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Background: Cladribine tablets are contraindicated during pregnancy; therefore, safety data on pregnancies exposed to this treatment are limited. CLEAR collects and describes pregnancy outcomes in this understudied population. Objectives: To describe the main features of the CLEAR study design, including the data sources and the methodological approach, and provide a status update. Design: CLEAR is a non-interventional, multi-database, comparative cohort study. Four cohorts are included: pregnancies of women with multiple sclerosis (MS) exposed to cladribine tablets (maternal cohort exposed); pregnancies of women with MS unexposed to any disease-modifying therapy (DMT; maternal cohort unexposed); pregnancies fathered by men with MS exposed to cladribine tablets; and pregnancies fathered by men with MS unexposed to any DMT. Methods: A staggered methodological approach, using data from Denmark, Finland, France, Germany, Norway, Scotland, and Sweden, will be applied to analyze the occurrence of major congenital anomalies (primary outcome) and selected pregnancy outcomes. The first interim analysis (performed using German pregnancy cohorts) was conducted when ⩾75 pregnant women (including 25 women from the maternal cohort exposed) were cumulatively reached across all participating countries. The end of the study period will be established once pregnancy counts reach 149 in the maternal cohort exposed and 298 in the maternal cohort unexposed in all countries combined, or 5 years after pregnancy counts are first assessed (whichever occurs first). Results: As of January 2024, data on pregnancies of women exposed to cladribine tablets (n = 28–36 (numbers are approximate due to masking of some counts)), and pregnancies of women unexposed to cladribine tablets (n = 2834) were available from Denmark, Finland, Germany, Scotland, and Sweden. Conclusion: The CLEAR study, using a staggered methodological approach, aims to provide further insight into the safety outcome data for cladribine tablets in pregnant women, as a regulatory commitment with the European Medicines Agency. Trial registration: EU PAS Register number, EUPAS25027. [ABSTRACT FROM AUTHOR]

Appropriate animal models of human diseases are a cornerstone in the advancement of science and medicine. To create animal models of neuropsychiatric and neurobehavioral diseases such as autism spectrum disorder (ASD) necessitates the development of sufficient neurobehavioral measuring tools to translate human behavior to expected measurable behavioral features in animals. If possible, the severity of the symptoms should also be assessed. Indeed, at least in rodents, adequate neurobehavioral and neurological tests have been developed. Since ASD is characterized by a number of specific behavioral trends with significant severity, animal models of autistic-like behavior have to demonstrate the specific characteristic features, namely impaired social interactions, communication deficits, and restricted, repetitive behavioral patterns, with association to several additional impairments such as somatosensory, motor, and memory impairments. Thus, an appropriate model must show behavioral impairment of a minimal number of neurobehavioral characteristics using an adequate number of behavioral tests. The proper animal models enable the study of ASD-like-behavior from the etiologic, pathogenetic, and therapeutic aspects. From the etiologic aspects, models have been developed by the use of immunogenic substances like polyinosinic-polycytidylic acid (PolyIC), lipopolysaccharide (LPS), and propionic acid, or other well-documented immunogens or pathogens, like Mycobacterium tuberculosis. Another approach is the use of chemicals like valproic acid, polychlorinated biphenyls (PCBs), organophosphate pesticides like chlorpyrifos (CPF), and others. These substances were administered either prenatally, generally after the period of major organogenesis, or, especially in rodents, during early postnatal life. In addition, using modern genetic manipulation methods, genetic models have been created of almost all human genetic diseases that are manifested by autistic-like behavior (i.e., fragile X, Rett syndrome, SHANK gene mutation, neuroligin genes, and others). Ideally, we should not only evaluate the different behavioral modes affected by the ASD-like behavior, but also assess the severity of the behavioral deviations by an appropriate scoring system, as applied to humans. We therefore propose a scoring system for improved assessment of ASD-like behavior in animal models. [ABSTRACT FROM AUTHOR]

