Enduring language deficits in children of women with epilepsy and the potential role of intrauterine exposure to antiepileptic drugs.

OBJECTIVE: Exposure to certain intrauterine antiepileptic drugs (AEDs) can negatively influence the language skills and intelligence of young children. It remains unanswered whether these deficits are transient or persist as children grow up. This study aims to evaluate the language function of children of women with epilepsy (CWE) aged 9-13 years in comparison with their peers, and its relationship with intrauterine AED exposure. METHODS: We included 191 CWE in our study from the Kerala Registry of Epilepsy and Pregnancy. Children in the same age group (n = 144) and without maternal epilepsy or antenatal AED exposure served as controls. We used Clinical Examination for Language Function version IV to assess language in both groups. Relevant data related to maternal epilepsy and AED use were obtained from the registry records. RESULTS: The average Core Language Scaled Score (CLSS) was significantly lower in CWE as compared to controls (83.19 vs 90.18, P = .001). Similarly, the mean scaled scores in other language parameters were also significantly lower in CWE. In the multivariate analysis, compared to control children, the average CLSS in CWE was 4.5 units lower (95% confidence interval [CI] = -8.8 to -0.2, P = .04) with AED monotherapy exposure and 7.3 units lower with exposure to AED polytherapy (95% CI = -13.8 to -0.8, P = .03). Intrauterine exposure to phenobarbitone (n = 61) and valproate (n = 55) as either monotherapy or polytherapy showed a negative effect on CLSS in CWE as compared to control children. However, carbamazepine (n = 75) and phenytoin (n = 37) use was not associated with significant variation of CLSS. In head-to-head comparisons between AED monotherapies in CWE, phenobarbitone showed a negative effect on CLSS (-14.7, 95% CI = -23.1 to -6.4, P = .001) as compared to carbamazepine. SIGNIFICANCE: Intrauterine exposure to phenobarbitone and valproate impairs language development in CWE, with effects persisting into the second decade.

Neurodevelopmental Outcomes of Children Born to Opioid-Dependent Mothers: A Systematic Review and Meta-Analysis.

BACKGROUND: Children born to opioid-dependent mothers are at risk of adverse neurodevelopment. The magnitude of this risk remains inconclusive. OBJECTIVE: To conduct a meta-analysis of studies that assessed neurodevelopmental outcomes of children aged 0 to 12 years born to opioid-dependent mothers, compared with children born to nonopioid-dependent mothers, across general cognitive, language, motor, and social-emotional domains. DATA SOURCES: PubMed, CINAHL, PsycINFO, and Google Scholar databases. STUDY ELIGIBILITY CRITERIA: English-language publications between January 1993 and November 2018, including prenatally opioid-exposed and nonopioid-exposed comparison children, reporting outcomes data on standardized assessments. STUDY APPRAISAL AND SYNTHESIS METHODS: Two reviewers independently extracted data. Pooled standardized mean differences (SMDs) were analyzed using random effects models. Risk of bias was assessed with the Newcastle-Ottawa Quality Assessment Scale. RESULTS: Across 16 studies, individual domain outcomes data were examined for between 93 to 430 opioid-exposed and 75 to 505 nonopioid-exposed infants/children. Opioid-exposed infants and children performed more poorly than their nonopioid-exposed peers across all outcomes examined, demonstrated by lower infant cognitive (SMD = 0.77) and psychomotor scores (SMD = 0.52), lower general cognition/IQ (SMD = 0.76) and language scores (SMD = 0.65-0.74), and higher parent-rated internalizing (SMD = 0.42), externalizing (SMD = 0.66), and attention problems (SMD = 0.72). LIMITATIONS: Most studies examined early neurodevelopment; only 3 reported school-age outcomes thereby limiting the ability to assess longer-term impacts of prenatal opioid exposures. CONCLUSIONS AND IMPLICATIONS OF FINDINGS: Children born to opioid-dependent mothers are at modest- to high-risk of adverse neurodevelopment at least to middle childhood. Future studies should identify specific clinical and social factors underlying these challenges to improve outcomes.

