Does in utero exposure to antiseizure medications affect the trajectory of cognitive development from 2 to 6years of age?

Multiple factors constrain the trajectories of child cognitive development, but the drivers that differentiate the trajectories are unknown. We examine how multiple early life experiences differentiate patterns of cognitive development over the first 5 years of life in low-and middle-income settings. Cognitive development of 835 children from the Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) multisite observational cohort study was assessed at 6, 15, 24 (Bayley Scales of Infant and Toddler Development), and 60 months (Wechsler Preschool and Primary Scale of Intelligence). Markers of socioeconomic status, infection, illness, dietary intake and status, anthropometry, and maternal factors were also assessed. Trajectories of development were determined by latent class-mixed models, and factors associated with class membership were examined by discriminant analysis. Five trajectory groups of cognitive development are described. The variables that best discriminated between trajectories included presence of stimulating and learning resources in the home, emotional or verbal responsivity of caregiver and the safety of the home environment (especially at 24 and 60 months), proportion of days (0-24 months) for which the child had diarrhea, acute lower respiratory infection, fever or vomiting, maternal reasoning ability, mean nutrient densities of zinc and phytate, and total energy from complementary foods (9-24 months). A supporting and nurturing environment was the variable most strongly differentiating the most and least preferable trajectories of cognitive development. In addition, a higher quality diet promoted cognitive development while prolonged illness was indicative of less favorable patterns of development.

IntroductionThe effect of prenatal cannabis exposure (PCE) on childhood neurodevelopment remains poorly understood. There is a paucity of studies describing the neurodevelopment impact of PCE in infancy. The Mullen Scale of Early Learning (MSEL) is a cognitive screening tool that can be used from birth to 68 months and includes language and motor domains. Here we aim to explore the association between PCE during pregnancy and neurodevelopmental outcomes at 12 months of age.MethodsParticipants were pregnant persons/infant pairs enrolled in The Safe Passage Study, a large prospective cohort study. Inclusion criteria included data available on PCE with associated MSEL scores at 12 months of age. Exposed participants were defined as early exposure (1st trimester only) or late exposure (2nd or 3rd trimester) and were randomly matched with unexposed participants. Multiple linear regression models were performed to test associations between prenatal cannabis exposure and the five Mullen subscales: gross motor, fine motor, expressive language, receptive language, and visual reception.ResultsSixty-nine exposed and 138 randomly matched unexposed infants were included in the analyses. Mothers of children with PCE were younger with the mean age 23.7 years for early exposure (n = 51) and 22.8 years for late exposure (n = 18). Maternal characteristics with prenatal cannabis use include a high-school education, American Indian or Alaska Native descent, lower socioeconomic status and co-use of tobacco. There were no gestational age or sex difference among the groups. Expressive (95% CI: 2.54–12.76; p = 0.0036,) and receptive language scores (95% CI: 0.39–8.72; p = 0.0322) were significantly increased between late-exposed infants compared to unexposed infants following adjustment for covariates. Gross motor scores (95% CI: 1.75–13; p = 0.0105) were also significantly increased for early-exposed infants with no difference in visual reception scores.ConclusionPreclinical studies have shown abnormal brain connectivity in offspring exposed to cannabis affecting emotional regulation, hyperactivity, and language development. Results from this study link PCE to altered early language development within the first year of life. Exposed infants demonstrated increased expressive and receptive language scores at 12 months of age, which can translate to better performance in school. However, further research is needed to determine the implications of these results later in childhood.

BackgroundCognitive development after age three tends to be stable and can therefore predict cognitive skills in later childhood. However, there is evidence that cognitive development is less stable before age three. In rural China, research has found large shares of children under age three are developmentally delayed, yet little is known about the trajectories of cognitive development between 0 and 3 years of age or how developmental trajectories predict later cognitive skills. This study seeks to describe the trajectories of child cognitive development between the ages of 0–3 years and examine how different trajectories predict cognitive development at preschool age.MethodsWe collected three waves of longitudinal panel data from 1245 children in rural Western China. Child cognitive development was measured by the Bayley Scales of Infant Development when the child was 6–12 months and 22–30 months, and by the Wechsler Preschool and Primary Scale of Intelligence-Fourth Edition when the child was 49–65 months. We used the two measures of cognitive development before age three to determine the trajectories of child cognitive development.ResultsOf the children, 39% were never cognitively delayed; 13% were persistently delayed; 7% experienced improving cognitive development; and 41% experienced deteriorating development before age 3. Compared to children who had never experienced cognitive delay, children with persistent cognitive delay and those with deteriorating development before age 3 had significantly lower cognitive scores at preschool age. Children with improving development before age 3 showed similar levels of cognition at preschool age as children who had never experienced cognitive delay.ConclusionsLarge shares of children under age 3 in rural Western China show deteriorating cognitive development from infancy to toddlerhood, which predict lower levels of cognition at preschool age. Policymakers should invest in improving cognitive development before age 3 to prevent long-term poor cognition among China’s rural children.

