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Neurodevelopment Not Impacted by Maternal Antiseizure Medication Use

Higher maximum third-trimester ASM blood levels were associated with significantly lower BSID-III scores for the motor domain and lower scores for the general adaptive domain.

Data from the Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study (NCT01730170) showed that children of women with epilepsy (WWE) taking antiseizure medications (ASMs) did not differ in neurodevelopmental outcomes compared to those of healthy women.

Senior author Page B. Pennell, MD, director of epilepsy research, Brigham and Women’s Hospital, and professor of neurology, Harvard Medical School, and colleagues analyzed 292 children at 2 years of age on the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III) and compared outcomes of that to 90 children of healthy women. The association between BSID-III language domain and ASM blood levels (ABLs) was also assessed in the third trimester in children of WWE.

Overall, investigators found no significant differences between children of WWE vs healthy women for the primary language domain outcome. In the full model, significant factors such as higher maternal IQ (0.3 [95% CI, 0.1-0.4]), birth weight (3.0 [95% CI, 0.3-5.6]) and female child sex (6.4 [95% CI, 3.3-9.4]) were associated with higher language domain scores.

"This encouraging finding may be due to the use of newer ASMs with lower risk of affecting the immature brain. However, these findings must be interpreted within the context that neuropsychological assessments conducted at 2 years of age are not as strongly associated with adolescent/adult functioning as assessments performed in older children, which will be conducted subsequently in the MONEAD study,” Pennell et al wrote.

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Children of mothers with lower educational level had lower BSID-III scores (college degree [not advanced] vs college degree [advanced]: –5.0 [95% CI, –8.8 to –1.2]; no college degree vs college degree [advanced]: –8.3 [95% CI, –13.3 to –3.4]). Additionally, child Hispanic ethnicity (–9.2 [95% CI, –13.3 to –5.1]) and higher postpartum maternal anxiety (–0.5 [95% CI, –0.9 to –0.2]) were associated with lower scores as well.

More specifically, postpartum maternal anxiety was associated with lower scores in the cognitive (–0.44 [95% CI, –0.73 to –0.15]), social-emotional (–0.61 [95% CI, –0.99 to –0.23]) and general adaptive (–0.70 [95% CI, –1.06 to –0.33]) domains. Depression and perceived stress were also associated with lower scores in same domains. Poorer postpartum sleep quality was associated with lower scores in the cognitive (–0.63 [95% CI, –1.17 to –0.09]) social-emotional (–0.85 [95% CI, –1.56 to –0.14]), and general adaptive (–0.75 [95% CI, –1.42 to –0.07]) domains among all children, but not when restricted to children of WWE on ASM.

Higher maximum third-trimester ABLs were associated with significantly lower BSID-III scores for the motor domain (–5.6 [95% CI, –10.7 to –0.5]) and lower scores for the general adaptive domain (–6.1 [95% CI, –12.3 to 0.05]). In the motor domain, these associated were observed for children of women receiving monotherapy (–8.1 [95% CI, –14.4 to –1.8) and individually for levetiracetam monotherapy during the third trimester (–13.0 [95% CI, –22.1 to –4.0]).

Children who were receiving folate or breastfeeding showed higher mean scores for most domains; however, the only significant association was between breastfeeding and higher social-emotional domain scores (mean social-domain scores for children breastfed vs not breastfed, 107.2 [95% CI, 105.4 to 109.0] vs 102.7 [95% CI, 98.9 to 106.5]).

There was no significant differences for the language domain or other BSID-III domains when comparing patients on monotherapy vs polytherapy. Additionally, no significant differences were observed in language domain score across individual ASMs at enrollment. The investigators did note that these sample sizes were relatively small.

In all sensitivity analyses with twins, the association between maximum third-trimester ABLs was significant with the general adaptive domain score (–7.2 [95% CI, –13.9 to –0.5]) and with the motor domain score (–6.6 [95% CI, –12.0 to –1.3), when excluding all twins. All other results were similar with the second twin excluded or using the generalized estimating equation model to account for the non-independence of twin pairs. A higher maximum ratio of defined daily dose in the third trimester was also associated with lower scores in the general adaptive domain (–1.4 [95% CI, –2.8 to –0.05]).

Children in the study were followed up from birth to 6 years of age, with assessment at 2 years of age for this study. Women included in the study were enrolled from December 19, 2012 to January 13, 2016, with the data analyzed from February 20 to December 4, 2020.

Meador J, Cohen MJ, Loring DW, et al. 2-year-old cognitive outcomes in children of pregnant women with epilepsy in the maternal outcomes and neurodevelopmental effects of antiepileptic drugs study. JAMA Neurol. published online June 7, 2021. doi: 10.1001/jamaneurol.2021.1583