Valproic acid (VPA) is a very effective anticonvulsant and mood stabilizer with relatively few side effects. Being an epigenetic modulator, it undergoes clinical trials for the treatment of advanced prostatic and breast cancer. However, in pregnancy, it seems to be the most teratogenic antiepileptic drug. Among the proven effects are congenital malformations in about 10%. The more common congenital malformations are neural tube defects, cardiac anomalies, urogenital malformations including hypospadias, skeletal malformations and orofacial clefts. These effects are dose related; daily doses below 600 mg have a limited teratogenic potential. VPA, when added to other anti-seizure medications, increases the malformations rate. It induces malformations even when taken for indications other than epilepsy, adding to the data that epilepsy is not responsible for the teratogenic effects. VPA increases the rate of neurodevelopmental problems causing reduced cognitive abilities and language impairment. It also increases the prevalence of specific neurodevelopmental syndromes like autism (ASD) and Attention Deficit Hyperactivity Disorder (ADHD). High doses of folic acid administered prior to and during pregnancy might alleviate some of the teratogenic effect of VPA and other AEDs. Several teratogenic mechanisms are proposed for VPA, but the most important mechanisms seem to be its effects on the metabolism of folate, SAMe and histones, thus affecting DNA methylation. VPA crosses the human placenta and was found at higher concentrations in fetal blood. Its concentrations in milk are low, therefore nursing is permitted. Animal studies generally recapitulate human data. [ABSTRACT FROM AUTHOR]

Objectives: Prenatal exposure to heroin may have long-term consequences for development during early and middle childhood. The present research studied the cognitive, social, and emotional functioning of adolescents exposed to drugs prenatally, and investigated the extent to which the early adoption of children exposed prenatally to drugs would alleviate the possible effects of exposure. Methods: The study included 191 adolescents (12-16 years of age) and their parents in Israel, who had or had not been exposed prenatally to drugs and differing in socio-economic status (SES), and in adoptive status. They were administered five subtests of the Wechsler Intelligence Scale for Children (WISC-III), and the Youth Self-Report Form for assessing behavior problems that measures problems associated with attention deficit, self-esteem and risk-taking. Parents were administered the Child Behavior Checklist (CBCL) for assessing behavior problems, the Conners Rating Scale (CRS) for assessing attention deficit problems in their children and the Wender Utah Rating Scale (WURS), a self-report measure of ADHD-related problems. Results: Adolescents exposed to at least one risk factor (exposure to drugs, low SES, or adoption) performed more poorly than those exposed to none of these risk factors on the WISC-III subtests, the CBCL and the CRS. The effects of risk factors did not cumulate. Contrary to our hypothesis, adoption did not mitigate the effects of prenatal exposure to drugs: for cognitive functioning exposure to drugs was associated with poorer performance among the exposed High SES Adopted versus non-exposed High SES non-adopted children on three of the WISC-III subtests. Exposed low SES children living with their parents performed at the same relatively low level as non-exposed low SES controls. Exposure to drugs was associated with adult ADHD-related problems assessed by the WURS. There were no direct or interaction effects of exposure on neurological functioning, self-competence, behavior problems on the CBCL or risk-taking. Conclusions: Children exposed to drugs of abuse prenatally, including those adopted away, and children who grow up in low SES backgrounds, may be at risk of relatively reduced cognitive functioning (though still within the normal range) in adolescence. Children exposed to drugs, who are from low SES backgrounds, or who are adopted, may be at risk for lower cognitive or social functioning than children who have not experienced such risks. Practice implications: There is a need for implementing early monitoring and long-term intervention programs featuring encouragement of cognitive and social skills for children prenatally exposed to drugs in order to alleviate the possible long-term effects of exposure to risk. (Contains 6 tables.)

Aim: There is a lack of investigation into the functional developmental profile of children with Down syndrome. On the basis of current international health paradigms, the purpose of this study was to assess the developmental profile of these children. Method: Sixty children (33 males, 27 females) with Down syndrome (age range 6-16y; mean age 9y 3mo, SD 28.8mo), who had received standard, holistic, early intervention, were assessed. Of these, 42 (70%) had congenital anomalies, 12 had severe congenital heart defects. Participants were assessed on measures of cognitive function (Beery-Buktenica Developmental Test of Visual-Motor Integration; Stanford-Binet Intelligence Scale) and participation (Vineland Adaptive Behaviour Scales). Results: No difference was found on any measure on the basis of severity of congenital anomaly. Results showed improvements in age-related body function and correlations between specific body functions and participation. No decline in IQ was found with age, and significant correlations between IQ and all other measures were noted. Although sex differences were found in the body functions of short-term memory and motor function, no difference in measures of activity performance and participation was found. Interpretation: Our findings emphasize the need for paediatric Down syndrome intervention to encourage improved body functions while emphasizing the acquisition of functional skills that enable enhanced participation in age-appropriate activities. (Contains 2 tables.)