Prenatal Valproate Exposure May Boost ADHD Risk by Almost 50%

Pauline Anderson

January 08, 2019

Jakob Christensen,

Prenatal exposure to the anti-epileptic drug (AED) valproate is associated with a 48% increased risk of attention deficit/hyperactivity disorder (ADHD) in offspring, a large population-based study shows.

This finding is "both worrying and reassuring," principal investigator Jakob Christensen, MD, PhD, Aarhus University Hospital, Denmark, told Medscape Medical News.

"There is a significant increased risk" of ADHD in children exposed prenatally to valproate, but the actual number of valproate exposures is small, he said.

"If you're treating a woman who needs to be on valproate in pregnancy in order to control seizures, you would now be able to give information on the associated risk," Christensen added.

The study was published online January 4 in JAMA Network Open.

Large, Longitudinal Study

Previous research has linked prenatal exposure to valproate to an increased risk for congenital malformations, poor cognitive function, and autism in offspring. Studies looking at valproate and ADHD outcomes have generally been small.

The new study included all live-born singleton children in Denmark between January 1, 1997, and December 31, 2011. The cohort was followed from birth until an ADHD diagnosis, death, emigration, or December 31, 2015, whichever came first.

Because every individual in Denmark has a unique identification number, researchers were able to link individual information in various national registries. This included the Danish National Prescription Registry, which gathers information on all prescriptions purchased by patients, including AEDs.

In addition to valproate, the study also estimated the risk of ADHD in the offspring to mothers who took other AEDs, including carbamazepine, clonazepam, lamotrigine, and oxcarbazepine. These drugs were the most commonly used AEDs in Denmark during the study period.

The drug exposure window ranged from 30 days before the estimated day of conception to the date of birth.

For ADHD information, researchers gathered data on filled prescriptions for drugs used to treat this condition and diagnoses from hospital-based registers.

The investigators also tapped into the Danish Medical Birth Registry for information on parity. From this registry, they identified children diagnosed with congenital malformations and mothers diagnosed with epilepsy before the birth of the child.

In addition, researchers identified mothers diagnosed with psychiatric disorders before their child's birth from the Danish Psychiatric Central Research Register. The study included 913,302 children who were a mean age of 10.1 years.

Of these, 580 children were exposed to valproate during pregnancy (monotherapy and polytherapy combined) and 912,722 were not.

Compared with women who didn't use valproate during pregnancy, those who did were younger and more often diagnosed with epilepsy and psychiatric disorders. More exposed children were diagnosed with congenital malformations during the first year of life (11.7% vs 4.3%).

Increased Risk of 48%

A total of 29,445 children were identified as having ADHD. The mean age at diagnosis was 8.8 years.

Of the children unexposed to valproate, 3.2% had ADHD. Of the exposed children, 8.4% had ADHD.

Compared with the unexposed children, those who were prenatally exposed to valproate had a 48% increased risk of ADHD (hazard ratio [HR], 1.48; 95% CI, 1.09 - 2.00) after adjusting for maternal age, psychiatric history, epilepsy, diabetes, sex of the child, year of birth, and parity.

Christensen explained that adjusting for year of birth was important as use of valproate has diminished in recent years because of concerns over congenital malformations.

That the risk of ADHD was still significant after adjusting for congenital malformations and then excluding all children diagnosed with congenital malformations "suggests that the increased ADHD risk was not confined to children with valproate-induced congenital malformations," the authors write.

The absolute 15-year risk of ADHD was 4.6% (95% CI, 4.5% - 4.6%) in children unexposed to valproate and 11.0% (95% CI, 8.2% - 14.2%) in those exposed to valproate in pregnancy.

When looking only at children born to women with epilepsy, valproate use during pregnancy was associated with a 39% higher risk of ADHD (aHR, 1.39; 95% CI, 1.00 - 1.93) compared with those whose moms didn't take valproate during pregnancy.

There was no significant difference in risk of ADHD between children of mothers without epilepsy who did and did not take valproate during pregnancy.

Almost all the women taking valproate did so in the first trimester; only a minority used it later in pregnancy. "We were unable to show any consistent difference" between exposure at different stages of pregnancy, said Christensen.

"You would rarely expect women who are pregnant to start using valproate during the second or third trimesters."

Dose Makes No Difference to Risk

The association persisted when examining different doses of valproate.

"It's been shown that there is an association with dose for congenital malformations, and possibly for the IQ of children, but we found almost similar estimates of ADHD for high and low doses of valproate," said Christensen.

He and his colleagues also did not find a difference in ADHD risk between valproate monotherapy and polytherapy. "We had a chance to study a number of other drugs frequently used in Denmark to look for similar associations, but we were unable to show any clear association," said Christensen.

Researchers stressed that the number of exposed children and the statistical precision were low for analyses pertaining to valproate dose and polytherapy, so results for these should be interpreted with caution.

Valproate exposure was relatively rare (63.5 children per 100,000 children), and the association with offspring ADHD was modest. "Thus, even in a cohort of this size, the additional number of children who would develop ADHD due to prenatal valproate exposure is low", wrote the authors.