Many modern pesticides have endocrine disrupting abilities and early-life exposure may affect growth and disease risk later in life. Previously, we reported associations between prenatal pesticide exposure and higher childhood body fat content measured by anthropometry. The associations were affected by child PON1 Q192R genotype. We aimed to study whether prenatal pesticide exposure was still associated with body fat content and distribution in the children at puberty and the potential impact of both maternal and child PON1 Q192R genotype. In this prospective cohort study of 247 children born by occupationally exposed or unexposed women (greenhouse workers and controls) two follow-up examinations (age 10-15 and 11-16years) including simple anthropometry, skinfold measurements, pubertal staging and blood sampling were performed. Total and regional fat% was determined by dual X-ray absorptiometry (DXA) at age 10-15. Prenatal pesticide exposure was associated with increased total, android, and gynoid fat percentage (DXA) at age 10-15years after adjustment for sex, socioeconomic status, and puberty (all β=0.5 standard deviation score (SDS) p<0.05). Stratified by sex, the associations were significant in girls (total fat: β=0.7 SDS, android-gynoid ratio: β=0.1, both p<0.05), but not in boys. Carrying the R-allele (child or mother, separately, or both) augmented the differences between exposed and unexposed children (total fat: β=1.0 SDS, β=0.8 SDS, p<0.05, respectively, and β=1.2 SDS, p<0.01). No exposure-related differences were found if either the child or mother had the QQ wild-type. At age 11-16, exposed children tended to have a higher total fat% estimated by skinfolds than unexposed children (p=0.06). No significant associations between prenatal exposure and body mass index or waist circumference were found. Prenatal pesticide exposure was associated with higher adolescent body fat content, including android fat deposition, independent of puberty. Girls appeared more susceptible than boys. Furthermore, the association depended on maternal and child PON1 Q192R genotype.

Cognitive outcomes at age 3 years in children with fetal exposure to antiseizure medications (MONEAD study) in the USA: a prospective, observational cohort study

Prenatal smoking exposure modulates brain development, which may deviate mental development of the offspring. To study the effects of prenatal smoking exposure on psychiatric morbidity and mortality among Finnish young adults by means of population-based longitudinal register data. Information on maternal smoking as reported by the mothers (0, <10, or >10 cigarettes a day) and other background factors (maternal age and parity and child's sex, gestational age, birth weight, and 5-minute Apgar score) was derived from the Finnish Medical Birth Register. Information on children's psychiatric diagnoses related to outpatient visits (1998-2007), children's inpatient care (1987-2007), and mothers' psychiatric inpatient care (1969-1989) was derived from the Finnish Hospital Discharge Register. Information on deaths and their causes for the children (1987-2007) was received from the Cause-of-Death Register. Population-based study of all singletons born in Finland from 1987 to 1989 with information on prenatal smoking exposure. Patients The source population included all singleton births in Finland from January 1, 1987, through December 31, 1989 (n = 175 869), excluding children with major congenital anomalies (3.1%) and children who died during the first week of life (0.3%). Psychiatric morbidity and mortality. The prevalence of maternal smoking was 15.3%. The risk of psychiatric morbidity was significantly higher in the exposed children than in the unexposed children. Among the offspring of mothers who smoked fewer than 10 cigarettes a day, 21.0% had any psychiatric diagnoses (adjusted odds ratio [OR], 1.53 [95% confidence interval (CI), 1.47-1.60]) compared with 24.7% among those of mothers who smoked more than 10 cigarettes a day (1.85 [1.74-1.96]) and 13.7% in the unexposed children (the reference group). The risk was significantly increased for most of the psychiatric diagnoses. The strongest effects were in psychiatric disorders due to psychoactive substance use and in behavioral and emotional disorders. The risk of mortality was significantly higher in children exposed to more than 10 cigarettes a day (OR, 1.69 [95% CI, 1.31-2.19]) compared with unexposed children. Prenatal smoking exposure is associated with an increased risk of psychiatric morbidity, whereas prenatal exposure to more than 10 cigarettes a day increases the risk of mortality in childhood, adolescence, and young adulthood.

This study investigates relations between language and cognitive scores in children with receptive language (RL) delay and suggests guidelines for referral for cognitive testing. This retrospective review of the test scores of 41 children, ages 17 to 76 months (mean = 37.7 months), focuses on examining associations between RL and cognitive scores. Results show that mean RL scores are positively correlated with mean cognitive scores and that receptive scores are significant predictors of cognitive performance. Children with RL scores of >1 standard deviation below the mean are at risk for concomitant cognitive deficits. Because children with RL delay are at considerable risk for cognitive deficits, the authors recommend considering referral for cognitive testing when RL standard scores fall below 85.

