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Background: Language problems at an early age in very preterm (VP) children can have a detrimental effect on other developmental domains and often persist throughout childhood. The aim of this study was to examine the concurrent and predictive validity of an early language parent-report questionnaire for language disorder in VP children from 2 to 10 years of age. Materials and methods: In 80 VP children (

Background Infant exposure to persistent organic pollutants (POPs) may contribute to obesity. However, many studies so far have been small, focused on transplacental exposure, used an inappropriate measure to assess postnatal exposure through breastfeeding if any, or did not discern between prenatal and postnatal effects. Objectives We investigated prenatal and postnatal exposure to POPs and infant growth (a predictor of obesity). Methods We pooled data from seven European birth cohorts with biomarker concentrations of polychlorinated biphenyl 153 (PCB-153) (n = 2,487), and p,p´-dichlorodiphenyldichloroethylene (p,p´-DDE) (n = 1,864), estimating prenatal and postnatal POPs exposure using a validated pharmacokinetic model. Growth was change in weight-for-age z-score between birth and 24 months. Per compound, multilevel models were fitted with either POPs total exposure from conception to 24 months or prenatal or postnatal exposure. Results We found a significant increase in growth associated with p,p´-DDE, seemingly due to prenatal exposure (per interquartile increase in exposure, adjusted β = 0.12; 95% CI: 0.03, 0.22). Due to heterogeneity across cohorts, this estimate cannot be considered precise, but does indicate that an association with infant growth is present on average. In contrast, a significant decrease in growth was associated with postnatal PCB-153 exposure (β = –0.10; 95% CI: –0.19, –0.01). Conclusion To our knowledge, this is the largest study to date of POPs exposure and infant growth, and it contains state-of-the-art exposure modeling. Prenatal p,p´-DDE was associated with increased infant growth, and postnatal PCB-153 with decreased growth at European exposure levels. Citation Iszatt N, Stigum H, Verner MA, White RA, Govarts E, Palkovicova Murinova L, Schoeters G, Trnovec T, Legler J, Pelé F, Botton J, Chevrier C, Wittsiepe J, Ranft U, Vandentorren S, Kasper-Sonnenberg M, Klümper C, Weisglas-Kuperus N, Polder A, Eggesbø M, OBELIX. 2015. Prenatal and postnatal exposure to persistent organic pollutants and infant growth: a pooled analysis of seven European birth cohorts. Environ Health Perspect 123:730–736; http://dx.doi.org/10.1289/ehp.1308005

Several reports have investigated amino acid administration in premature infants during the early postnatal phase. Most of these previous studies, however, have only evaluated short-term in-hospital outcomes. Our aim was to describe long-term outcomes in premature infants previously subjected to different nutritional regimens in a randomized controlled trial. The primary outcome was survival without major disabilities, and the secondary outcomes included anthropometry and mental development. Infants born

Aim Very preterm infants are at risk of neonatal hearing loss. However, it is unknown whether infants with a normal neonatal hearing screening result risk sensorineural hearing loss (SNHL) at a later age. Methods This cohort study was conducted at the Erasmus Medical University Center Rotterdam, the Netherlands, on 77 very preterm infants born between October 2005 and September 2008. All infants underwent auditory brainstem response audiometry during neonatal hearing screening and at two years of corrected age. The frequency of SNHL in infants with a normal neonatal hearing screening was analysed and the risk factors associated with newly diagnosed SNHL in these infants were examined. Results We found that 3.9% (3/77) of the very preterm infants showed permanent hearing loss during their neonatal hearing screening. In addition, a relatively high prevalence of newly diagnosed SNHL (4.3%) was found in three of the 70 infants followed up at the age of two. The total prevalence rate of permanent hearing loss in the cohort was approximately 8%. Conclusion A normal outcome of neonatal hearing screening did not guarantee normal hearing at two years of age in this very preterm cohort and paediatricians should be alert to the possibility of late-onset SNHL. This article is protected by copyright. All rights reserved.

