Elsevier

Neurotoxicology and Teratology

Volume 54, March–April 2016, Pages 5-14
Neurotoxicology and Teratology

Behavioral outcomes in children exposed prenatally to lamotrigine, valproate, or carbamazepine

https://doi.org/10.1016/j.ntt.2016.01.001Get rights and content

Highlights

  • Adaptive functioning is worse in children when exposed prenatally to VPA compared to LTG or CBZ.

  • Compared to LTG or CBZ, VPA-exposed children have worse socialization, communication, and motor skills.

  • Higher prenatal VPA doses are associated with worse adaptive functioning, especially socialization and motor skills.

Abstract

Objectives

To evaluate adaptive behavior outcomes of children prenatally exposed to lamotrigine, valproate, or carbamazepine, and to determine if these outcomes were dose-dependent.

Methods

Data were collected from women enrolled in the North American Anti epileptic Drug (AED) Pregnancy Registry who had taken lamotrigine, valproate, or carbamazepine monotherapies throughout pregnancy to suppress seizures. The adaptive behavior of 252 exposed children (including 104 lamotrigine-exposed, 97 carbamazepine-exposed, and 51 valproate-exposed), ages 3- to 6-years-old, was measured using the Vineland-II Adaptive Behavior Scales, administered to each mother by telephone. Mean Adaptive Behavior Composite (ABC), domain standard scores for communication, daily living, socialization and motor skills, and adaptive levels were analyzed and correlated with first trimester drug dose.

Results

After adjusting for maternal age, education, folate use, cigarette and alcohol exposure, gestational age, and birth weight by propensity score analysis, the mean ABC score for valproate-exposed children was 95.6 (95% CI [91, 101]), versus 100.8 (95% CI [98, 103]) and 103.5 (95% CI [101, 106]) for carbamazepine- and lamotrigine-exposed children, respectively (ANOVA; p = 0.017). Significant differences were observed among the three drug groups in the ABC (p = 0.017), socialization (p = 0.026), and motor (p = 0.018) domains, with a trend toward significance in the communication domain (p = 0.053). Valproate-exposed children scored lowest and lamotrigine-exposed children scored highest in every category. Valproate-exposed children were most likely to perform at a low or moderately low adaptive level in each category. Higher valproate dose was associated with significantly lower ABC (p = 0.020), socialization (p = 0.009), and motor (p = 0.041) scores before adjusting for confounders. After adjusting for the above variables, increasing VPA dose was associated with decreasing Vineland scores in all domains, but the relationships were not statistically significant. No dose effect was observed for carbamazepine or lamotrigine.

Conclusions

Unlike carbamazepine and lamotrigine, prenatal valproate exposure was associated with adaptive behavior impairments with specific deficits in socialization and motor function, along with a relative weakness in communication. Increasing valproate dose was associated with a decline in adaptive functioning. This finding of a linear dose-dependent teratogenic effect suggests that valproate should be avoided at any dose during pregnancy. However, some women with epilepsy controlled only by valproate will decide, in consultation with their provider, that the benefits of continuing valproate during pregnancy outweigh the fetal risks. Faced with difficult choices, clinicians should be supportive as these patients consider their options.

Introduction

Fetal exposure to anti-epileptic drugs (AEDs) carries elevated risk for birth defects (Samren et al., 1997, Meador et al., 2006, Dean et al., 2002, Campbell et al., 2014, Morrow et al., 2006, Artama et al., 2005, Wyszynski et al., 2005, Wide et al., 2004), and may be associated with cognitive dysfunction (Scolnik et al., 1994, Titze et al., 2008, Veiby et al., 2013, Moore et al., 2000). Valproate, especially, has been associated with lower IQ (Titze et al., 2008, Adab et al., 2004, Vinten et al., 2005, Eriksson et al., 2005, Meador et al., 2009, Meador et al., 2013), increased special education needs (Viinikainen et al., 2006), behavioral problems (Dean et al., 2002, Viinikainen et al., 2006, Vinten et al., 2009, Cohen et al., 2013), and increased risk of autism spectrum disorder (Christensen et al., 2013, Bromley et al., 2008, Bromley et al., 2013, Rasalam et al., 2005), when compared to several other AEDs, namely phenytoin, carbamazepine, and lamotrigine.

