Major malformations in infants exposed to antiepileptic drugs in utero, with emphasis on carbamazepine and valproic acid: a nation-wide, population-based register study

Abstract Background Cerebrovascular disorders have occurred more frequently in some Central Nervous System (CNS) disorders, such as epilepsy. Some CNS drugs have been associated with increased stroke risk. Our aim was to estimate the risk of ischaemic stroke in patients exposed to antiepileptic drugs (AED). Methods Population-based matched case-control study using SIDIAP database, based in electronic health records from primary healthcare from Catalonia, Spain. Cases were those patients with a registered diagnosis of first stroke during 2009–2014. Up to 10 controls were selected for each case and matched by sex, age, and geographic area and without a prior diagnosis of stroke. We considered global drug exposure to AED, past and current exposure and exposure in monotherapy to each AED. Results 2,865 cases and 19,406 controls were exposed to AED during the study period. Global exposure to levetiracetam [(ORadj3.3, CI95 % 2.8-4.0)], phenytoin [ORadj1.5, CI95 % 1.2–41.9)], and valproic acid [(ORadj 1.3, CI95 % 1.1–1.6)], showed significantly association to ischaemic stroke that was also maintained with current exposure of levetiracetam [ORadj4.1, CI95 % 3.3–5.2)] and valproic acid [ORadj1.4, CI95 % 1.1–1.9)]. Current levetiracetam monotherapy showed a very high risk of ischaemic stroke [(ORadj 5.1, CI95 % 3.7–6.9)]. Conclusions Drugs used for other conditions than epilepsy (pregabalin, gabapentin) were the most used AED and both did not show a risk. Levetiracetam shows a risk for stroke even when assessed in current monotherapy. The lack of data regarding the link with diagnosis and severity in our study makes it necessary to conduct further studies to confirm or dismiss our results, focussing on levetiracetam.

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Relation of in-utero exposure to antiepileptic drugs to pregnancy duration and size at birth

10.1101/574269 ◽

2019 ◽

Author(s):

Andrea V Margulis ◽

Sonia Hernandez-Diaz ◽

Thomas McElrath ◽

Kenneth J Rothman ◽

Estel Plana ◽

...

Keyword(s):

Valproic Acid ◽

Birth Weight ◽

Antiepileptic Drugs ◽

Head Circumference ◽

In Utero ◽

Z Score ◽

Reference Drug ◽

Z Scores ◽

Effect Measure Modification ◽

Size At Birth

ABSTRACTBackgroundThe associations of individual antiepileptic drugs (AEDs) with pregnancy duration and size at birth, and potential dose relations, are not well characterized.MethodsThis cohort study used nationwide Swedish register data (1996-2013). Adjusting for smoking, epilepsy and other AED indications, we used linear and quantile regression to explore associations with pregnancy duration, and birth weight, length, and head circumference (the last three operationalized as z-scores). We used logistic regression for preterm delivery, small for gestational age, and microcephaly. Lamotrigine was the reference drug.Results6,720 infants were exposed to AEDs in utero; AED exposure increased over the study period. Relative to lamotrigine-exposed infants, carbamazepine-exposed infants were born, on average, 1.3 days earlier (mean [95% confidence interval]: −1.3 [−2.3 to −0.3]); were 0.1 standard deviations (SDs) lighter (−0.1 [−0.2 to 0.0]); and had a head circumference that was 0.2 SDs smaller (−0.2 [−0.3 to −0.1]). Pregabalin-exposed infants were born, on average, 1.1 days earlier (1.1 [−3.0 to 0.8]); were 0.1 SDs lighter (−0.1 [−0.3 to 0.0]); and had the same head circumference. Levetiracetam-exposed infants were born, on average, 0.5 days earlier (−0.5 [−2.6 to 1.6]); were 0. 1 SDs lighter (−0.1 [−0.3 to 0.0]); and were 0.1 SDs smaller (−0.1 [−0.3 to 0.1]) in head circumference. Valproic acid–exposed infants had, on average, the same duration of gestation and birth weight z-score, but were 0.2 SDs smaller (−0.2 [−0.2 to −0.1]) in head circumference. More negative associations at the left tail of pregnancy duration and birth weight z-score, effect-measure modification, and dose-response relations were noted for some of the associations. Observed associations were generally of smaller magnitude than that of smoking, assessed as a potential confounder in the same models.ConclusionsIn comparison with lamotrigine, valproic acid and carbamazepine had a more negative association with head circumference than other study AEDs.

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School performance at age 16 in children exposed to antiepileptic drugs in utero-A population-based study

Epilepsia ◽

10.1111/j.1528-1167.2010.02778.x ◽

2010 ◽

pp. no-no

Author(s):

Lisa Forsberg ◽

Katarina Wide ◽

Bengt Källén

Keyword(s):

Antiepileptic Drugs ◽

School Performance ◽

Population Based ◽

In Utero ◽

Population Based Study

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Risk of early neurodevelopmental disorders associated with in utero exposure to valproate and other antiepileptic drugs: a nationwide cohort study in France

Scientific Reports ◽

10.1038/s41598-020-74409-x ◽

2020 ◽

Vol 10 (1) ◽

Cited By ~ 2

Author(s):

Joël Coste ◽

Pierre-Olivier Blotiere ◽

Sara Miranda ◽

Yann Mikaeloff ◽

Hugo Peyre ◽

...

Keyword(s):

Cohort Study ◽

Antiepileptic Drugs ◽

Neurodevelopmental Disorders ◽

Speech Therapy ◽

Population Based ◽

In Utero ◽

In Utero Exposure ◽

Cox Proportional Hazard ◽

Increased Risk ◽

Cox Proportional Hazard Models

Abstract Information available on the risks of neurodevelopmental disorders (NDs) associated with in utero exposure to valproate (VPA) and to other antiepileptic drugs (AEDs) is limited. A nationwide population-based cohort study was conducted based on comprehensive data of the French National Health Data System (SNDS). Liveborn infants without brain malformation, born between January 2011 and December 2014, were followed from birth up to December 2016. NDs were identified based on diagnoses of mental or behavioural disorders and utilization of speech therapy, orthoptic or psychiatric services. The risk of NDs was compared between children exposed in utero to AED monotherapy and unexposed children, using Cox proportional hazard models adjusted for maternal and neonatal characteristics. The cohort included 1,721,990 children, 8848 of whom were exposed in utero to AED monotherapy. During a mean follow-up of 3.6 years, 15,458 children had a diagnosis of mental or behavioural disorder. In utero exposure to VPA was associated with an increased risk of NDs overall (aHR: 3.7; 95% CI 2.8–4.9) and among children born to a mother without mental illness (aHR 5.1; 95% CI 3.6–7.3). A dose–response relationship was demonstrated and the risk of NDs was more particularly increased for an exposure to VPA during the second or third trimesters of pregnancy. Among the other AEDs, only pregabalin was consistently associated with an increased risk of NDs (aHR: 1.5; 95% CI 1.0–2.1). This study confirms a four to fivefold increased risk of early NDs associated with exposure to VPA during pregnancy. The risk associated with other AEDs appears much lower.

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