Morphine is widely used to treat severe pain in neonatal intensive care unit patients. Animal studies suggest adverse long-term side effects of neonatal morphine, but a follow-up study of 5-year-old children who participated in a morphine-placebo controlled trial as newborns found no such effects on the child's general functioning. This study indicated that morphine may negatively affect response inhibition, a domain of executive functions. Therefore, we performed a second follow-up study in the same population at the age of 8 to 9 years, focused on the child's general functioning in terms of intelligence, visual motor integration, and behavior and on executive functions. Children in the morphine group showed significantly less externalizing problems according to the parents but more internalizing behavior according to the teachers, but only after adjustment for intelligence quotient (IQ), potential confounders using a propensity score, and additional open-label morphine. Morphine-treated children showed significantly fewer problems with executive functions in daily life as rated by parents for the subscales inhibition and organization of materials and for planning/organizing as rated by the teachers. After adjustment for IQ and the propensity score, executive functioning as rated by the parents remained statistically significantly better in the morphine-treated group. The influence of the additional morphine given was not of a significant influence for any of the outcome variables. Overall, the present study demonstrates that continuous morphine infusion of 10 μg/kg/h during the neonatal period does not harm general functioning and may even have a positive influence on executive functions at 8 to 9 years.

AIM: Children born preterm often have neurodevelopmental problems later in life. Abnormal maturation of the auditory brainstem in the presence of normal hearing might be a marker for these problems. We conducted a meta-analysis of auditory brainstem response (ABR) latencies at term age to describe differences in auditory brainstem maturation between normal-hearing preterm and term-born infants. METHOD: Computerized databases were searched for studies published between 1995 and 2014 that reported ABR measurements at term age in infants born preterm in a case-control design. Five peaks reflect the conduction of a neural signal along the brainstem auditory pathway. We collected I to V interpeak latency data, and III to V interpeak latency data, which refers to the more central part of the pathway. RESULTS: Preterm-born infants' III to V interval is significantly longer compared to infants born at term (0.081ms, effect-size=0.974), which also reflects on the I to V interval. Moreover, significantly increased ABR interpeak latencies of infants born preterm are related to lower gestational age and the need for neonatal intensive care treatment. INTERPRETATION: The delayed conduction time towards and into the auditory brainstem at term age suggests atypical maturation of the brainstem in normal-hearing infants born preterm. Both the duration of gestation and the consequences of the preterm birth (intensive care needed) negatively affect maturation of the auditory brainstem, which may influence later development.

BACKGROUND AND OBJECTIVE: Preterm-born children ( METHODS: Computerized databases Embase, PubMed, Web of Knowledge, and PsycInfo were searched for studies published between January 1995 and March 2011 reporting language functions in preterm-born children. Outcome measures were simple language function assessed by using the Peabody Picture Vocabulary Test and complex language function assessed by using the Clinical Evaluation of Language Fundamentals. Pooled effect sizes (in terms of Cohen’s d) and 95% confidence intervals (CI) for simple and complex language functions were calculated by using random-effects models. Meta-regression was conducted with mean difference of effect size as the outcome variable and assessment age as the explanatory variable. RESULTS: Preterm-born children scored significantly lower compared with term-born children on simple (d = –0.45 [95% CI: –0.59 to –0.30]; P < .001) and on complex (d = –0.62 [95% CI: –0.82 to –0.43]; P < .001) language function tests, even in the absence of major disabilities and independent of social economic status. For complex language function (but not for simple language function), group differences between preterm- and term-born children increased significantly from 3 to 12 years of age (slope = –0.05; P = .03). CONCLUSIONS: While growing up, preterm-born children have increasing difficulties with complex language function.

Aim To examine executive functioning in very preterm (gestational age ≤30wks) children at 4 to 12years of age. Method Two-hundred very preterm (106 males, 94 females; mean gestational age 28.1wks, SD 1.4; mean age 8y 2mo, SD 2y 6mo) and 230 term children (106 males, 124 females; mean gestational age 39.9wks, SD 1.2; mean age 8y 4mo, SD 2y 3mo) without severe disabilities, born between 1996 and 2004, were assessed on an executive function battery comprising response inhibition, interference control, switching, verbal fluency, verbal and spatial working memory, and planning. Multiple regression analyses examined group differences while adjusting for effects of parental education, age, sex, and speed indices. Results Relative to children born at term, very preterm children had significant (ps

