Prenatal exposure to PCBs and neurological and sexual/pubertal development from birth to adolescence

Several chemical compounds are resistant to degradation and end up in the food chain. One group of these chemicals is poly-chlorinated biphenyls (PCBs) which are used as flame retardants and plasticizers. Although PCBs were banned several decades ago, PCBs are still found in environmental media, including in the body of humans. PCBs are transferred from mother to fetus via the placenta during pregnancy. Considering that the prenatal period is a sensitive period during which essential developmental processes take place, exposure to environmental chemicals might have considerable and permanent consequences for outcomes in later life. The aim of this review is to provide an update on the latest insights on the effects of prenatal exposure to PCBs on neurological, sexual and pubertal development in children. We give an overview of recent literature, and discuss it in the light of the findings in a unique Dutch birth cohort, with data on both neurological and pubertal development into adolescence. The findings in the studies included in this review, together with the findings in the Dutch cohort, demonstrate that prenatal exposure to PCBs can interfere with normal child development, not only during the perinatal period, but up to and including adolescence. Higher prenatal exposure to PCBs was found to be both negatively and positively associated with neurodevelopmental outcomes. Regarding pubertal development, higher prenatal PCB exposure was found to be associated with more advanced pubertal development, also in the Dutch cohort, whereas other studies also found delayed pubertal development. These findings raise concern regarding the effects of man-made chemical compounds on child development. They further contribute to the awareness of how environmental chemical compounds can interfere with child development and negatively influence healthy ageing

Multi-domain cognitive impairments at school age in very preterm-born children compared to term-born peers

Background Preterm infants are at risk for functional impairments in motor, cognitive, and behavioral development that may persist into childhood. The aim of this study was to determine the co-occurrence of cognitive impairments in multiple cognitive domains at school age in very preterm born children compared to term-born children. Methods Comparative study including 60 very preterm-born children (gestational age = 2), versus 3% of the controls (odds ratio, OR 4.65, 95%-confidence interval, CI 1.33-16.35). For multiple suspect-abnormal cognitive outcomes, rates were 55% versus 25% (OR 3.02, 95%-CI 1.49-6.12). We found no pattern of co-occurrence of cognitive impairments among preterm children that deviated from term-born controls. However, low performance IQ was more frequently accompanied by additional cognitive impairments in preterms than in controls (OR 5.43, 95%-CI 1.75-16.81). Conclusions A majority of preterm children showed co-occurrence of impairments in multiple cognitive domains, but with no specific pattern of impairments. The occurrence of multi-domain cognitive impairments is higher in preterms but this seems to reflect a general increase, not one with a pattern specific for preterm-born children

Prenatal Exposure to Organohalogens, Including Brominated Flame Retardants, Influences Motor, Cognitive, and Behavioral Performance at School Age

BACKGROUND: Organohalogen compounds (OHCs) are known to have neurotoxic effects on the developing brain. OBJECTIVE: We investigated the influence of prenatal exposure to OHCs, including brominated flame retardants, on motor, cognitive, and behavioral outcome in healthy children of school age. METHODS: This study was part of the prospective Groningen infant COMPARE (Comparison of Exposure-Effect Pathways to Improve the Assessment of Human Health Risks of Complex Environmental Mixtures of Organohalogens) study. It included 62 children in whose mothers the following compounds had been determined in the 35th week of pregnancy: 2,2'-bis-(4 chlorophenyl)1,1'-dichloroethene, pentachlorophenol (PCP), polychlorinated biphenyl congener 153 (PCB-153), 4-hydroxy-2,3,3',4',5-pentachlorobiphenyl (4OH-CB-107),4OH-CB-146,4OH-CB-187,2,2',4,4'-tetrabromodipheryl ether (BDE-47), BDE-99, BDE-100, BDE-153, BDE-154, and hexabromocy-clododecane. Thyroid hormones were determined in umbilical cord blood. When the children were 5-6 years of age, we assessed their neuropsychological functioning: motor performance (coordination, fine motor skills), cognition (intelligence, visual perception, visuomotor integration, inhibitory control, verbal memory, and attention), and behavior. RESULTS: Brominated flame retardants correlated with worse fine manipulative abilities, worse attention, better coordination, better visual perception, and better behavior. Chlorinated OHCs correlated with less choreiform, dyskinesia. Hydroxylated polychlorinated biphenyls correlated with worse fine manipulative abilities, better attention, and better visual perception. The wood protective agent (PCP) correlated with worse coordination, less sensory integrity, worse attention, and worse visuomotor integration. CONCLUSIONS: Our results demonstrate for the first time that transplacental transfer of polybrominated flame retardants is associated with the development of children at school age. Because of the widespread use of these compounds, especially in the United States, where concentrations in the environment are four times higher than in Europe, these results cause serious concern

