The use of parent-completed questionnaires to investigate developmental outcomes in large populations of children exposed to antiseizure medications in pregnancy.

OBJECTIVE: This study was undertaken to assess the utility of the Ages and Stages Questionnaire-3rd Edition (ASQ-3) and the Vineland Adaptive Behavior Scales-2nd Edition (VABS-II) as neurodevelopmental screening tools for infants exposed to antiseizure medications in utero, and to examine their suitability for use in large-population signal generation initiatives. METHODS: Participants were women with epilepsy who were recruited from 21 hospitals in England and Northern Ireland during pregnancy between 2014 and 2016. Offspring were assessed at 24 months old using the Bayley Scales of Infant Development-3rd Edition (BSID-III), the VABS-II, and the ASQ-3 (n = 223). The sensitivity and specificity of the ASQ-3 and VABS-II to identify developmental delay at 24 months were examined, using the BSID-III to define cases. RESULTS: The ASQ-3 identified 65 children (29.1%) as at risk of developmental delay at 24 months using standard referral criteria. Using a categorical approach and standard referral criteria to identify delay in the ASQ-3 and BSID-III at 24 months, the ASQ-3 showed excellent sensitivity (90.9%) and moderate specificity (74.1%). Utilizing different cut-points resulted in improved properties and may be preferred in certain contexts. The VABS-II exhibited the strongest psychometric properties when borderline impairment (>1 SD below the mean) was compared to BSID-III referral data (sensitivity = 100.0%, specificity = 96.6%). SIGNIFICANCE: Both the ASQ-3 and VABS-II have good psychometric properties in a sample of children exposed to antiseizure medications when the purpose is the identification of at-risk groups. These findings identify the ASQ-3 as a measure that could be used effectively as part of a tiered surveillance system for teratogenic exposure by identifying a subset of individuals for more detailed investigations. Although the VABS-II has excellent psychometric properties, it is more labor-intensive for both the research team and participants and is available in fewer languages than the ASQ-3.

Experience and Reporting of Postnatal Depression Across Cultures: A Comparison Using Anchoring Vignettes of Mothers in the United Kingdom and India.

Postnatal mental health is often assessed using self-assessment questionnaires in epidemiologic research. Differences in response style, influenced by language, culture, and experience, may mean that the same response may not have the same meaning in different settings. These differences need to be identified and accounted for in cross-cultural comparisons. Here we describe the development and application of anchoring vignettes to investigate the cross-cultural functioning of the Edinburgh Postnatal Depression Scale (EPDS) in urban community samples in India (n = 549) and the United Kingdom (n = 828), alongside a UK calibration sample (n = 226). Participants completed the EPDS and anchoring vignettes when their children were 12-24 months old. In an unadjusted item-response theory model, UK mothers reported higher depressive symptoms than Indian mothers (d = 0.48, 95% confidence interval: 0.358, 0.599). Following adjustment for differences in response style, these positions were reversed (d = -0.25, 95% confidence interval: -0.391, -0.103). Response styles vary between India and the United Kingdom, indicating a need to take these differences into account when making cross-cultural comparisons. Anchoring vignettes offer a valid and feasible method for global data harmonization.

Core Data Elements for Pregnancy Pharmacovigilance Studies Using Primary Source Data Collection Methods: Recommendations from the IMI ConcePTION Project.

INTRODUCTION AND OBJECTIVE: The risks and benefits of medication use in pregnancy are typically established through post-marketing observational studies. As there is currently no standardised or systematic approach to the post-marketing assessment of medication safety in pregnancy, data generated through pregnancy pharmacovigilance (PregPV) research can be heterogenous and difficult to interpret. The aim of this article is to describe the development of a reference framework of core data elements (CDEs) for collection in primary source PregPV studies that can be used to standardise data collection procedures and, thereby, improve data harmonisation and evidence synthesis capabilities. METHODS: This CDE reference framework was developed within the Innovative Medicines Initiative (IMI) ConcePTION project by experts in pharmacovigilance, pharmacoepidemiology, medical statistics, risk-benefit communication, clinical teratology, reproductive toxicology, genetics, obstetrics, paediatrics, and child psychology. The framework was produced through a scoping review of data collection systems used by established PregPV datasets, followed by extensive discussion and debate around the value, definition, and derivation of each data item identified from these systems. RESULTS: The finalised listing of CDEs comprises 98 individual data elements, arranged into 14 tables of related fields. These data elements are openly available on the European Network of Teratology Information Services (ENTIS) website ( http://www.entis-org.eu/cde ). DISCUSSION: With this set of recommendations, we aim to standardise PregPV primary source data collection processes to improve the speed at which high-quality evidence-based statements can be provided about the safety of medication use in pregnancy.