Does the home environment and the sex of the child modify the adverse effects of prenatal exposure to chlorpyrifos on child working memory?

Up to 1% of pregnant women undergo anaesthesia for non-obstetric surgery. This study investigated neurodevelopmental outcomes after prenatal anaesthesia for maternal surgery. A bidirectional cohort study of children born between 2001 and 2018 was performed: neurodevelopmental outcomes of children who had received prenatal anaesthesia for maternal surgery were prospectively compared with unexposed children, with exposure status being assessed retrospectively. Children exposed to anaesthesia for obstetric and fetal surgery were excluded. The primary outcome was the global executive composite of the behaviour rating inventory of executive function score. Our secondary outcomes were: total problems; internalising problems and externalising problems derived from the child behaviour checklist; psychiatric diagnoses; and learning disorders. In 90% of exposed children, there was a single mean (SD) antenatal anaesthesia exposure lasting 91(94) min. There was a broad spectrum of indications, with abdominal surgery being most frequent. Parents of 129 exposed (response rate 68%) and 453 unexposed (response rate 63%) children participated. There were no arguments for non-response bias. After propensity weighting, there were no statistically significant differences in primary outcome, with a weighted mean difference (95%CI) of exposed minus unexposed children of 1.9 (-0.4-4.2), p = 0.10; or any of the secondary outcomes. Sensitivity analyses confirmed the robustness. Exploratory analyses, however, showed significant differences in certain subgroups for the primary outcome, (e.g. for intra-abdominal surgery, exposure duration > 1 h) and some cognitive subdomains (e.g. working memory and attention). This bidirectional cohort study, the largest investigation on the subject to date, has found no evidence in the general population for an association between prenatal exposure to anaesthesia and impaired neurodevelopmental outcomes.

Exposure to surgery and anesthesia in early childhood has been found to be associated with an increased risk of behavioral deficits. While the US Food and Drug Administration (FDA) has warned against prenatal exposure to anesthetic drugs, little clinical evidence exists to support this recommendation. This study evaluates the association between prenatal exposure to general anesthesia due to maternal procedures during pregnancy and neuropsychological and behavioral outcome scores at age 10. This is an observational cohort study of children born in Perth, Western Australia, with 2 generations of participants contributing data to the Raine Study. In the Raine Study, the first generation (Gen1) are mothers enrolled during pregnancy, and the second generation (Gen2) are the children born to these mothers from 1989 to 1992 with neuropsychological and behavioral tests at age 10 (n=2024). In the primary analysis, 6 neuropsychological and behavioral tests were evaluated at age 10: Raven's Colored Progressive Matrices (CPM), McCarron Assessment of Neuromuscular Development (MAND), Peabody Picture Vocabulary Test (PPVT), Symbol Digit Modality Test (SDMT) with written and oral scores, Clinical Evaluation of Language Fundamentals (CELF) with Expressive, Receptive, and Total language scores, and Child Behavior Checklist (CBCL) with Internalizing, Externalizing, and Total behavior scores. Outcome scores of children prenatally exposed to general anesthesia were compared to children without prenatal exposure using multivariable linear regression models adjusting for demographic and clinical covariates (sex, race, income, and maternal education, alcohol or tobacco use, and clinical diagnoses: diabetes, epilepsy, hypertension, psychiatric disorders, or thyroid dysfunction). Bonferroni adjustment was used for the 6 independent tests in the primary analysis, so a corrected P value <.0083 (P = .05 divided by 6 tests, or a 99.17% confidence interval [CI]) was required for statistical significance. Among 2024 children with available outcome scores, 22 (1.1%) were prenatally exposed to general anesthesia. Prenatally exposed children had higher CBCL Externalizing behavioral scores (score difference of 6.1 [99.17% CI, 0.2-12.0]; P = .006) than unexposed children. Of 6 tests including 11 scores and subscores, only CBCL Externalizing behavioral scores remained significant after multiple comparisons adjustment with no significant differences found in any other score. Prenatal exposure to general anesthetics is associated with increased externalizing behavioral problems in childhood. However, given the limitations of this study and that avoiding necessary surgery during pregnancy can have significant detrimental effects on the mother and the child, further studies are needed before changes to clinical practice are made.

