Neurodevelopmental outcomes in children exposed to newer antiseizure medications: A systematic review

Knight, Rebecca A.; Wittkowski, Anja; Bromley, Rebecca

doi:10.1111/epi.16953

Cited by 40 publications

(47 citation statements)

References 59 publications

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“…This section provides a review of human data for specific ASMs, where available. A Medline (OVID) search was conducted (updated March 2021) and compared to the obtained results from two previously completed systematic reviews competed by this group [ 5 , 6 ].…”

Section: Specific Neurodevelopmental Outcomes For Specific Antiseizur...mentioning

confidence: 99%

Neurodevelopment Following Exposure to Antiseizure Medications in Utero: A Review

Bromley

Bluett-Duncan

2021

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: Exposure in the womb to antiseizure medications and their potential impact on the developing child's brain has long been researched. Despite this long period of interest, this review highlights above the well-known risks associated with valproate exposure; more data is required for conclusions regarding all other antiseizure medications. Limited experience with phenytoin and phenobarbital in monotherapy clearly defines the risk to later child postnatal functioning difficult. However, the evidence of an impact is stronger for phenobarbital than for phenytoin. The widely prescribed lamotrigine is limited in its investigation compared to unexposed control children. It has been demonstrated to carry a lower risk than valproate for specific outcomes; whether associated with a more moderate impact on broader aspects of neurodevelopmental functioning is still to be understood. Data for levetiracetam, topiramate, and oxcarbazepine are too limited to conclude most neurodevelopmental outcomes confidently. This slow accumulation of evidence impacts the safest use of medications in pregnancy and makes counseling women regarding the risks and benefits of specific antiseizure drugs difficult. Improved focus, funding, and research methodologies are urgently needed.

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Section: Specific Neurodevelopmental Outcomes For Specific Antiseizur...mentioning

confidence: 99%

Neurodevelopment Following Exposure to Antiseizure Medications in Utero: A Review

Bromley

Bluett-Duncan

2021

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“…In addition, parent-administered scales may pose risk of biased rating because parents are not blinded to type of medication exposure. 21 …”

Section: Levetiracetam Versus Controlsmentioning

confidence: 99%

“…This is inadequate to establish long-term effects on cognitive and behavioral development beyond childhood. 21 , 34 , 42 , 43 An evaluation in their adolescent years of exposed children is required. In addition, evaluation of dose effects is a key principle in neurobehavioral teratology and is important in supporting real-world clinical decision-making.…”

Section: Future Directionsmentioning

confidence: 99%

“…Nevertheless, in order to reveal dose effects, adequate sample sizes, utilizing ASM blood levels, are required. 21 Furthermore, most studies compared levetiracetam to unexposed or valproate and were important to show the relative risks. However, valproate now must be avoided in women of childbearing potential.…”

Section: Future Directionsmentioning

confidence: 99%

“…Adjustments for potential confounders are also required. 21 , 42 Finally, further research is needed for a better understanding of the underlying mechanisms of the neurodevelopmental effects of levetiracetam.…”

Section: Future Directionsmentioning

confidence: 99%

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Neurodevelopmental outcomes in children exposed prenatally to levetiracetam

Alsfouk

2022

Therapeutic Advances in Drug Safety

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Some old antiseizure medications (ASMs) pose teratogenic risks, including major congenital malformations and neurodevelopmental delay. Therefore, the use of new ASMs in pregnancy is increasing, particularly lamotrigine and levetiracetam. This is likely due to evidence of low risk of anatomical teratogenicity for both lamotrigine and levetiracetam. Regarding neurodevelopmental effects, lamotrigine is the most frequently investigated new ASM with information available for children up to 14 years of age. However, fewer data are available for the effects of levetiracetam on cognitive and behavioral development, with smaller cohorts and shorter follow-up. The aim of the present review was to explicate neurodevelopmental outcomes in children exposed prenatally to levetiracetam to support clinical decision-making. The available data do not indicate an increased risk of abnormal neurodevelopmental outcomes in children exposed prenatally to levetiracetam. Findings demonstrated comparable outcomes for levetiracetam versus controls and favorable outcomes for levetiracetam versus valproate on global and specific cognitive abilities, and behavioral problems. In addition, the available evidence shows no significant dose-effect association for levetiracetam on neurodevelopmental outcomes. However, this evidence cannot be determined definitively due to the limited numbers of exposures with relatively short follow-up. Therefore, further research is required. Plain Language Summary Antiseizure medications (ASMs) are medicines that inhibit the occurrence of seizures. Levetiracetam is a new ASM. Some old ASMs are linked with an increased risk of physical birth abnormalities and adverse effects on the child’s brain development. Therefore, the use of new ASMs in pregnancy is increasing, especially lamotrigine and levetiracetam. This is likely due to evidence of low risk of birth abnormalities for both lamotrigine and levetiracetam. Regarding effects on development of the brain, lamotrigine is the most frequently examined new ASM with information available for children up to 14 years of age. However, fewer data are available for the effects of levetiracetam on cognitive and behavioral development. Also, levetiracetam studies were smaller and shorter compared with studies investigating lamotrigine effects. The aim of this article was to review the child’s brain development effects after exposure to levetiracetam during pregnancy. The available data do not suggest an increased risk of the child having learning or thinking difficulties. Findings demonstrated comparable outcomes for levetiracetam versus controls (i.e. children unexposed to levetiracetam), and favorable outcomes for levetiracetam versus valproate. In addition, the available evidence shows no link between the higher dose of levetiracetam and an increased risk of adverse effects on the child’s brain development. However, this evidence cannot be determined definitively due to the limited numbers of children exposed to levetiracetam with relatively short duration of follow-up. Therefore, further research is required.

