Impact of In Utero Exposure to Antiepileptic Drugs on Neonatal Brain Function.
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ABSTRACT:
SUBMITTER: Tokariev A
PROVIDER: S-EPMC9157298 | biostudies-literature | 2022 May
REPOSITORIES: biostudies-literature
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Impact of In Utero Exposure to Antiepileptic Drugs on Neonatal Brain Function.
Tokariev Anton A Breakspear Michael M Videman Mari M Stjerna Susanna S Scholtens Lianne H LH van den Heuvel Martijn P MP Cocchi Luca L Vanhatalo Sampsa S
Cerebral cortex (New York, N.Y. : 1991) 20220501 11
In utero brain development underpins brain health across the lifespan but is vulnerable to physiological and pharmacological perturbation. Here, we show that antiepileptic medication during pregnancy impacts on cortical activity during neonatal sleep, a potent indicator of newborn brain health. These effects are evident in frequency-specific functional brain networks and carry prognostic information for later neurodevelopment. Notably, such effects differ between different antiepileptic drugs th ...[more]
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Project description:Drug exposure during critical periods of brain development may adversely affect nervous system function, posing a challenge for treating infants. This is of particular concern for treating neonatal seizures, as early life exposure to drugs such as phenobarbital is associated with adverse neurological outcomes in patients and induction of neuronal apoptosis in animal models. The functional significance of the preclinical neurotoxicity has been questioned due to the absence of evidence for functional impairment associated with drug-induced developmental apoptosis.We used patch-clamp recordings to examine functional synaptic maturation in striatal medium spiny neurons from neonatal rats exposed to antiepileptic drugs with proapoptotic action (phenobarbital, phenytoin, lamotrigine) and without proapoptotic action (levetiracetam). Phenobarbital-exposed rats were also assessed for reversal learning at weaning.Recordings from control animals revealed increased inhibitory and excitatory synaptic connectivity between postnatal day (P)10 and P18. This maturation was absent in rats exposed at P7 to a single dose of phenobarbital, phenytoin, or lamotrigine. Additionally, phenobarbital exposure impaired striatal-mediated behavior on P25. Neuroprotective pretreatment with melatonin, which prevents drug-induced neurodevelopmental apoptosis, prevented the drug-induced disruption in maturation. Levetiracetam was found not to disrupt synaptic development.Our results provide the first evidence that exposure to antiepileptic drugs during a sensitive postnatal period impairs physiological maturation of synapses in neurons that survive the initial drug insult. These findings suggest a mechanism by which early life exposure to antiepileptic drugs can impact cognitive and behavioral outcomes, underscoring the need to identify therapies that control seizures without compromising synaptic maturation.
| S-EPMC3421036 | biostudies-literature
Project description:Antiepileptic drugs may cause congenital malformations. Less is known about the effect on development in infancy and childhood. The aim of this study was to examine whether exposure to antiepileptic drugs during pregnancy has an effect on early child development.From mid-1999 through December 2008, children of mothers recruited at 13-17 weeks of pregnancy were studied in the ongoing prospective Norwegian Mother and Child Cohort Study. Information on birth outcomes were obtained from the Medical Birth Registry (108,264 children), and mothers reported on their child's motor development, language, social skills, and autistic traits using items from standardized screening tools at 18 months (61,351 children) and 36 months (44,147 children) of age. The relative risk of adverse outcomes in children according to maternal or paternal epilepsy with and without prenatal exposure to antiepileptic drugs was estimated as odds ratios (ORs), using logistic regression with adjustment for maternal age, parity, education, smoking, depression/anxiety, folate supplementation, and child congenital malformation or low birth weight.A total of 333 children were exposed to antiepileptic drugs in utero. At 18 months, the exposed children had increased risk of abnormal scores for gross motor skills (7.1% vs. 2.9%; OR 2.0, 95% confidence interval [CI] 1.1-3.7) and autistic traits (3.5% vs. 0.9%; OR 2.7, CI 1.1-6.7) compared to children of parents without epilepsy. At 36 months, the exposed children had increased risk of abnormal score for gross motor skills (7.5% vs. 3.3%; OR 2.2, CI 1.1-4.2), sentence skills (11.2% vs. 4.8%; OR 2.1, CI 1.2-3.6), and autistic traits (6.0% vs. 1.5%; OR 3.4, CI 1.6-7.0). The drug-exposed children also had increased risk of congenital malformations (6.1% vs. 2.9%; OR 2.1, CI 1.4-3.4), but exclusion of congenital malformations did not affect the risk of adverse development. Children born to women with epilepsy who did not use antiepileptic drugs had no increased risks. Children of fathers with epilepsy generally scored within the normal range.Exposure to antiepileptic drugs during pregnancy is associated with adverse development at 18 and 36 months of age, measured as low scores within key developmental domains rated by mothers. Exposures to valproate, lamotrigine, carbamazepine, or multiple antiepileptic drugs were associated with adverse outcome within different developmental domains.
