Cognition in school-age children exposed to levetiracetam, topiramate, or sodium valproate

Bromley, Rebecca; Calderbank, Rebecca; Cheyne, Christopher P.; Rooney, Claire; Trayner, Penny; Clayton‐Smith, Jill; Garcı́a-Fiñana, Marta; Irwin, B.; Morrow, James; Shallcross, Rebekah; Baker, Gus A.

doi:10.1212/wnl.0000000000003157

Cited by 100 publications

(126 citation statements)

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“…In the mothers not taking folic acid supplementation, 63% (n = 5) of AED-exposed children had language Table 1 Characteristics of children of mothers with and without epilepsy Characteristics AED-exposed children of mothers with epilepsy n = 346 AED-unexposed children of mothers with epilepsy n = 388 15 (5) 17 (4) 2418 (2) Maternal report of seldom/never helping their child read letters and sounds during a typical week at age 5 years 17 (15) 22 (15) 6675 (16) Maternal report of never reading to their child at age 8 years 6 (5) 9 (6) 2959 (7) Language impairment age 1.5 years i 43 (20) 24 (9) 7896 (11) Language impairment age 3 years j 22 (12) 14 (7) 4182 (7) AED, antiepileptic drug; BMI, body mass index; TC seizure(s), tonic-clonic seizure(s). N may vary within the groups due to missing data.…”

Section: Maternal Folate Status and Language Impairmentmentioning

confidence: 99%

Language impairment in children aged 5 and 8 years after antiepileptic drug exposure in utero – the Norwegian Mother and Child Cohort Study

Husebye

Gilhus

Spigset

et al. 2019

Euro J of Neurology

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Background and purpose The purpose was to examine the consequences of antiepileptic drug (AED) exposure during pregnancy on language abilities in children aged 5 and 8 years of mothers with epilepsy. Methods The study population included children of mothers with and without epilepsy enrolled in the Norwegian Mother and Child Cohort Study 1999–2008. Mothers prospectively provided information on epilepsy diagnosis, AED use during pregnancy and the child’s language abilities at age 5 and 8 years, in questionnaires with validated language screening tools. AED concentrations in gestation week 17–19 and in the umbilical cord were measured. Results The study population included 346 AED‐exposed and 388 AED‐unexposed children of mothers with epilepsy, and 113 674 children of mothers without epilepsy. Mothers of 117 and 121 AED‐exposed children responded to the questionnaires at age 5 and 8 years, respectively. For AED‐exposed children, the adjusted odds ratio for language impairment was 1.6 [confidence interval (CI) 1.1–2.5, P = 0.03] at age 5 years and 2.0 (CI 1.4–3.0, P < 0.001) at age 8 years, compared to children of mothers without epilepsy. Children exposed to carbamazepine monotherapy had a significantly increased risk of language impairment compared to control children at age 8 years (adjusted odds ratio 3.8, CI 1.6–9.0, P = 0.002). Higher maternal valproate concentrations correlated with language impairment at age 5 years. Periconceptional folic acid supplement use protected against AED‐associated language impairment. Conclusion Foetal AED exposure in utero is associated with an increased risk of language impairment in children aged 5 and 8 years of mothers with epilepsy. Periconceptional folic acid use had a protective effect on AED‐associated language impairment.

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Section: Maternal Folate Status and Language Impairmentmentioning

confidence: 99%

Language impairment in children aged 5 and 8 years after antiepileptic drug exposure in utero – the Norwegian Mother and Child Cohort Study

Husebye

Gilhus

Spigset

et al. 2019

Euro J of Neurology

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“…5 Behavioral problems occur predominantly in valproate (VPA)-exposed children 3,6-11 ; they have a higher risk of autism spectrum disorders (ASDs) [12][13][14] and attention-deficit/hyperactivity disorder (ADHD). 11 Because most studies, so far, used different methodologies, in children of different ages, using different rating systems, this may have led to different results. 3,6,7,9 The only study that examined behavioral functioning of school-aged children exposed to levetiracetam (LEV) found no risk of behavioral problems.…”

Section: Introductionmentioning

confidence: 99%

Behavioral problems in children of mothers with epilepsy prenatally exposed to valproate, carbamazepine, lamotrigine, or levetiracetam monotherapy