Lamotrigine, an AED commonly used for epilepsy in Denmark, does not seem to be associated with an increased ADHD risk. Compared with prenatal exposure to lamotrigine, the risk of ADHD associated with prenatal valproate exposure in this study was increased by more than twofold (aHR, 2.16; 95% CI, 1.34 - 3.48).

Although not significant, analyses of other AEDs compared with lamotrigine suggest that some may also carry a risk of ADHD in offspring. For example, there was an increased risk associated with carbamazepine (aHR, 1.79; 95% CI, 1.06 - 3.04) and clonazepam (aHR, 1.96; 95% CI, 1.09 - 3.50), which has not been previously described.

These associations "were kind of unexpected, at least to me," said Christensen. It's cause for additional and larger studies to see if that's something that can be replicated or was just a chance finding. We will have to keep monitoring this association," he said.

The results run counter to a recent meta-analysis that showed no association between prenatal valproate exposure and ADHD symptoms in offspring. Christensen pointed out that this new study was larger, had longer follow-up, and had greater power than the studies in this meta-analysis.

How might valproate affect the developing fetus? It's not exactly clear, but this drug, which is chemically different from other AEDs, may interfere in some way with the folding of DNA or with the developing central nervous system.

"If you look at the behavior of animals exposed to valproate prenatally, it's clearly different from other animals not exposed," said Christensen.

Public Health Warnings

The US Department of Health and Human Services and European Medicines Agency recently issued measures to avoid valproate exposure in pregnancy to protect the fetus.

But more than 50% of valproate-exposed children in the study were born before valproate was contraindicated.

To account for risk of ADHD transmitted from the mother, researchers excluded women with ADHD from the analyses. This only had a very limited impact on the risk estimate.

As symptoms of ADHD may not be recognized before age 3 years, researchers included another sensitivity analysis in which follow-up started at age 3 years for each of the AEDs analyzed as monotherapy. This analysis also found an increased risk associated with valproate exposure in pregnancy.

A potential limitation of the study was that valproate is now contraindicated in pregnant women, so those who continue to be prescribed the drug during pregnancy may differ from their counterparts who aren't.

"We may not have fully adjusted for all possible contributing factors, but this may be impossible," said Christensen.

"Clearly, epilepsy severity would be a factor. Who would take valproate unless they were pressed to do so?"

He noted that there are patients who only respond to valproate for seizure control.

Another potential limitation was that the study used registry data and women may not have taken the prescribed valproate or taken all that was prescribed.

However, for drugs used to treat chronic conditions, including AEDs, the agreement between self-reports and dispensing data is high, the authors note.

In addition, investigators estimated the average daily dose based on the total amount of redeemed prescriptions throughout pregnancy. It's unlikely, Christensen noted, that women would repeatedly purchase medication and not take it.

The investigators did not control for medications other than AEDs, including folic acid, which may affect neurodevelopment.

The new findings reinforce the need for "sufficient follow-up and support and medication if needed" of these women and their children, he added.

He said he would like to see the results replicated using different cohorts, perhaps in the UK or United States.

Risk Confirmed

Commenting on the study for Medscape Medical News, Kimford J. Meador, MD, Stanford University School of Medicine, Palo Alto, California, said "the findings demonstrate that fetal valproate exposure poses a risk for ADHD and are consistent with multiple studies demonstrating that fetal valproate exposure poses a risk for other adverse neurodevelopmental effects."

The study has a number of strengths, which Meador said include the large population-based sample, lack of attrition, confirmed ADHD diagnosis combined with drug prescriptions for ADHD, and control for multiple potentially confounding factors.

However, he said the study also has limitations, such as its observational nature, no assessment of seizures or drug blood levels, and the lack of control for all other fetal drug exposures, he said.

Mounting research shows that fetal valproate exposure poses risks for behavioral as well as anatomical teratogenesis, said Meador. As for risks of ADHD, he noted that prior literature has had "mixed results."

He agreed that the discrepancy between the current study and the recent meta-analysis that found no statistically significant increased risk of ADHD due to prenatal valproate exposure "might be due to the meta-analysis using different analytical approaches and examining studies with smaller sample sizes, higher attrition rates, shorter follow-ups, and cohort differences."  

Christensen was supported by the Danish Epilepsy Association, Central Denmark Region, and a Novo Nordisk Foundation grant. He has reported receiving honoraria from serving on the scientific advisory boards of and giving lectures for UCB Nordic and Eisai AB and travel funding from UCB Nordic. Meador has reported receiving research support from the National Institutes of Health and Sunovion Pharmaceuticals and travel support from UCB Pharma. The Epilepsy Study Consortium pays Meador's university for his research consultant time related to Eisai, GW Pharmaceuticals, NeuroPace, Novartis, Supernus, Upsher-Smith Laboratories, UCB Pharma, and Vivus Pharmaceuticals.

JAMA Netw Open. Published online January 4, 2019. Full text

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