Parent-Completed Developmental Screening in Premature Children: A Valid Tool for Follow-Up Programs

Our goals were to (1) validate the parental Ages and Stages Questionnaires (ASQ) as a screening tool for psychomotor development among a cohort of ex-premature infants reaching 2 years, and (2) analyse the influence of parental socio-economic status and maternal education on the efficacy of the questionnaire. A regional population of 703 very preterm infants (<35 weeks gestational age) born between 2003 and 2006 were evaluated at 2 years by their parents who completed the ASQ, by a pediatric clinical examination, and by the revised Brunet Lezine psychometric test with establishment of a DQ score. Detailed information regarding parental socio-economic status was available for 419 infants. At 2 years corrected age, 630 infants (89.6%) had an optimal neuromotor examination. Overall ASQ scores for predicting a DQ score ≤85 produced an area under the receiver operator curve value of 0.85 (95% Confidence Interval:0.82–0.87). An ASQ cut-off score of ≤220 had optimal discriminatory power for identifying a DQ score ≤85 with a sensitivity of 0.85 (95%CI:0.75–0.91), a specificity of 0.72 (95%CI:0.69–0.75), a positive likelihood ratio of 3, and a negative likelihood ratio of 0.21. The median value for ASQ was not significantly associated with socio-economic level or maternal education. ASQ is an easy and reliable tool regardless of the socio-economic status of the family to predict normal neurologic outcome in ex-premature infants at 2 years of age. ASQ may be beneficial with a low-cost impact to some follow-up programs, and helps to establish a genuine sense of parental involvement

COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P &lt; 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men

Functional development at school age of newborn infants at risk

Dit proefschrift beschrijft de functionele ontwikkeling op schoolleeftijd van pasgeboren kinderen met diverse perinatale risicofactoren. We hebben voor het eerst aangetoond dat de transplacentale overdracht van gebromeerde vlamvertragers geassocieerd is met de motorische, cognitieve en gedragsmatige ontwikkeling van gezonde kinderen op schoolleeftijd. Het feit dat deze stoffen nog steeds wereldwijd op grote schaal toegepast worden is zorgelijk. Wat betreft prematuur geboren kinderen met een cerebraal veneus infarct vonden we dat de functionele ontwikkeling op schoolleeftijd beter is dan tot nu toe werd aangenomen. Deze ernstige hersenlaesie is in het verleden geassocieerd met behandelingsbeperkingen op diverse neonatale intensive care afdelingen. Hoewel een groot deel van de kinderen een spastische cerebrale parese ontwikkelt, zijn de functionele mogelijkheden in de meerderheid van de kinderen relatief goed. Ook het intelligentieniveau valt bij de meerderheid van de kinderen binnen een standaarddeviatie van het IQ van prematuren zonder deze hersenlaesie. Bij kinderen met systemische ziekte in de neonatale periode (necrotiserende enterocolitis en late-onset sepsis) vonden we juist dat de ontwikkeling op schoolleeftijd ernstiger aangedaan is dan voorheen gedacht. In vergelijking met de kinderen met een ernstige hersenlaesie was bijvoorbeeld het IQ slechts enkele punten hoger. De pathofysiologische mechanismen verantwoordelijk voor deze functionele beperkingen zijn vaak complex en multifactorieel. Bij prematuren speelt diffuse witte stof schade in de hersenen als gevolg van neuroinflammatie een centrale rol. We pleiten op basis van deze bevindingen voor een follow-up programma tot schoolleeftijd waarin zowel de motorische, cognitieve, als gedragsmatige ontwikkeling vervolgd wordt. This thesis deals with the functional development at school age of newborn infants with perinatal risk factors for adverse outcome. We showed for the first time that the transplacental transfer of brominated flame retardants is associated with the motor, cognitive, and behavioral outcome of healthy newborn infants. Because of the widespread use of these compounds we concluded that these results are a cause of serious concern. In addition we found that in preterm children with periventricular hemorrhagic infarction, the majority had cerebral palsy with limited functional impairment at school age. We concluded that the functional outcome at school age of preterm children with this brain lesion was better than previously thought. In contrast, in infants with systemic disease in the neonatal period such as necrotizing enterocolitis and late-onset sepsis, we found that the outcome at school age was worse than one would expect. Their intelligence, for example, was barely better compared to preterm children with severe brain lesions. The pathophysiological mechanisms responsible for the functional impairments that we found at school age are complex and multifactorial. In preterm born infants white matter damage to the brain as a result of neuroinflammation plays a prominent role. We recommend to include measures of motor, intellectual, neuropsychological and behavioral functioning in a follow-up program. Adequate follow-up of newborn infants could lead to the early identification of functional impairments so as to identify opportunities for early intervention.