Objectives: Exposure to high concentrations of persistent organochlorines may cause fetal toxicity, but the evidence at low exposure levels is limited. Large studies with substantial exposure contrasts and appropriate exposure assessment are warranted. Within the framework of the EU (European Union) ENRIECO (ENvironmental Health RIsks in European Birth Cohorts) and EU OBELIX (OBesogenic Endocrine disrupting chemicals: LInking prenatal eXposure to the development of obesity later in life) projects, we examined the hypothesis that the combination of polychlorinated biphenyls (PCBs) and dichlorodiphenyldichloroethylene (DDE) adversely affects birth weight. Methods: We used maternal and cord blood and breast milk samples of 7,990 women enrolled in 15 study populations from 12 European birth cohorts from 1990 through 2008. Using identical variable definitions, we performed for each cohort linear regression of birth weight on estimates of cord serum concentration of PCB-153 and p,p´-DDE adjusted for gestational age and a priori selected covariates. We obtained summary estimates by meta-analysis and performed analyses of interactions. Results: The median concentration of cord serum PCB-153 was 140 ng/L (range of cohort medians 20484 ng/L) and that of p,p´-DDE was 528 ng/L (range of cohort medians 501,208 ng/L). Birth weight decreased with increasing cord serum concentration of PCB-153 after adjustment for potential confounders in 12 of 15 study populations. The meta-analysis including all cohorts indicated a birth weight decline of 150 g [95% confidence interval (CI): 250, 50 g] per 1-µg/L increase in PCB-153, an exposure contrast that is close to the range of exposures across the cohorts. A 1-µg/L increase in p,p´-DDE was associated with a 7-g decrease in birth weight (95% CI: 18, 4 g). Conclusions: The findings suggest that low-level exposure to PCB (or correlated exposures) impairs fetal growth, but that exposure to p,p´-DDE does not. The study adds to mounting evidence that low-level exposure to PCBs is inversely associated with fetal growth.

Objective: To examine performance in preschool and academic skills in very preterm (gestational age ≤30 weeks) and term-born comparison children aged 4 to 12 years. Study design: Very preterm children (n = 200; mean age, 8.2 ± 2.5 years) born between 1996 and 2004 were compared with 230 term-born children (mean age, 8.3 ± 2.3). The Dutch National Pupil Monitoring System was used to measure preschool numerical reasoning and early linguistics, and primary school simple and complex word reading, reading comprehension, spelling, and mathematics/arithmetic. With univariate analyses of variance, we assessed the effects of preterm birth on performance across grades and on grade retention. Results: In preschool, very preterm children performed comparably with term-born children in early linguistics, but perform more poorly (0.7 standard deviation [SD]) in numerical reasoning skills. In primary school, very preterm children scored 0.3 SD lower in complex word reading and 0.6 SD lower in mathematics/arithmetic, but performed comparably with peers in reading comprehension and spelling. They had a higher grade repeat rate (25.5%), although grade repeat did not improve their academic skills. Conclusions: Very preterm children do well in early linguistics, reading comprehension, and spelling, but have clinically significant deficits in numerical reasoning skills and mathematics/arithmetic, which persist with time. © 2011 Mosby Inc. All rights reserved.

OBJECTIVE: Sequelae of academic underachievement, behavioral problems, and poor executive function (EF) have been extensively reported for very preterm (≤33 weeks' gestation) and/or very low birth weight (VLBW) (≤1500 g) children. Great variability in the published results, however, hinders the field in studying underlying dysfunctions and developing intervention strategies. We conducted a quantitative meta-analysis of studies published between 1998 and 2008 on academic achievement, behavioral functioning, and EF with the aim of providing aggregated measures of effect size for these outcome domains. METHODS: Suitable for inclusion were 14 studies on academic achievement, 9 studies on behavioral problems, and 12 studies on EF, which compared a total of 4125 very preterm and/or VLBW children with 3197 term-born controls. Combined effect sizes for the 3 outcome domains were calculated in terms of Cohen's d. Q-test statistics were performed to test homogeneity among the obtained effect sizes. Pearson's correlation coefficients were calculated to examine the impact of mean birth weight and mean gestational age, as well as the influence of mean age at assessment on the effect sizes for academic achievement, behavioral problems, and EF. RESULTS: Combined effect sizes show that very preterm and/or VLBW children score 0.60 SD lower on mathematics tests, 0.48 SD on reading tests, and 0.76 SD on spelling tests than term-born peers. Of all behavioral problems stacked, attention problems were most pronounced in very preterm and/or VLBW children, with teacher and parent ratings being 0.43 to 0.59 SD higher than for controls, respectively. Combined effect sizes for parent and teacher ratings of internalizing behavior problems were small ( 0.51). CONCLUSIONS: Very preterm and/or VLBW children have moderate-to-severe deficits in academic achievement, attention problems, and internalizing behavioral problems and poor EF, which are adverse outcomes that were strongly correlated to their immaturity at birth. During transition to young adulthood these children continue to lag behind term-born peers.