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

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.

Verbal Memory and Learning in Schoolchildren Exposed to Manganese in Mexico.

Manganese (Mn) is an essential nutrient for cellular function, but in high concentrations, it is neurotoxic. Environmental exposure to Mn has been associated with cognitive effects in children. This study aimed to assess the effect of environmental exposure to Mn on verbal memory and learning in schoolchildren residents from two municipalities in the state of Hidalgo, Mexico. Cross-sectional studies were conducted in 2006 and 2013 with a total of 265 schoolchildren of 7 to 11 years old. Children's Auditory Verbal Learning Test-2 (CAVLT-2) was used to assess verbal memory and learning. Mn exposure tertiles were defined according to hair manganese (MnH) levels determined by atomic absorption spectrophotometry. Linear regression models were used to estimate the association between MnH levels and CAVLT-2 scores. The models were adjusted by potential confounders. The lowest and highest exposure tertiles were defined below and above MnH levels of ≤ 0.72 and ≥ 3.96 µg/g, respectively. Mn exposure was significantly associated with an average of 5- to 9-point decrease in learning curves and summary CAVLT-2 scores in the highest tertile. This study adds to the evidence of decreased verbal memory and learning in schoolchildren environmentally exposed to manganese.

Association of Prenatal Phthalate Exposure With Language Development in Early Childhood.

Importance: Prenatal exposure to phthalates has been associated with neurodevelopmental outcomes, but little is known about the association with language development. Objective: To examine the association of prenatal phthalate exposure with language development in children in 2 population-based pregnancy cohort studies. Design, Setting, and Participants: Data for this study were obtained from the Swedish Environmental Longitudinal Mother and Child, Asthma and Allergy (SELMA) study conducted in prenatal clinics throughout Värmland county in Sweden and The Infant Development and the Environment Study (TIDES) conducted in 4 academic centers in the United States. Participants recruited into both studies were women in their first trimester of pregnancy who had literacy in Swedish (SELMA) or English or Spanish (TIDES). This study included mothers and their children from both the SELMA study (n = 963) and TIDES (n = 370) who had complete data on prenatal urinary phthalate metabolite levels, language delay, and modeled covariables. For SELMA, the data were collected from November 1, 2007, to June 30, 2013, and data analysis was conducted from November 1, 2016, to June 30, 2018. For TIDES, data collection began January 1, 2010, and ended March 29, 2016, and data analysis was performed from September 15, 2016, to June 30, 2018. Main Outcomes and Measures: Mothers completed a language development questionnaire that asked the number of words their children could understand or use at a median of 30 months of age (SELMA) and 37 months of age (TIDES). The responses were categorized as fewer than 25, 25 to 50, and more than 50 words, with 50 words or fewer classified as language delay. Results: In the SELMA study, 963 mothers, 455 (47.2%) girls, and 508 (52.8%) boys were included. In TIDES, 370 mothers, 185 (50.0%) girls, and 185 (50.0%) boys were included in this analysis. The prevalence of language delay was 10.0% in both SELMA (96 reported) and TIDES (37 reported), with higher rates of delay in boys than girls (SELMA: 69 [13.5%] vs 27 [6.0%]; TIDES: 23 [12.4%] vs 14 [7.6%]). In crude analyses, the metabolite levels of dibutyl phthalate and butyl benzyl phthalate were statistically significantly associated with language delay in both cohorts. In adjusted analyses, a doubling of prenatal exposure of dibutyl phthalate and butyl benzyl phthalate metabolites increased the odds ratio (OR) for language delay by approximately 25% to 40%, with statistically significant results in the SELMA study (dibutyl phthalate OR, 1.29 [95% CI, 1.03-1.63; P = .03]; butyl benzyl phthalate OR, 1.26 [95% CI, 1.07-1.49; P = .003]). A doubling of prenatal monoethyl phthalate exposure was associated with an approximately 15% increase in the OR for language delay in the SELMA study (OR, 1.14; 95% CI, 1.00-1.31; P = .05), but no such association was found in TIDES (OR, 0.98; 95% CI, 0.79-1.23). Conclusions and Relevance: In findings from this study, prenatal exposure to dibutyl phthalate and butyl benzyl phthalate was statistically significantly associated with language delay in children in both the SELMA study and TIDES. These findings, along with the prevalence of prenatal exposure to phthalates, the importance of language development, and the inconsistent results from a 2017 Danish study, suggest that the association of phthalates with language delay may warrant further examination.