Unfortunately, most studies investigating neurodevelopmental outcomes of exposed children have relied on language testing and IQ to assess cognitive function, while adaptive behavior outcomes have been significantly less well-studied. Although IQ tests measure general intelligence, they neither assess functional abilities nor adaptive behaviors required for independent daily living, such as socialization, communication, self-care, and motor skills. Deficits in these areas have significant implications for long-term behavioral outcomes. Impairments in socialization and communication, along with repetitive, stereotyped behaviors, form the basis for diagnosis of autism spectrum disorder (American Psychiatric A et al., 2013).

While studies have suggested that IQ is a strong predictor of adaptive impairments for individuals with cognitive disabilities, research has also shown that the gap between IQ and adaptive skills is greater among higher functioning individuals (Kanne et al., 2011, Klin et al., 2007). In individuals with autism spectrum disorder, severe social deficits have been observed even with relatively high IQ (Kanne et al., 2011, Klin et al., 2007). Thus, using IQ scores alone to evaluate neurodevelopmental outcomes for children exposed to AEDs in utero is not sufficient to identify those individuals with adaptive behavior impairments despite high cognitive potential. As a result, information on the long-term behavioral effects of prenatal AED exposure is lacking, and significant limitations exist for physicians counseling women of childbearing age with epilepsy (WWE). We present a cohort study to evaluate adaptive behavior outcomes among children born to WWE who received one of three AED treatments as monotherapy during pregnancy. The a priori hypotheses were that prenatal exposure to carbamazepine (CBZ), lamotrigine (LTG), or valproate (VPA) monotherapies would be associated with adaptive behavior impairments, and that exposure to higher doses during the first trimester would be associated with lower adaptive behavior levels.

Section snippets

Recruitment, inclusion, and exclusion criteria

Recruitment letters were sent by mail to WWE who had prospectively enrolled in the North American AED Pregnancy Registry (“the Registry”) while taking LTG, VPA, or CBZ as monotherapy to suppress seizures throughout pregnancy, and whose exposed children were 3- to 6-years-old. The Registry's methodology has been described previously (Holmes et al., 2011). Children were excluded if they were exposed to other known teratogens, such as isotretinoin or warfarin, or if the AED was not taken

Recruitment process

Recruitment letters were mailed to 972 women (with 1032 children) who had enrolled in the Registry while taking LTG, VPA, or CBZ as monotherapy to treat epilepsy throughout pregnancy, and whose exposed children were 3- to 6-years-old (mean 4.9 years, SD 1.1 years). Of those contacted, mothers of 495 children responded, 455 expressed interest, and 346 completed the initial screening to assess eligibility.

Of the 495 respondents, 149 were never screened, including 40 who explicitly refused to

Discussion

Prenatal exposure to VPA was associated with poorer adaptive behavior outcomes in all of the measured domains, when compared to the test mean and to children exposed to CBZ or LTG. Significant differences from the LTG-exposed group were noted in the ABC, socialization, communication, and motor domains after adjusting for propensity scores from a variety of potential confounders. While the VPA-exposed group scored the lowest in the daily living domain, these scores did not differ significantly

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Acknowledgments

The investigators thank the women and families who generously volunteered their time to participate in this study.

We would also like to acknowledge the tragic passing in 2013 of our co-author, Autumn Klein, MD, PhD. Her contribution to the field of Neurology in general, and Women's Neurology in particular, was invaluable, and she continues to be sorely missed. It was an honor to collaborate with her on this project, and we hope that the knowledge gained from this work adds to her legacy.

We

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