Parent and clinician reports of behaviour problems among very low-birthweight (VLBW) children at 3 1/2 years of age were studied in relation to indicators of neonatal cerebral damage, cognition and social factors. VLBW children had more depressed behaviour and more internalizing problems by parent report, and also scored significantly more often within the clinical range on total problem scores, than children in the comparison group. Neither neonatal cerebral ultrasound nor neurological examinations were directly associated with behavioural outcome. Cerebral damage was related to cognitive development. Cognition directly influenced behaviour problems according to clinician report, while the home environment did so according to parent report. The authors suggest that depressed behaviour of preschool VLBW children might be associated with parental reactions to the birth of a VLBW child, and that their attention problems might be linked indirectly to brain damage via cognitive impairments.

SUMMARY The association of cerebral ultrasound images and developmental outcome at age 3 1/2 years was studied in 50 preterm infants (mean gestational age 31 weeks, mean birthweight 1450g). 25 children had normal neonatal scans and 25 had abnormal neonatal scans; 11 without and 14 with ventricular dilatation. At one year a repeat scan was done and neurodevelopmental outcome was assessed. Follow-up results at 3 1/2 years stress the importance of long-term follow-up: at one year four of the 50 children had developmental deficits, at 3 1/2 years 13 had such deficits. At 3 1/2 years the risk of neurodevelopmental deficits was extremely high for children with persistent haemorrhagic and/or atrophic ventricular dilatation. There was significant over-representation of children with developmental deficits in the group with abnormal scans, both neonatally and at one year. The incidence of cerebral palsy was high in the group with large haemorrhages extending into the parenchyma and/or periventricular leucomalacia. In the group with periventricular leucomalacia there was also a greater risk of mental retardation with severe behavioural problems. Follow-up at a later age than 3 1/2 years will be necessary to determine the effects on the motor, intellectual and emotional development of these children. RESUME Hemorragies ventriculaires et lesions hypoxiques-ischemiques chez le premature: devenir neurodeveloppement a trois ans et demi L'association ďimages ďechographie cerebrale et du devenir developpemental a ľâge de trois ans et demi a ete etudiee chez 50 prematures (age moyen de gestation de 31 semaines, poids moyen de naissance de 1450g). 25 nourrissons avaient des scanners neonataux normaux, 25 des scanners neonataux anormaux dont 11 sans et 14 avec dilatation ventriculaire. Un nouveau scanner fut fait a un an et le devenir neurodeveloppemental fut alors aprecie. Les resultats du suivi a trois ans et demi ont souligne ľimportance de suivi a long terme: a un an, quatre des 50 enfants presentaient des deficits de developpement.; a trois ans et demi, 13 avaient de tels deficits. A trois ans et demi, le risque de deficits neurodeveloppementaux etait extremement eleve pour les enfants avec dilatation ventriculaire persistante, hemorragique et/ou atrophique. II etait note une surrepresentation des enfants avec deficits de developpement dans le groupe des scanners anormaux aussi bien a la naissance qu'a un an. L'incidence ďinfirmite motrice cerebrale etait elevee dans le groupe avec larges hemorragies etendues dans le parenchyme et/ou leucomalacie periventriculaire. Dans le groupe avec leucomalacie periventriculaire, il y avait egalement un risque eleve de retard mental avec des problemes comportementaux graves. Un suivi au dela de trois ans et demi sera necessaire pour determiner les effets sur les developpements moteurs, intellectuels et affectifs de ces enfants. ZUSAMMENFASSUNG Ventrikulare Blutungen und hypoxisch-ischamische Lasionen bei Frugeborenen: neurologische Entwicklung mit 3 1/2 Jahren Bei 50 Frugeborenen (mittlers Gestationslater 31 Wochen, mittleres Geburtsgewicht 1450g) wurde die Beziehung von Ultraschallbefunden des Gehirns und Entwicklungsergebnissen im Alter von 3 1/2 Jahren untersucht. 