Association between maternal exposure to phthalates and lower language ability in offspring derived from hair metabolome analysis.

The fetus undergoes a crucial period of neurodevelopment in utero. The maternal hair metabolome provides an integrated record of the metabolic state of the mother prior to, and during pregnancy. We investigated whether variation in the maternal hair metabolome was associated with neurodevelopmental differences across infants. Maternal hair samples and infant neurocognitive assessments (using the Bayley III Scales of Infant Development at 24 months) were obtained for 373 infant-mother dyads between 26-28 weeks' gestation from the Growing Up in Singapore Towards Healthy Outcomes cohort. The hair metabolome was analysed using gas chromatography-mass spectrometry. Intensity measurements were obtained for 276 compounds. After controlling for maternal education, ethnicity, and infant sex, associations between metabolites and expressive language skills were detected, but not for receptive language, cognitive or motor skills. The results confirm previous research associating higher levels of phthalates with lower language ability. In addition, scores were positively associated with a cluster of compounds, including adipic acid and medium-chain fatty acids. The data support associations between the maternal hair metabolome and neurodevelopmental processes of the fetus. The association between phthalates and lower language ability highlights a modifiable risk factor that warrants further investigation.

Prenatal Cocaine Exposure Impacts Language and Reading Into Late Adolescence: Behavioral and ERP Evidence.

Extant research documents impaired language among children with prenatal cocaine exposure (PCE) relative to nondrug exposed (NDE) children, suggesting that cocaine alters development of neurobiological systems that support language. The current study examines behavioral and neural (electrophysiological) indices of language function in older adolescents. Specifically, we compare performance of PCE (N = 59) and NDE (N = 51) adolescents on a battery of cognitive and linguistic assessments that tap word reading, reading comprehension, semantic and grammatical processing, and IQ. In addition, we examine event related potential (ERP) responses in in a subset of these children across three experimental tasks that examine word level phonological processing (rhyme priming), word level semantic processing (semantic priming), and sentence level semantic processing (semantic anomaly). Findings reveal deficits across a number of reading and language assessments, after controlling for socioeconomic status and exposure to other substances. Additionally, ERP data reveal atypical orthography to phonology mapping (reduced N1/P2 response) and atypical rhyme and semantic processing (N400 response). These findings suggest that PCE continues to impact language and reading skills into the late teenage years.

Language competence and communication skills in 3-year-old children after prenatal exposure to analgesic opioids.

PURPOSE: An increasing consumption of opioids in the general population has been reported in several countries also among pregnant women. Limited information is available regarding the effect of prenatal exposure to analgesic opioids on long-term neurocognitive function in children. The primary aim of the study was to determine the association between prenatal exposure to analgesic opioids and language competence and communication skills at 3 years of age. METHODS: The Norwegian Mother and Child Cohort Study (MoBa) prospectively included pregnant women during the period from 1999 to 2008. Participants reported medication use at pregnancy weeks 17-18 and 30, and 6 months after birth. Children's language competence and communication skills were reported by mothers on validated scales. RESULTS: A total of 45 211 women with 51 679 singleton pregnancies were included. The use of analgesic opioids was reported in 892 pregnancies (1.7%). In adjusted analyses, no association between opioid use and reduced language competence or communication skills was found, OR = 1.04 (95%CI: 0.89-1.22) and OR = 1.10 (95%CI: 0.95-1.27), respectively. Both pain and use of paracetamol were associated with a small reduction in communication skills. No such association was found for language competence. CONCLUSION: The use of analgesic opioids in pregnant women does not seem to affect language development or communication skills in children at 3 years of age. Copyright © 2017 John Wiley & Sons, Ltd.

