NDs, with the very best danger of NDs noticed in kids uncovered to > 1100 mg of VPA per day.   Nevertheless, danger for psychological retardation was as excessive within the lowest dose group as within the highest.  

The outcomes of the current research don’t counsel an elevated danger of a prognosis of NDs related to publicity to lamotrigine, clonazepam, gabapentin, levetiracetam or oxcarbazepine throughout being pregnant. Among the many different AEDs, solely pregabalin was persistently related to an elevated danger of NDs (aHR: 1.5; 95% CI 1.0–2.1); nonetheless, it must be famous that if a 95% CI consists of the null worth of 1, there’s inadequate proof to conclude that the teams are statistically considerably completely different.  It is a sign that wants additional investigation.          

The Backside Line

Publicity to valproic acid in the course of the second and third trimesters was related to a four- to five-fold enhance in danger for neurodevelopmental issues.  This discovering is according to earlier research exhibiting an affiliation between valproate publicity and elevated danger of autistic traits, attentional issues, and poor faculty efficiency. Because the oldest kids on this research have been 5 years of age, it’s doable that this research really underestimates the chance for NDs, as some NDs, together with attention-deficit/hyperactivity dysfunction (ADHD) and studying disabilities, could grow to be evident solely in older kids.  

Whereas different AEDs, together with clonazepam, gabapentin, and topiramate, weren’t related to elevated danger of NDs, we must always interpret these outcomes cautiously.  In distinction to lamotrigine and valproic acid which have been usually prescribed all through being pregnant, publicity to clonazepam, gabapentin, pregabalin and topiramate, was normally restricted to the primary trimester of being pregnant.  As a result of it seems that VPA confers the best danger for NDs when administered in the course of the second and third trimesters, we have to particularly have a look at the developmental outcomes of kids uncovered to those different AEDs in the course of the second and third trimesters.  

There have lengthy been considerations relating to the usage of the anticonvulsant valproic acid throughout being pregnant.  First trimester use of valproate has been related to a 3-5% danger of neural tube defects, in addition to an elevated danger of different malformations affecting the guts, limbs, and genitals. Whereas the FDA has not restricted the usage of this medicine in ladies, the European Drugs Company (EMA)’s Pharmacovigilance and Threat Evaluation Committee beneficial proscribing the usage of valproic acid in ladies of reproductive age.  Given this teratogenic danger and a rising physique of literature indicating a better danger of neurodevelopmental issues in kids with prenatal publicity to VPA, we should query the usage of valproic acid in ladies of reproductive age. 


Ruta Nonacs, MD PhD 


Coste J, Blotiere PO, Miranda S, Mikaeloff Y, Peyre H, Ramus F, Zureik M, Weill A, Dray-Spira R.  Threat of early neurodevelopmental issues related to in utero publicity to valproate and different antiepileptic medication: a nationwide cohort research in France.  Sci Rep. 2020 Oct 22;10(1):17362. Free Article.


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