25 Kinder hatten normale neonatale Scans und 25 hatten abnorme Scans, davon 11 mit und 14 ohne Ventrikelerweiterung. Mit einem Jahr wurden erneute Ultraschalluntersuchungen vorgenommen und die neurologische Entwicklung beurteilt. Kontrolluntersuchungsergebnisse im Alter von 3 1/2 Jahren unterstreichen die Bedeutung von Langzeituntersuchungen: mit einem Jahr hatten vier der 50 Kinder Entwicklungsverzogerungen, mit 3 1/2 Jahren wiesen 13 solche Verzogerungen auf. Mit 3 1/2 Jahren war das Risiko einer Entwicklungsverzogerung bei den Kindern besonders hoch, die eine persistierende hamorrhagische und/oder atrophische Ventrikelerweiterung hatten. In der Gruppe mit abnormen Scans, sowohl neonatal als auch mit einem Jahr, fanden sich signifikant mehr Kinder mit Entwicklungsverzogerungen. Die Cerebralparese war in der Gruppe mit grosen, bis ins Parenchym reichenden Blutungen und/oder periventrikularen Leukomalazien besonders haufig vertreten. In der Gruppe mit periventrikularer Leukomalazie bestand auserdem ein hohnes Risiko fur geistige Retardierung mit schweren Verhaltensproblemen. Es werden weitere Kontrolluntersuchungen uber das Alter von 3 1/2 Jahren hinaus erforderlich sein, um die Auswirkungen auf die motorische, intellektuelle und emotionale Entwicklung dieser Kinder zu erfassen. RESUMEN Hemorragias ventriculares y lesiones hipoxico-isquemicas en lactantes pretermino: evolucion del desarrollo neurologico a los 3 1/2 anos de edad Se estudio la asociacion de las imagenes ultrasonicas cerebrales y el desarrollo a los 3 1/2 anos de edad en un grupo de 50 lactantes pretermino (edad gestacional media: 31 semanas y peso medio: 1450g). 25 ninos tenian unas imagenes normales y 25 anormales al nacer; 11 sin y 14 con dilatacion ventricular. Al ano de edad se repitio el examen ultrasonico y se evaluo su estado neuroevolutivo. La situacion a los 3 1/2 anos apoya la importancia de un seguimento a largo plazo: a la edad de un ano cuatro de 50 ninos tenian deficits de desarrollo, a los 3 1/2 anos 13 tenian tales deficits. A los 3 1/2 anos el riesgo de deficits neuroevolutivos era extremadamente alto para los ninos con persistente y/o atrofica dilatacion ventricular. Habia una representacion significativamente muy alta de ninos con deficits de desarrollo en el grupo con imagenes anomalas al nacer y al ano de edad. La incidencia de paralisis cerebral era alta en el grupo con grandes hemorragias extendidas al parenquima o con leucomalacia periventricular. En el grupo con leucomalacia periventricular habia tambien un gran riesgo de retraso mental con graves problemas de comportamiento. Sera necesario el seguimiento a una edad superior a los 3 1/2 anos para determinar los efectos sobre el desarrollo motor, intelectual y emocional de estos ninos.

This study investigated the effect of early feeding mode on the neurological condition at 42 months. For this purpose, healthy pregnant women were recruited in Groningen and Rotterdam, The Netherlands. Children were healthy and born at term. At 42 months, the children were neurologically examined by means of the Touwen/Hempel technique. In addition to the clinical diagnosis, the neurological findings were interpreted in terms of optimality. Special attention was paid to the quality of movements in terms of fluency. In total, 200 (51%) exclusively breastfed (for greater than or equal to 6 weeks) and 194 (49%) formula-fed children were studied. Twelve (3%) 42-month-old children were considered to be neurologically mildly abnormal and 1 child was diagnosed as abnormal. No effect of the type of feeding was found on the clinical diagnosis or the neurological optimality. After adjustments for study centre and social, obstetric, perinatal and neonatal neurological differences, a beneficial effect of breastfeeding on the fluency of movements was found (odds ratio for non-optimal fluency 0.56; 95% confidence interval 0.37-0.85). The prolongation of full breastfeeding beyond 6 weeks did not influence the quality of movements. In conclusion, among Dutch preschool children, there was a small advantageous effect of full breastfeeding during the first 6 weeks of life on the fluency of movements.