Nonfunctioning Adrenocortical Carcinoma in Pediatric Acute Lymphoblastic Leukemia: A Case Report of a Rare Multiple Primaries Combination.

Childhood adrenocortical carcinoma (ACC) is a rare tumor and its association with acute lymphoblastic leukemia (ALL) is even rarer. One such case is discussed in this case report. A 3-year-old patient was concomitantly diagnosed with ALL and an initially nonmetastatic ACC. Management started by following the Total XV protocol without a window phase. Left adrenalectomy was conducted after the consolidation phase. Recurrence of a mass at the tumor bed was discovered at week 33 of the continuation phase. Reexcision was conducted, followed by the administration of an ACC protocol including cisplatin, etoposide, and doxirubicin. Mitotane was added when a pulmonary metastasis was discovered and then stopped after the patient suffered from an arachnoid cyst and speech difficulties. The ALL protocol was resumed from week 34 of the continuation phase. Progression of pulmonary nodules was noted after week 45. A pulmonary metastectomy was performed. The ALL protocol was resumed up to week 51 with a good response as proven by assessment of minimal residual disease. A further recurrence was diagnosed at the abdominal tumor bed with a paravertebral mass and a pulmonary nodule. The patient was assigned to palliative treatment and died after a 32-month survival. Such rare associations need more extensive discussions of the best possible management in scientific literature.

Latent Class Analysis of Neurodevelopmental Deficit After Exposure to Anesthesia in Early Childhood.

INTRODUCTION: Although some studies have reported an association between early exposure to anesthesia and surgery and long-term neurodevelopmental deficit, the clinical phenotype of children exposed to anesthesia is still unknown. METHODS: Data were obtained from the Western Australian Pregnancy Cohort Study (Raine) with neuropsychological tests at age 10 years measuring language, cognition, motor function, and behavior. Latent class analysis of the tests was used to divide the cohort into mutually exclusive subclasses of neurodevelopmental deficit. Multivariable polytomous logistic regression was used to evaluate the association between exposure to surgery and anesthesia and each latent class, adjusting for demographic and medical covariates. RESULTS: In our cohort of 1444 children, latent class analysis identified 4 subclasses: (1) Normal: few deficits (n=1135, 78.6%); (2) Language and Cognitive deficits: primarily language, cognitive, and motor deficits (n=96, 6.6%); (3) Behavioral deficits: primarily behavioral deficits, (n=151, 10.5%); and (4) Severe deficits: deficits in all neuropsychological domains (n=62, 4.3%). Language and cognitive deficit group children were more likely to have exposure before age 3 (adjusted odds ratio [aOR], 2.11; 95% confidence interval [CI], 1.17-3.81), whereas a difference in exposure was not found between Behavioral or Severe deficit children (aOR, 1.00; 95% CI, 0.58-1.73, and aOR, 0.85; 95% CI, 0.34-2.15, respectively) and Normal children. CONCLUSIONS: Our results suggest that in evaluating children exposed to surgery and anesthesia at an early age, the phenotype of interest may be children with deficits primarily in language and cognition, and not children with broad neurodevelopmental delay or primarily behavioral deficits.

Association of Selective Serotonin Reuptake Inhibitor Exposure During Pregnancy With Speech, Scholastic, and Motor Disorders in Offspring.