| S-EPMC3766256 | biostudies-literature
Project description:BackgroundThe associations of individual antiepileptic drugs (AEDs) with pregnancy duration and size at birth, and potential dose relations, are not well characterized.MethodsThis cohort study used nationwide Swedish register data (1996-2013). Adjusting for smoking, epilepsy and other AED indications, we used linear and quantile regression to explore associations with pregnancy duration, and birth weight, length, and head circumference (the last three operationalized as z-scores). We used logistic regression for preterm delivery, small for gestational age, and microcephaly. Lamotrigine was the reference drug.Results6,720 infants were exposed to AEDs in utero; AED exposure increased over the study period. Relative to lamotrigine-exposed infants, carbamazepine-exposed infants were born, on average, 1.3 days earlier (mean [95% confidence interval]: -1.3 [-2.3 to -0.3]); were 0.1 standard deviations (SDs) lighter (-0.1 [-0.2 to 0.0]); and had a head circumference that was 0.2 SDs smaller (-0.2 [-0.3 to -0.1]). Pregabalin-exposed infants were born, on average, 1.1 days earlier (-1.1 [-3.0 to 0.8]); were 0.1 SDs lighter (-0.1 [-0.3 to 0.0]); and had the same head circumference as lamotrigine-exposed infants. Levetiracetam-exposed infants were born, on average, 0.5 days earlier (-0.5 [-2.6 to 1.6]); were 0.1 SDs lighter (-0.1 [-0.3 to 0.0]); and had a head circumference 0.1 SDs smaller (-0.1 [-0.3 to 0.1]). Valproic acid-exposed infants had, on average, the same duration of gestation and birth weight z-score as lamotrigine-exposed infants, but had a head circumference 0.2 SDs smaller (-0.2 [-0.2 to -0.1]). Associations between carbamazepine exposure and pregnancy duration and between valproic acid exposure and pregnancy duration and birth weight z-score were more negative at the left than at the right tails of the outcome distributions. Effect-measure modification and dose-response relations were noted for some of the associations.ConclusionsRelative to lamotrigine, valproic acid and carbamazepine were associated with smaller head circumference.
| S-EPMC6681941 | biostudies-literature
Project description:ObjectiveTo delineate the risk to child IQ associated with frequently prescribed antiepileptic drugs.MethodsChildren born to women with epilepsy (n = 243) and women without epilepsy (n = 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.ResultsThe adjusted mean IQ was 9.7 points lower (95% confidence interval [CI] -4.9 to -14.6; 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 (-5.6, 95% CI -11.1 to -0.1; p = 0.04) and a 6-fold increase in educational intervention (95% CI 1.4-18.0; p = 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 (-4.2, 95% CI -0.6 to -7.8; p = 0.02) and increased frequency of IQ <85.ConclusionsConsistent 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.