et al. 2019

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ObjectiveTo examine the behavioral functioning of children prenatally exposed to carbamazepine (CBZ), lamotrigine (LTG), levetiracetam (LEV), or valproate (VPA) monotherapy.MethodsIn collaboration with the European Registry of Antiepileptic Drugs and Pregnancy (EURAP), the Dutch EURAP & Development study was designed, a prospective observational study. Between January 2015 and March 2018, the Child Behavior Checklist and the Social Emotional Questionnaire were used to examine the nature and severity of behavioral problems. VPA‐exposed children were compared to children exposed to CBZ, LTG, or LEV, taking potential confounders into account. A direct comparison was also made between LTG and LEV, as these are first‐choice treatments for many women with epilepsy of childbearing potential.ResultsOf the 405 invited, 181 children were included; 26 were exposed to VPA, 37 to CBZ, 88 to LTG, and 30 to LEV. For most children, both parents completed the behavioral questionnaires. Across all four antiepileptic drug (AED) exposure groups, high percentages of children with clinically relevant behavior problems were found, with behavioral problems occurring in 32% of VPA‐exposed children, 14% of CBZ, 16% of LTG, and 14% of LEV. After controlling for potential confounders, VPA‐exposed children had significantly more social problems than those exposed to LTG (−2.8, 95% confidence interval [CI] = −5.2 to −0.4; P = 0.022) or LEV (−3.2, CI: −6.1 to −0.3; P = 0.028), and significantly more attention problems than LEV‐exposed children (−3.7, CI: −6.7 to −0.8; P = 0.013). LTG‐exposed children had significantly more attention deficit (−9.2, CI: −17.3 to 1.1; P = 0.026), but significantly less anxious behavior when compared to LEV‐exposed children (9.0, CI: 0.3‐17.6; P = 0.042).SignificanceCompared to population norms, a high proportion of children of mothers with epilepsy exposed prenatally to monotherapy with four common AEDs had clinical behavioral problems reported by parents. Different patterns were seen, with some but not all subscales raised for all AED exposure groups. It is important that prenatally AED‐exposed children are regularly screened for behavioral problems so that appropriate help can be provided.

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“…They found no difference between the developmental scores of levetiracetam prenatally exposed children and controls, while VPA-exposed children scored, on average, 15.8 points below that of children exposed to levetiracetam on measures of gross motor skills (95% CI, 24.5-27.1; p < 0.001), 6.4 points below on comprehension language abilities (95% CI, 11.0-21.8; p 5 0.005), and 9.5 points below on expressive language abilities (95% CI, 14.7-24.4; p < 0.001) (Shallcross et al, 2014). Bromley et al (2016) also found that 42 children born to levetiracetam treated mothers had similar developmental scores to 55 control children . In summary, levetiracetam seems to be a relatively safe drug in pregnancy.…”

Section: Levetiracetammentioning

confidence: 99%

“…Over half of the exposed children received speech, occupational, or physical therapy (Rihtman et al, ). In a recently published study, Bromley et al () compared the cognitive functioning of children exposed to levetiracetam ( n = 42), topiramate ( n = 27), or valproate ( n = 47), and control children ( n = 55). They reported no association between the IQ, memory, language, or attentional abilities, and prenatal exposure to levetiracetam or topiramate, although the children born to VPA‐treated mothers had developmental delays (Bromley et al, ).…”

Section: Mood Stabilizersmentioning

confidence: 99%

Antidepressants, Antipsychotics, and Mood Stabilizers in Pregnancy: What Do We Know and How Should We Treat Pregnant Women with Depression

Ornoy¹,

Weinstein-Fudim²,

Ergaz³

2017

Birth Defects Research

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Depression is generally treated with antidepressants, but may often need antipsychotics and mood stabilizers. We discuss the updated data regarding the safety in pregnancy of antidepressants and antipsychotics, except selective serotonin reuptake inhibitors, and their possible impact on the long-term development of the offspring. Several earlier studies demonstrated a slight increase in the rate of major anomalies following maternal tricyclic antidepressant treatment, but most current literature shows their relative safety in pregnancy. Data on the development of the offspring are also reassuring. The antipsychotic drugs are also safe for the developing fetus and do not seem to induce developmental delay. Both groups of drugs may cause perinatal withdrawal symptoms and difficulties in neonatal adaptation. The mood stabilizers, lithium, and several anti-epileptic drugs, may adversely affect the developing embryo and fetus. While valproic acid, carbamazepine, and topiramate are teratogenic and may also affect postnatal development, the newer antiepileptic and mood stabilizers, lamotrigine and levetiracetam, seem to be safe in pregnancy and apparently have no long-term neurodevelopmental damage. Lithium may increase the rate of cardiac anomalies, especially of Ebstein's anomaly, and may warrant a mid-trimester fetal echocardiography. Although data on the development of the offspring are reassuring, we should remember that most studies were carried out during early childhood, at a time when inattention, learning difficulties, behavioral and psychiatric problems are not yet identifiable. When considering medical treatment for depression in women at child-bearing age, we have to weigh the severity of the symptoms and their impact on the developing fetus and child. Birth Defects Research 109:933-956, 2017.© 2017 Wiley Periodicals, Inc.

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Cognition in school-age children exposed to levetiracetam, topiramate, or sodium valproate

Abstract: Preconception counseling should include discussion of neurodevelopmental outcomes for specific treatments and their doses and women should be made aware of the limited nature of the evidence base for newer antiepileptic drugs.

Cited by 100 publications

References 27 publications

Language impairment in children aged 5 and 8 years after antiepileptic drug exposure in utero – the Norwegian Mother and Child Cohort Study

Language impairment in children aged 5 and 8 years after antiepileptic drug exposure in utero – the Norwegian Mother and Child Cohort Study

Behavioral problems in children of mothers with epilepsy prenatally exposed to valproate, carbamazepine, lamotrigine, or levetiracetam monotherapy

Antidepressants, Antipsychotics, and Mood Stabilizers in Pregnancy: What Do We Know and How Should We Treat Pregnant Women with Depression

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