IMPORTANCE: Speech/language, scholastic, and motor disorders are common in children. It is unknown whether exposure to selective serotonin reuptake inhibitors (SSRIs) during pregnancy influences susceptibility to these disorders. OBJECTIVE: To examine whether SSRI exposure during pregnancy is associated with speech/language, scholastic, and motor disorders in offspring up to early adolescence. DESIGN, SETTING, AND PARTICIPANTS: This prospective birth cohort study examined national population-based register data in Finland from 1996 to 2010. The sampling frame includes 845 345 pregnant women and their singleton offspring with data on maternal use of antidepressants and depression-related psychiatric disorders during pregnancy. EXPOSURES: There were 3 groups of offspring: 15 596 were in the SSRI-exposed group, ie, had mothers diagnosed as having depression-related psychiatric disorders with a history of purchasing SSRIs during pregnancy; 9537 were in the unmedicated group, ie, had mothers diagnosed as having depression-related psychiatric disorders without a history of purchasing SSRIs during pregnancy; and 31 207 were in the unexposed group, ie, had mothers without a psychiatric diagnosis or a history of purchasing SSRIs. MAIN OUTCOMES AND MEASURES: Cumulative incidence of speech/language, scholastic, or motor disorders (829, 187, and 285 instances, respectively) from birth to 14 years. All hypotheses tested were formulated before data collection. RESULTS: Of the 56 340 infants included in the final cohort, 28 684 (50.9%) were male and 48 782 (86.6%) were 9 years or younger. The mean (SD) ages of children at diagnosis were 4.43 (1.67), 3.55 (2.67), and 7.73 (2.38) for speech/language, scholastic, and motor disorders, respectively. Offspring of mothers who purchased SSRIs at least twice during pregnancy had a significant 37% increased risk of speech/language disorders compared with offspring in the unmedicated group. The cumulative hazard of speech/language disorders was 0.0087 in the SSRI-exposed group vs 0.0061 in the unmedicated group (hazard ratio, 1.37; 95% CI, 1.11-1.70; P = .004). There was a significantly increased risk of these disorders in offspring in the SSRI-exposed and unmedicated groups compared with offspring in the unexposed group. For scholastic and motor disorders, there were no differences between offspring in the SSRI-exposed group and in the unmedicated group. CONCLUSIONS AND RELEVANCE: Exposure to SSRIs during pregnancy was associated with an increased risk of speech/language disorders. This finding may have implications for understanding associations between SSRIs and child development.

Evidence for spared attention to faces in 7-month-old infants after prenatal exposure to antiepileptic drugs.

INTRODUCTION: Prenatal antiepileptic drug (AED) exposure is associated with an increased risk of cognitive impairment and autism spectrum disorders detected mainly at the age of two to six years. We examined whether the developmental aberrations associated with prenatal AED exposure could be detected already in infancy and whether effects on visual attention can be observed at this early age. MATERIAL AND METHODS: We compared a prospective cohort of infants with in utero exposure to AED (n=56) with infants without drug exposures (n=62). The assessments performed at the age of seven months included standardized neurodevelopmental scores (Griffiths Mental Developmental Scale and Hammersmith Infant Neurological Examination) as well as a novel eye-tracking-based test for visual attention and orienting to faces. Background information included prospective collection of AED exposure data, pregnancy outcome, neuropsychological evaluation of the mothers, and information on maternal epilepsy type. RESULTS: Carbamazepine, oxcarbazepine, and valproate, but not lamotrigine or levetiracetam, were associated with impaired early language abilities at the age of seven months. The general speed of visuospatial orienting or attentional bias for faces measured by eye-tracker-based tests did not differ between AED-exposed and control infants. DISCUSSION: Our findings support the idea that prenatal AED exposure may impair verbal abilities, and this effect may be detected already in infancy. In contrast, the early development of attention to faces was spared after in utero AED exposure.

Prenatal methylmercury exposure and language delay at three years of age in the Norwegian Mother and Child Cohort Study.