| S-EPMC4336006 | biostudies-literature
Project description:ObjectiveThe human brain undergoes an activity-dependent organization during late gestation, making it very sensitive to all effects on the spontaneous neuronal activity. Pregnant mothers with epilepsy are treated with antiepileptic drugs (AEDs) that may reach the fetus and cause altered cortical network activity after birth. However, it is not known whether these functional effects of intrauterine AED exposure persist later in childhood.MethodsWe studied cortical activity networks computed from electroencephalographic recordings during sleep of 25, 6-year-old children with in utero exposure to AEDs and 21 without exposure. The frequency-specific networks were determined for N1 and N2 sleep states, and the study groups were compared for sleep-state-specific changes and dynamic differences between sleep states. Finally, we correlated these difference networks with the children's neurophysiological performance at 6 years.ResultsWe found brain-wide changes in the cortical activity networks and their sleep-state dynamics in the children with intrauterine AED exposure. Moreover, the strength of cortical network connectivity was significantly associated with multiple domains of neurocognitive performance, in particular, verbal comprehension, processing speed, and IQ. Our findings together suggest that fetal AED exposure causes very long-lasting changes in the cortical networks with significant links to early school-age cognitive performance.SignificanceAED treatment of pregnant mothers is indicated for maternal health reasons; however, the long-term neurodevelopmental effects on the offspring are poorly understood. Our present study shows that in utero exposure to AEDs causes persisting changes in the cortical activity networks, which can be measured with electroencephalography at 6 years of age. Moreover, these network changes correlate to the child's neurocognitive performance at the same age. These findings together suggest a pathway for how fetal drug exposures may cause persisting and neurocognitively meaningful changes in cortical connectivity patterns.
| S-EPMC11827741 | biostudies-literature
Project description:Introduction: Despite the prevalence of the perception that electronic cigarettes (e-cig) are a safer alternative to tobacco smoke, growing concern about their potential toxic impact warrants adequate investigation focusing on special populations like maternal and pediatric groups. This study evaluated the consequences of maternal e-cig use on neonatal neuroinflammation, oxidative stress, and mitochondrial function in primary cultured neurons and postnatal day (PD) 7 and 90 brain. Methodology: Pregnant CD1 mice were exposed to e-cig vapor (2.4% nicotine) from gestational day 5 (E5) till PD7, and the primary neurons were isolated from pups at E16/17. Cellular total reactive oxygen species (ROS) and mitochondrial superoxide were measured in primary neurons using CM-H2DCFDA and Mitosox red, respectively. Mitochondrial function was assessed by Seahorse XF Cell Mitostress analysis. The level of pro-inflammatory cytokines was measured in primary neurons and PD7 and PD90 brains by RT-PCR and immunobead assay. Western blot analysis evaluated the expression of antioxidative markers (SOD-2, HO-1, NRF2, NQO1) and that of the proinflammatory modulator NF-κB. Results: Significantly higher level of total cellular ROS (p < 0.05) and mitochondrial superoxide (p < 0.01) was observed in prenatally e-cig-exposed primary neurons. We also observed significantly reduced antioxidative marker expression and increased proinflammatory modulator and cytokines expression in primary neurons and PD7 (p < 0.05) but not in PD90 postnatal brain. Conclusion: Our findings suggest that prenatal e-cig exposure induces postnatal neuroinflammation by promoting oxidative stress (OS), increasing cytokines' levels, and disrupting mitochondrial function. These damaging events can alter the fetal brain's immune functions, making such offspring more vulnerable to brain insults.
| S-EPMC10484598 | biostudies-literature
Project description:BackgroundFetal exposure of animals to antiepileptic drugs at doses lower than those required to produce congenital malformations can produce cognitive and behavioral abnormalities, but cognitive effects of fetal exposure of humans to antiepileptic drugs are uncertain.MethodsBetween 1999 and 2004, we enrolled pregnant women with epilepsy who were taking a single antiepileptic agent (carbamazepine, lamotrigine, phenytoin, or valproate) in a prospective, observational, multicenter study in the United States and the United Kingdom. The primary analysis is a comparison of neurodevelopmental outcomes at the age of 6 years after exposure to different antiepileptic drugs in utero. This report focuses on a planned interim analysis of cognitive outcomes in 309 children at 3 years of age.ResultsAt 3 years of age, children who had been exposed to valproate in utero had significantly lower IQ scores than those who had been exposed to other antiepileptic drugs. After adjustment for maternal IQ, maternal age, antiepileptic-drug dose, gestational age at birth, and maternal preconception use of folate, the mean IQ was 101 for children exposed to lamotrigine, 99 for those exposed to phenytoin, 98 for those exposed to carbamazepine, and 92 for those exposed to valproate. On average, children exposed to valproate had an IQ score 9 points lower than the score of those exposed to lamotrigine (95% confidence interval [CI], 3.1 to 14.6; P=0.009), 7 points lower than the score of those exposed to phenytoin (95% CI, 0.2 to 14.0; P=0.04), and 6 points lower than the score of those exposed to carbamazepine (95% CI, 0.6 to 12.0; P=0.04). The association between valproate use and IQ was dose dependent. Children's IQs were significantly related to maternal IQs among children exposed to carbamazepine, lamotrigine, or phenytoin but not among those exposed to valproate.ConclusionsIn utero exposure to valproate, as compared with other commonly used antiepileptic drugs, is associated with an increased risk of impaired cognitive function at 3 years of age. This finding supports a recommendation that valproate not be used as a first-choice drug in women of childbearing potential.
