Neurodevelopmental delay in children exposed to antiepileptic drugs in utero: A critical review directed at structural study-bias

Nicolai, Joost; Vles, Johan S.H.; Aldenkamp, Albert P.

doi:10.1016/j.jns.2008.03.004

Cited by 44 publications

(25 citation statements)

References 113 publications

(131 reference statements)

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“…1 Determining the association between exposure to AEDs and child cognitive functioning represents a challenge, and a number of different methodologies have been utilized in its investigation including case studies, [2][3][4] retrospective studies, 5,6 and prospective studies. [7][8][9][10][11][12][13][14][15] Despite limitations, 16 there is growing evidence that exposure to sodium valproate (VPA) in utero is associated with significantly poorer functioning. [10][11][12]15,17 Prospective studies consistently document that VPA is associated with an increase in risk of cognitive impairment in young children, 10,12,15 but any longer-term effects are unlikely to be comprehensively documented until the children studied are of school age, when cognitive development is more stable.…”

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confidence: 99%

IQ at 6 years after in utero exposure to antiepileptic drugs

et al. 2015

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Objective: To delineate the risk to child IQ associated with frequently prescribed antiepileptic drugs.Methods: Children born to women with epilepsy (n 5 243) and women without epilepsy (n 5 287) were recruited during pregnancy and followed prospectively. Of these, 408 were blindly assessed at 6 years of age. Maternal and child demographics were collected and entered into statistical models.Results: The adjusted mean IQ was 9.7 points lower (95% confidence interval [CI] 24.9 to 214.6; p , 0.001) for children exposed to high-dose (.800 mg daily) valproate, with a similar significant effect observed for the verbal, nonverbal, and spatial subscales. Children exposed to high-dose valproate had an 8-fold increased need of educational intervention relative to control children (adjusted relative risk, 95% CI 8.0, 2.5-19.7; p , 0.001). Valproate at doses ,800 mg daily was not associated with reduced IQ, but was associated with impaired verbal abilities (25.6, 95% CI 211.1 to 20.1; p 5 0.04) and a 6-fold increase in educational intervention (95% CI 1.4-18.0; p 5 0.01). In utero exposure to carbamazepine or lamotrigine did not have a significant effect on IQ, but carbamazepine was associated with reduced verbal abilities (24.2, 95% CI 20.6 to 27.8; p 5 0.02) and increased frequency of IQ ,85.Conclusions: Consistent with data from younger cohorts, school-aged children exposed to valproate at maternal doses more than 800 mg daily continue to experience significantly poorer cognitive development than control children or children exposed to lamotrigine and carbamazepine. Antiepileptic drugs (AEDs) are associated with teratogenic risk to the development of the fetus, with the prevalence of major congenital malformations differing by treatment type and dose. Determining the association between exposure to AEDs and child cognitive functioning represents a challenge, and a number of different methodologies have been utilized in its investigation including case studies, 2-4 retrospective studies, 5,6 and prospective studies. 7-15 Despite limitations, 16 there is growing evidence that exposure to sodium valproate (VPA) in utero is associated with significantly poorer functioning. [10][11][12]15,17 Prospective studies consistently document that VPA is associated with an increase in risk of cognitive impairment in young children, 10,12,15 but any longer-term effects are unlikely to be comprehensively documented until the children studied are of school age, when cognitive development is more stable.10 In a comparison across AED monotherapies, a significantly poorer IQ in school-aged children exposed in utero to

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IQ at 6 years after in utero exposure to antiepileptic drugs

et al. 2015

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“…NTDs and hypospadias have been mostly associated with valproate Citation: Lee J, Nam SK, Jun YH (2017) A New-born with Severe Hydrocephalus and Myelomeningocele Associated with Maternal Antiepileptic [10,11], and a facial cleft with lamotrigine [12]. Neurodevelopmental delay, behavioral disorders, or learning disabilities as an outcome of in utero exposure to valproate, have also been observed [13]. Lamotrigine or carbamazepine monotherapy at lower doses have been known to show the least risk of fetal major congenital malformation [9].…”

Section: Discussionmentioning

confidence: 99%

A New-born with Severe Hydrocephalus and Myelomeningocele Associated with Maternal Antiepileptic Medication: A Case Report

Nam¹,

Lee²,

Jun³

2017

J Gen Pract

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The possible teratogenic effects of maternal antiepileptic drugs (AEDs) on the development of the fetus are of major concern. The fetal risks imposed by these drugs must be weighed against the risks associated with untreated maternal epilepsy not being treated. Here, we describe an infant with a neural tube defect caused by AEDs prescribed to the mother during her pregnancy. A female infant was delivered by means of cesarean section after 37 +6 weeks of gestation. Her 21-year-old mother had been diagnosed with epilepsy at 2 years of age, following brain surgery performed for a traffic accident injury. Since the age of 6 years, the mother had been medicated with lamotrigine (Lamictal ® ), levetiracetam (Keppra ® ), and valproate (Depakote ® ). At birth, the baby exhibited pallor, severe macrocephaly, a large anterior fontanelle (4 cm × 4 cm), and sutural widening. On her lower back, there was a 3 cm open spinal dysraphism exposing nervous tissue. On the 11 th postnatal day, a ventriculo-peritoneal shunt was placed and a myelomeningocele removal operation was performed. After this operation, the head circumference decreased from 44.0 cm to 35.8 cm, and the post-operative period was uneventful. The patient was discharged on the 24 th day. Several case reports and studies have reported that valproate or multi-antiepileptic medication that contains valproate increased the risk of neural tube defects in the offspring. For women of childbearing age who use AEDs, clinicians should review pregnancy risk regularly and consider adjusting medication whenever possible. Additionally, while examing newborns with neural tube defects, clinicians should review prenatal maternal medication history thoroughly.

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“…During the period of organogenesis, when the cells have lost pluripotency and are lineage committed, the damage is difficult to repair causing developmental malformation [14]. Pregnant epileptic women on CBZ therapy may be less susceptible to CBZ teratogenicity either by altered epoxide hydrolase enzyme levels or polymorphism in folate metabolism associated genes [9,39]. But generally a higher rate of cardiovascular malformations and NTDs are experienced with CBZ treated mothers [4,5].…”

Section: Discussionmentioning

confidence: 99%