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Association of Prenatal Exposure to Antiseizure Medication With Risk of Autism and Intellectual Disability

et al. 2022

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IMPORTANCEWomen with epilepsy frequently need antiseizure medication (ASM) to prevent seizures in pregnancy. Risk of neurodevelopmental disorders after prenatal exposure to AMSs is uncertain.OBJECTIVE To determine whether children exposed prenatally to ASMs in monotherapy and duotherapy have increased risk of neurodevelopmental disorders. DESIGN, SETTING, AND PARTICIPANTSThe Nordic register-based study of antiepileptic drugs in pregnancy (SCAN-AED) is a population-based cohort study using health register and social register data from Denmark, Finland, Iceland, Norway, and Sweden (1996-2017; analysis performed February 2022). From 4 702 774 alive-born children with available mother-child identities and maternal prescription data, this study included 4 494 926 participants. Children from a multiple pregnancy or with chromosomal disorders or uncertain pregnancy length were excluded (n = 207 848).EXPOSURES Prenatal exposure to ASM determined from maternal prescription fills between last menstrual period and birth. MAIN OUTCOMES AND MEASURESWe estimated cumulative incidence at age 8 years in exposed and unexposed children. Cox regression adjusted for potential confounders yielded adjusted hazard ratios (aHRs) with 95% CIs for autism spectrum disorder (ASD), intellectual disability (ID), or any neurodevelopmental disorder (ASD and/or ID).RESULTS A total of 4 494 926 children were included; 2 306 993 (51.3%) were male, and the median (IQR) age at end of follow-up was 8 (4.0-12.1) years. Among 21 634 unexposed children of mothers with epilepsy, 1.5% had a diagnosis of ASD and 0.8% (numerators were not available because of personal data regulations in Denmark) of ID by age 8 years. In same-aged children of mothers with epilepsy exposed to topiramate and valproate monotherapy, 4.3% and 2.7%, respectively, had ASD, and 3.1% and 2.4% had ID. The aHRs for ASD and ID after topiramate exposure were 2.8 (95% CI, 1.4-5.7) and 3.5 (95% CI, 1.4-8.6), respectively, and after valproate exposure were 2.4 (95% CI, 1.7-3.3) and 2.5 (95% CI, 1.7-3.7). The aHRs were elevated with higher ASM doses compared with children from the general population. The duotherapies levetiracetam with carbamazepine and lamotrigine with topiramate were associated with increased risks of neurodevelopmental disorders in children of women with epilepsy: levetiracetam with carbamazepine: 8-year cumulative incidence, 5.7%; aHR, 3.5; 95% CI, 1.5-8.2; lamotrigine with topiramate: 8-year cumulative incidence, 7.5%; aHR, 2.4; 95% CI, 1.1-4.9. No increased risk was associated with levetiracetam with lamotrigine (8-year cumulative incidence, 1.6%; aHR, 0.9; 95% CI, 0.3-2.5). No consistently increased risks were observed for neurodevelopmental disorders after prenatal exposure to monotherapy with lamotrigine, levetiracetam, carbamazepin, oxcarbazepine, gapapentin, pregabalin, clonazepam, or phenobarbital. CONCLUSIONS AND RELEVANCEIn this cohort study, prenatal exposure to topiramate, valproate, and several duotherapies were associated with increased risks of neurodevel...

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Neurodevelopmental outcomes in children exposed to newer antiseizure medications: A systematic review

Cited by 40 publications

References 59 publications

Neurodevelopment Following Exposure to Antiseizure Medications in Utero: A Review

Neurodevelopment Following Exposure to Antiseizure Medications in Utero: A Review

Neurodevelopmental outcomes in children exposed prenatally to levetiracetam

Association of Prenatal Exposure to Antiseizure Medication With Risk of Autism and Intellectual Disability

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