Neurodevelopment Following Exposure to Antiseizure Medications in Utero: A Review.

Exposure in the womb to antiseizure medications and their potential impact on the brain of the developing child has long been researched. Despite this long period of interest, this review highlights that above the well-known risks associated with valproate exposure, there are more data required for conclusions regarding all other antiseizure medications. Limited experience with phenytoin and phenobarbital in monotherapy makes clearly defining the risk to later child postnatal functioning difficult, although the evidence of an impact is stronger for phenobarbital than for phenytoin. The widely prescribed lamotrigine is limited in its investigation in comparison to unexposed control children, and whilst it has been demonstrated to carry a lower risk than valproate for certain outcomes, whether it is associated with a more moderate impact on wider aspects of neurodevelopmental functioning is still to be understood. Data for levetiracetam, topiramate and oxcarbazepine are too limited to confidently draw conclusions for most neurodevelopmental outcomes. This slow accumulation of evidence impacts on the safest use of medications in pregnancy and makes counseling women regarding the risks and benefits of specific antiseizure medications difficult. Improved focus, funding, and research methodologies are urgently needed.

A systematic review of the association between perinatal depression and cognitive development in infancy in low and middle-income countries.

The association between perinatal depression and infant cognitive development has been well documented in research based in high-income contexts, but the literature regarding the same relationship in low and middle-income countries (LMICs) is less developed. The aim of this study is to systematically review what is known in this area in order to inform priorities for early intervention and future research in LMICs. The review protocol was pre-registered on Prospero (CRD42018108589) and relevant electronic databases were searched using a consistent set of keywords and 1473 articles were screened against the eligibility criteria. Sixteen articles were included in the review, seven focusing on the antenatal period, eight on the postnatal period, and one which included both. Five out of eight studies found a significant association between antenatal depression (d = .21-.93) and infant cognitive development, while four out of nine studies found a significant association with postnatal depression (d = .17-.47). Although the evidence suggests that LMICs should prioritise antenatal mental health care, many of the studies did not adequately isolate the effects of depression in each period. Furthermore, very few studies explored more complex interactions that may exist between perinatal depression and other relevant factors. More high-quality studies are needed in LMIC settings, driven by current theory, that test main effects and examine moderating or mediating pathways to cognitive development.

Emotion Recognition Performance in Children with Callous Unemotional Traits is Modulated by Co-occurring Autistic Traits.

OBJECTIVE: Atypical emotion recognition (ER) is characteristic of children with high callous unemotional (CU) traits. The current study aims to 1) replicate studies showing ER difficulties for static faces in relation to high CU-traits; 2) test whether ER difficulties remain when more naturalistic dynamic stimuli are used; 3) test whether ER performance for dynamic stimuli is moderated by eye-gaze direction and 4) assess the impact of co-occurring autistic traits on the association between CU and ER. METHODS: Participants were 292 (152 male) 7-year-olds from the Wirral Child Health and Development Study (WCHADS). Children completed a static and dynamic ER eye-tracking task, and accuracy, reaction time and attention to the eyes were recorded. RESULTS: Higher parent-reported CU-traits were significantly associated with reduced ER for static expressions, with lower accuracy for angry and happy faces. No association was found for dynamic expressions. However, parent-reported autistic traits were associated with ER difficulties for both static and dynamic expressions, and after controlling for autistic traits, the association between CU-traits and ER for static expressions became non-significant. CU-traits and looking to the eyes were not associated in either paradigm. CONCLUSION: The finding that CU-traits and ER are associated for static but not naturalistic dynamic expressions may be because motion cues in the dynamic stimuli draw attention to emotion-relevant features such as eyes and mouth. Further, results suggest that ER difficulties in CU-traits may be due, in part, to co-occurring autistic traits. Future developmental studies are required to tease apart pathways toward the apparently overlapping cognitive phenotype.