Prenatal methylmercury (MeHg) exposure and its possible neurodevelopmental effects in susceptible children are of concern. Studies of MeHg exposure and negative health outcomes have shown conflicting results and it has been suggested that co-exposure to other contaminants and/or nutrients in fish may confound the effect of MeHg. Our objective was to examine the association between prenatal exposure to MeHg and language and communication development at three years, adjusting for intake of fish, n-3 long chain polyunsaturated fatty acids (n-3 LCPUFAs) and co-exposure to dioxins and dioxin like polychlorinated biphenyls (dl-PCBs). We used data from the Norwegian Mother and Child Cohort Study (MoBa) collected between 2002 and 2008. The study sample consisted of 46,750 mother-child pairs. MeHg exposure was calculated from reported fish intake during pregnancy by a FFQ in mid-pregnancy. Children's language and communication skills were measured by maternal report on the Dale and Bishop grammar rating and the Ages and Stages communication scale (ASQ). We estimated odds ratios (OR) and 95% confidence intervals (CI) using logistic regressions. Median MeHg exposure was 1.3µg/day, corresponding to 0.14µg/kgbw/week. An exposure level above the 90th percentile (>2.6µg/day, >0.29µg/kgbw/week) was defined as the high MeHg exposure. Results indicated an association between high MeHg exposure and unintelligible speech with an adjusted OR 2.22 (1.31, 3.72). High MeHg exposure was also associated with weaker communication skills adjusted OR 1.33 (1.03, 1.70). Additional adjustment for fish intake strengthened the associations, while adjusting for PCBs and n-3 LCPUFA from diet or from supplements had minor impact. In conclusion, significant associations were found between prenatal MeHg exposure above the 90th percentile and delayed language and communication skills in a generally low exposed population.

Prenatal chemical exposures and child language development.

UNLABELLED: The goal of this review is to summarize the evidence that prenatal and/or early postnatal exposure to certain chemicals, both manmade (insulating materials, flame retardants, pesticides) and naturally occurring (e.g., lead, mercury), may be associated with delays or impairments in language development. We focus primarily on a subset of more extensively studied chemicals-polychlorinated biphenyls (PCBs), lead, and methyl mercury-for which a reasonable body of literature on neurodevelopmental outcomes is available. We also briefly summarize the smaller body of evidence for other chemicals including polybrominated diphenyl ether flame retardants (PBDEs) and organophosphate pesticides. Very few studies have used specific assessments of language development and function. Therefore, we included discussion of aspects of cognitive development such as overall intellectual functioning and verbal abilities that rely on language, as well as aspects of cognition such as verbal and auditory working memory that are critical underpinnings of language development. A high percentage of prospective birth cohort studies of PCBs, lead, and mercury have reported exposure-related reductions in overall IQ and/or verbal IQ that persist into middle or late childhood. Given these findings, it is important that clinicians and researchers in communication sciences and disorders are aware of the potential for environmental chemicals to impact language development. LEARNING OUTCOMES: The goal of this review is to summarize the evidence that prenatal and/or early postnatal exposure to certain chemicals may be associated with delays or impairments in language development. Readers will gain an understanding of the literature suggesting that early exposure to polychlorinated biphenyls (PCBs), lead, and mercury may be associated with decrements in cognitive domains that depend on language or are critical for language development. We also briefly summarize the smaller body of evidence regarding polybrominated diphenyl ether flame retardants (PBDEs) and organophosphate pesticides. Very few studies of exposure to these chemicals have used specific assessments of language development; thus, further investigation is needed before changes in clinical practice can be suggested.

Pregnancy and neurodevelopmental outcomes with in-utero antiepileptic agent exposure. A pilot study.