Neurodevelopmental outcome in preterm infants

AIM To determine the distribution of cognitive and motor scores in preterm children, and to establish the influence of brain lesions and decreasing gestational age thereon. METHOD One hundred and six very preterm children (63 males, 43 females; gestational age 24.0-31.6wk; birthweight 480-2275g) were assessed for cognition and motor outcome at 6 to 12 years. We assessed total, verbal, and performance IQ using the Wechsler Intelligence Scale for Children, and motor outcome using the Movement Assessment Battery for Children (Movement ABC). RESULTS The IQs and Movement ABC z-scores were normally distributed, but shifted to the left. Mean total IQ (SD) was 91 (12), performance IQ 89 (13), and verbal IQ 93 (15), being 0.60, 0.73, and 0.47 SD lower than the norm respectively. Movement ABC z-scores were -1.27 SD lower (SD 1.01). IQ and Movement ABC z-scores did not correlate with brain lesions or gestational age. INTERPRETATION The distribution curve for cognition and motor outcome at school age is shifted to the left in preterm children, with an effect size of 0.60 SD for IQ (nine IQ points) and 1.27 SD for motor outcome. These findings are restricted to the current group. Developmental disruptions, affecting cerebral white matter, cortex, cerebellum, and thalamus might be involved, although the exact pathogenetic mechanism is unclear

Development of the Corticospinal and Callosal Tracts from Extremely Premature Birth up to 2 Years of Age

White matter tracts mature asymmetrically during development, and this development can be studied using diffusion magnetic resonance imaging. The aims of this study were i. to generate dynamic population-averaged white matter registration templates covering in detail the period from 25 weeks gestational age to term, and extending to 2 years of age based on DTI and fractional anisotropy, ii. to produce tract-specific probability maps of the corticospinal tracts, forceps major and forceps minor using probabilistic tractography, and iii. to assess the development of these tracts throughout this critical period of neurodevelopment. We found evidence for asymmetric development across the fiber bundles studied, with the corticospinal tracts showing earlier maturation (as measured by fractional anisotropy) but slower volumetric growth compared to the callosal fibers. We also found evidence for an anterior to posterior gradient in white matter microstructure development (as measured by mean diffusivity) in the callosal fibers, with the posterior forceps major developing at a faster rate than the anterior forceps minor in this age range. Finally, we report a protocol for delineating callosal and corticospinal fibers in extremely premature cohorts, and make available population-averaged registration templates and a probabilistic tract atlas which we hope will be useful for future neonatal and infant white-matter imaging studies

Developmental neurotoxicity of persistent organic pollutants : an update on childhood outcome

Organohalogens are persistent organic pollutants that have a wide range of chemical application. There is growing evidence that several of these chemical compounds interfere with human development in various ways. The aim of this review is to provide an update on the relationship between various persistent organic pollutants and childhood neurodevelopmental outcome from studies from the past 10 years. This review focuses on exposure to polychlorinated biphenyls (PCBs), hydroxylated PCBs (OH-PCBs), polybrominated diphenyl ethers (PBDEs) and dichlorodiphenyldichloroethylene (DDE), and in addition on exposure to phthalates, bisphenol A, and perfluorinated compounds and their associations with neurodevelopmental outcome in childhood, up to 18 years of age. This review shows that exposure to environmental chemicals affects neurodevelopmental outcome in children. Regarding exposure to PCBs and OH-PCBs, most studies report no or inverse associations with neurodevelopmental outcomes. Regarding exposure to PBDEs, lower mental development, psychomotor development and IQ were found at preschool age, and poorer attention at school age. Regarding exposure to DDE, most studies reported inverse associations with outcome, while others found no associations. Significant relations were particularly found at early infancy on psychomotor development, on attention and ADHD, whereas at school age, no adverse relationships were described. Additionally, several studies report gender-related vulnerability. Future research should focus on the long-term effects of prenatal and childhood exposure to these environmental chemicals, on sex-specific and combined exposure effects of environmental chemicals, and on possible mechanisms by which these chemicals have their effects on neurodevelopmental and behavioral outcomes