Decreased Cerebral Blood Flow in Young Children With Prenatal Alcohol Exposure

In experimental models, prenatal cocaine exposure has been found to perturb GABA and dopamine development. Clinically, abnormalities in tone, posture and state regulation are noted in early infancy but the evolution of these findings over time is not well described. The current study assesses the longitudinal effects of prenatal cocaine exposure in dose-dependent fashion on developmental & behavioral and neurological trajectories over the first 2 years of life. Three hundred and eighty infants, 113 cocaine-exposed, were enrolled at birth from an urban hospital from 2000 to 2004. Exposure was determined by maternal interview, segmental hair analyses (RIAH™) in all, and meconium and urine in a subset. Developmental, behavioral and neurological assessments were carried out blind to drug exposure at 6, 12 and 24 months of age in the 306 children who returned in follow-up. Mixed-effects linear modeling (developmental growth curve) assessed change in outcome over time. The mental developmental growth curve showed a negative slope (2.2 points) in adjusted analyses among cocaine-exposed children over the first 2 years of life. (p=.04), while the slope of the motor development growth curve did not. Adjusting for microcephaly at 6 months diminished the strength of the association between cocaine exposure and mental developmental growth curve (effect modification). Cocaine exposure was marginally associated with behavioral outcomes in adjusted analyses. Total Behavior scores and Orientation/Engagement scores improved with age. At 1 year of age, prenatal cocaine exposure was significantly associated with lower motor development scores. High rates of hypertonia (global and diparesis) identified at the 6-month visit dropped dramatically in the first 2 years of life: cocaine-exposed children showed a more rapid rate of resolution of hypertonia than unexposed children, with hypertonia improving 2.2 times faster among those with heavy cocaine exposure. We found differences in mental performance over the first 2 years of life associated with prenatal cocaine exposure that was mediated by microcephaly implying that cocaine exerts a sustained teratogenic effect on brain development. Early neurological (hypertonia) and behavioral findings associated with prenatal cocaine exposure improved over time. Hypertonia did not predict long-term development impairments. Conceivably, the transient nature of neurobehavioral manifestations reflects postnatally a tendency towards homeostasis of cocaine-related embryopathic perturbations of GABA and dopaminergic systems.

Maternal depression and sex differences shape the infants’ trajectories of cognitive development

Identifying risk and protective factors for language development informs interventions for children with developmental language disorder (DLD). Maternal responsive and intrusive communicative behaviours are associated with language development. Mother-child interaction quality may influence how children use these behaviours in language learning. To identify (1) communicative behaviours and interaction quality associated with language outcomes; (2) whether the association between a maternal intrusive behaviour (directive) and child language scores changed alongside a maternal responsive behaviour (expansion); and (3) whether interaction quality modified these associations. Language skills were assessed at 24, 36 and 48 months in 197 community-recruited children who were slow to talk at 18 months. Mothers and 24-month-olds were video-recorded playing at home. Maternal praise, missed opportunities, and successful and unsuccessful directives (i.e., whether followed by the child) were coded during a 10-min segment. Interaction quality was rated using a seven-point fluency and connectedness (FC) scale, during a 5-min segment. Linear regressions examined associations between these behaviours/rating and language scores. Interaction analysis and simple slopes explored effect modification by FC. There was no evidence that missed opportunities or praise were associated with language scores. Higher rates of successful directives in the unadjusted model and unsuccessful directives in the adjusted model were associated with lower 24-month-old receptive language scores (e.g., unsuccessful directives effect size (ES) = -0.41). The association between unsuccessful directives and receptive language was weaker when adjusting for co-occurring expansions (ES = -0.34). Both types of directives were associated with poorer receptive and expressive language scores in adjusted models at 36 and 48 months (e.g., unsuccessful directive and 48-month receptive language, ES = -0.66). FC was positively associated with 24-, 36- and 48-month language scores in adjusted models (e.g., receptive language at 24 months, ES = 0.21, at 48 months, ES = 0.18). Interaction analysis showed the negative association between successful directives and 24-month receptive language existed primarily in poorly connected dyads with low FC levels. These findings illustrate the effects of the combined interaction between different maternal communicative behaviours and features of the interaction itself on child language development, and the need to consider both in research and practice. Whilst more intrusive directives were associated with poorer language scores, this association attenuated when adjusting for co-occurring responsive expansions, and the association was strongest for children in lower quality interactions. This work may inform clinical practice by helping clinicians target the most appropriate communicative behaviours for specific mother-child dyads.

Children prenatally exposed to tobacco exhibit higher rates of learning and emotional-behavioral problems related to worse working memory performance. Brain function, however, among tobacco exposed children while performing a working memory task has not previously been examined. This study compared the brain function of tobacco-exposed (n = 7) and unexposed (n = 11) 12-year-olds during a number N-back working memory task using an event-related functional magnetic resonance imaging (fMRI) design. Prenatal alcohol exposure, neonatal medical problems, environmental risk, and sex were statistically controlled. Tobacco-exposed children showed greater activation in inferior parietal regions, whereas unexposed children showed greater activation in inferior frontal regions. These differences were observed in the context of correct responses, suggesting that exposed and unexposed children use different brain regions and approaches to succeed in working memory tasks. Implications for future research and intervention are discussed.