| S-EPMC2737185 | biostudies-literature
Project description:Information available on the risks of neurodevelopmental disorders (NDs) associated with in utero exposure to valproate (VPA) and to other antiepileptic drugs (AEDs) is limited. A nationwide population-based cohort study was conducted based on comprehensive data of the French National Health Data System (SNDS). Liveborn infants without brain malformation, born between January 2011 and December 2014, were followed from birth up to December 2016. NDs were identified based on diagnoses of mental or behavioural disorders and utilization of speech therapy, orthoptic or psychiatric services. The risk of NDs was compared between children exposed in utero to AED monotherapy and unexposed children, using Cox proportional hazard models adjusted for maternal and neonatal characteristics. The cohort included 1,721,990 children, 8848 of whom were exposed in utero to AED monotherapy. During a mean follow-up of 3.6 years, 15,458 children had a diagnosis of mental or behavioural disorder. In utero exposure to VPA was associated with an increased risk of NDs overall (aHR: 3.7; 95% CI 2.8-4.9) and among children born to a mother without mental illness (aHR 5.1; 95% CI 3.6-7.3). A dose-response relationship was demonstrated and the risk of NDs was more particularly increased for an exposure to VPA during the second or third trimesters of pregnancy. Among the other AEDs, only pregabalin was consistently associated with an increased risk of NDs (aHR: 1.5; 95% CI 1.0-2.1). This study confirms a four to fivefold increased risk of early NDs associated with exposure to VPA during pregnancy. The risk associated with other AEDs appears much lower.
| S-EPMC7581762 | biostudies-literature
Project description:IntroductionSeizures are one of the most common neurological disorders of neonates, which is also an emergency in the neonatal intensive care unit. For neonates, the recommended first-line antiepileptic drugs (AEDs) include phenobarbitone, which may be effective in only 50% of seizures. Some new AEDs, such as levetiracetam, have been shown to be effective in adults and older children. However, their efficacy for neonatal seizures remains uncertain. The aim of this investigation is to conduct a systematic review to evaluate the efficacy of all AEDs in neonates. Additionally, the long-term outcomes following neonatal seizures, in relation to the development of cerebral palsy and epilepsy, will be studied.MethodWe will perform a systematic review including randomised controlled studies (RCTs), cohort studies, case-controlled studies and case series studies which evaluated the efficacy of AEDs and short-term and long-term outcomes in neonatal seizures. PubMed, Embase, Web of Science, Cochrane Library and Clinical trial.gov will be searched. There will be no language restriction. Risk bias in RCTs will be evaluated by the Cochrane risk-of-bias tool, while cohort and case-control studies will be evaluated by the Newcastle-Ottawa Scale. A network meta-analysis will be performed by the Bayesian model using WinBUGS V.1.4.3 and R software if there is a high degree of homogeneity among studies. Otherwise, we will perform a narrative review without pooling. Subgroup analyses will be performed in different AEDs and dosage groups.OutcomeThe primary outcomes will be seizure cessation confirmed by electroencephalogram and long-term neurodevelopmental outcome. Secondary outcomes will be neonatal mortality during hospitalisation and suspected drug toxicity.Ethics and disseminationFormal ethical approval is not required as no primary data are collected. This systematic review will be disseminated through a peer-reviewed publication.
| S-EPMC7326240 | biostudies-literature
Project description: Not available
| S-EPMC7933927 | biostudies-literature