OBJECTIVE: To assess pregnancy outcomes on women exposed to monotherapy with antiepileptic agents. METHODS: Questionnaires were sent to women with epilepsy in our practice who were pregnant between 2006 and 2011. 62/86 patients (72%) who responded were on monotherapy. 24 fetuses (63%) were exposed to lamotrigine, 11 (28%) to levetiracetam, 2 (5.2%) to topiramate, 1 (2.6%) to gabapentin, 17 (27%) to carbamazepine, 5 to phenytoin and 2 to valproate. RESULTS: There were 55 (88%) live births and 7 unsuccessful pregnancies (miscarriages/stillbirths). Unsuccessful pregnancies were reported in 2/24 gestations exposed to lamotrigine, 2/11 to levetiracetam and 3/17 to carbamazepine. Delayed motor development or speech delay requiring therapy and special programming was noted in 2/24 children prenatally exposed to lamotrigine, 3/17 exposed to carbamazepine and 1/2 children exposed to valproate. CONCLUSION: Our pilot study of children exposed to antiepileptic drug monotherapy in-utero demonstrated a favorable trend for successful pregnancy outcomes and developmental trajectory.

Milestone achievement and neurodevelopment of rural Amazonian toddlers (12 to 24 months) with different methylmercury and ethylmercury exposure.

Neurological outcomes (Gesell development schedules [GDS]), age of walking, and age of talking were studied in 299 toddlers (12 to 24 mo) in relation to environmental (fish consumption and tin mining) exposure. Exposure to fish methylmercury (MeHg) consumption and iatrogenic ethylmercury (EtHg) in Thimerosal-containing vaccines (TCV) was quantified in toddlers from two rural villages (n = 91, Itapuã; n = 218, Bom Futuro) respectively populated by fishers and cassiterite miners. Median total hair Hg (HHg) concentrations of infants from Itapuã (3.5 µg/g) were significantly higher than those of infants from Bom Futuro (2.2 µg/g). Median EtHg exposure from TCV was also significantly higher in toddlers from Itapuã (137.5 µg) than in those from Bom Futuro (112.5 µg). There were no significant differences between groups for any of the Gesell schedules; however, there were proportionally more compromised toddlers (GDS < 70) in Itapuã than Bom Futuro. Median age of talking was not statistically different but median age of walking was significantly higher in Bom Futuro. In toddlers from both villages, of fishers and miners, HHg concentrations were significantly correlated with family fish consumption. A logistic regression model was applied to all infants after classification into two groups: above or below the median Gesell schedules. Overall, there was no distinctive pattern of neurodevelopment associated with either HHg or EtHg exposure; however, nutritional status was significantly associated with GDS. In conclusion, milestone achievement was delayed in toddlers from tin-ore mining communities. Despite significantly higher exposure to both forms of organic Hg (MeHg from maternal fish consumption, and EtHg from TCV) in toddlers from the fishing village, significant differences were seen only among the proportions of most severely affected toddlers (GDS < 70).

The association between brain injury, perioperative anesthetic exposure, and 12-month neurodevelopmental outcomes after neonatal cardiac surgery: a retrospective cohort study.

BACKGROUND: Adverse neurodevelopmental outcomes are observed in up to 50% of infants after complex cardiac surgery. We sought to determine the association of perioperative anesthetic exposure with neurodevelopmental outcomes at age 12 months in neonates undergoing complex cardiac surgery and to determine the effect of brain injury determined by magnetic resonance imaging (MRI). METHODS: Retrospective cohort study of neonates undergoing complex cardiac surgery who had preoperative and 7-day postoperative brain MRI and 12-month neurodevelopmental testing with Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III). Doses of volatile anesthetics (VAA), benzodiazepines, and opioids were determined during the first 12 months of life. RESULTS: From a database of 97 infants, 59 met inclusion criteria. Mean ± sd composite standard scores were as follows: cognitive = 102.1 ± 13.3, language = 87.8 ± 12.5, and motor = 89.6 ± 14.1. After forward stepwise multivariable analysis, new postoperative MRI injury (P = 0.039) and higher VAA exposure (P = 0.028) were associated with lower cognitive scores. ICU length of stay (independent of brain injury) was associated with lower performance on all categories of the Bayley-III (P < 0.02). CONCLUSIONS: After adjustment for multiple relevant covariates, we demonstrated an association between VAA exposure, brain injury, ICU length of stay, and lower neurodevelopmental outcome scores at 12 months of age. These findings support the need for further studies to identify potential modifiable factors in the perioperative care of neonates with CHD to improve neurodevelopmental outcomes.

Evaluation of risk for late language emergence after in utero antiretroviral drug exposure in HIV-exposed uninfected infants.

BACKGROUND: Combination antiretroviral (cARV) regimens are recommended for pregnant women with HIV to prevent perinatal HIV transmission. Safety is a concern for infants who were HIV-exposed but uninfected, particularly for neurodevelopmental problems, such as language delays. METHODS: We studied late language emergence (LLE) in HIV-exposed but uninfected children enrolled in a US-based prospective cohort study. LLE was defined as a caregiver-reported score ≤10th percentile in any of 4 domains of the MacArthur-Bates Communicative Development Inventory for 1-year olds and as ≥1 standard deviation below age-specific norms for the Ages and Stages Questionnaire for 2-year olds. Logistic regression models were used to evaluate associations of in utero cARV exposure with LLE, adjusting for infant, maternal and environmental characteristics. RESULTS: 1129 language assessments were conducted among 792 1- and 2-year-old children (50% male, 62% black and 37% Hispanic). Overall, 86% had in utero exposure to cARV and 83% to protease inhibitors. LLE was identified in 26% of 1-year olds and 23% of 2-year olds, with higher rates among boys. In adjusted models, LLE was not associated with maternal cARV or ARV drug classes in either age group. Among cARV-exposed 1-year olds, increased odds of LLE was observed for those exposed to atazanavir (adjusted odds ratio = 1.83, 95% confidence interval: 1.10-3.04), particularly after the first trimester (adjusted odds ratio = 3.56, P = 0.001), compared with atazanavir-unexposed infants. No associations of individual ARV drugs with LLE were observed among 2-year olds. CONCLUSIONS: In utero cARV exposure showed little association with LLE, except for a higher risk of language delay observed in 1-year-old infants with atazanavir exposure.

Deviant ERP response to spoken non-words among adolescents exposed to cocaine in utero.

Concern for the impact of prenatal cocaine exposure (PCE) on human language development is based on observations of impaired performance on assessments of language skills in these children relative to non-exposed children. We investigated the effects of PCE on speech processing ability using event-related potentials (ERPs) among a sample of adolescents followed prospectively since birth. This study presents findings regarding cortical functioning in 107 prenatally cocaine-exposed (PCE) and 46 non-drug-exposed (NDE) 13-year-old adolescents. PCE and NDE groups differed in processing of auditorily presented non-words at very early sensory/phonemic processing components (N1/P2), in somewhat higher-level phonological processing components (N2), and in late high-level linguistic/memory components (P600). These findings suggest that children with PCE have atypical neural responses to spoken language stimuli during low-level phonological processing and at a later stage of processing of spoken stimuli.

Malformation of the superior olivary complex in an animal model of autism.

Autism is a neurodevelopmental disorder characterized by social difficulties, impaired communication skills and repetitive behavioral patterns. Additionally, there is evidence that auditory deficits are a common feature of the autism spectrum disorders. Despite the prevalence of autism, the neurobiology of this disorder is poorly understood. However, abnormalities in neuronal morphology, cell number and connectivity have been described throughout the autistic brain. Indeed, we have demonstrated significant dysmorphology in the superior olivary complex (SOC), a collection of auditory brainstem nuclei, in the autistic brain. Prenatal exposure to valproic acid (VPA) in humans has been associated with autism and in rodents prenatal VPA exposure produces many neuroanatomical and behavioral deficits associated with autism. Thus, in an effort to devise an animal model of the autistic auditory brainstem, we have investigated neuronal number and morphology in animals prenatally exposed to valproic acid (VPA). In VPA exposed rats, we find significantly fewer neurons and significant alterations in neuronal morphology. Thus, prenatal VPA exposure in rats appears to produce similar dysmorphology as we have reported in the autistic human brain.