The aim of the review of D.V. Cicchetti, A.S. Kaufman, and S.S. Sparrow (funded by the General Electric Company; this issue) is "to evaluate [the] literature relating the effects of prenatal and postnatal exposure to polychlorinated biphenyls (PCBs) upon neurobehavioral, health-related, and cognitive deficits in neonates, developing infants, children, and adults" (p. 589) on the basis of data derived from seven cohorts. One of these cohorts is the Dutch PCB/dioxin study. The paper of Cicchetti et al. presents a long, winding exercise in criticizing aspects of the design of the seven studies. Here we will give a comment on their review, as far as it concerns our own work. We applied the six fundamental sets of scientific criteria as proposed by Cichetti et al.

PCBs are known for their neurotoxic properties, especially on the developing brain. To increase insight into the neurotoxic effects of PCB exposure, the authors studied the effects of perinatal exposure to environmental levels of these compounds on different neuropsychological domains. In 9-year-old children of the Rotterdam PCB-dioxin cohort, higher prenatal PCB levels were associated with longer response times (RTs), more variation in RTs, and lower scores on the Tower of London (TOL; Shallice, 1982). A longer breast-feeding duration was associated with lower TOL scores and with better spatial organizational skills. There was some evidence of negative effects of lactational exposure to PCBs on scores on the TOL.

Objective. We report serial magnetic resonance (MR) and sonographic behavior of globus pallidus in 5 preterm and 3 term infants with kernicterus and describe the clinical context in very low birth weight preterm infants. On the basis of this information, we suggest means of diagnosis and prevention.Methods. Charts and MR and ultrasound images of 5 preterm infants and 3 term infants with suspected bilirubin-associated brain damage were reviewed. Included were preterm infants with severe hearing loss, quadriplegic hypertonia, and abnormal hypersignal of globus pallidus on T2-weighted MR imaging (MRI). In 1 infant who died on day 150, the diagnosis was confirmed during the neonatal period. The others were picked up as outpatients and scanned at 12 or 22 months’ corrected age. Three instances of term kernicterus were included for comparison of serial MRI in the neonatal period and early infancy: they were caused by glucose-6-phosphate dehydrogenase deficiency, urosepsis, and dehydration plus fructose 1–6 biphosphatase deficiency.Results. Five preterm infants of 25 to 29 weeks’ gestational age presented with total serum bilirubin (TSB) levels below exchange transfusion thresholds commonly advised. Mixed acidosis was present in 3 infants around the TSB peak. The bilirubin/albumin molar ratio was >0.5 in all, in the absence of displacing drugs. All failed to pass bedside hearing screen tests and had severe hearing loss on auditory brain response testing. Symmetrical homogeneous hyperechogenicity of globus pallidus was the alerting feature in 1 infant. Globus pallidus was hyperintense on T1-weighted MR images in this child. The other infants presented with severe developmental delay as a result of dyskinetic quadriplegia and hearing loss. Globus pallidus was normal on T1- but hyperintense on T2-weighted MR images at 12 or 22 months’ corrected age. Subthalamic involvement was documented in coronal fluid attenuated inversion recovery MRI in 2 infants. The term infants with classical clinical presentation in the neonatal period had MR behavior similar to the preterms, but pallidal injury was not recognized with targeted sonographic examination. Their neonatal MR images demonstrated pallidal T1 hyperintensity and mild T2 hyperintensity.Conclusion. Acidotic very low birth weight preterm infants with low serum albumin levels develop MR-confirmed pallidal injury and hearing loss facing “accepted” TSB levels. Serial MRI documents a shift from acute mainly T1 hypersignal to permanent T2 hypersignal in globus pallidus within the late neonatal period. Subthalamic and not thalamic involvement helps to differentiate from ischemic or metabolic disorder. As newborns, these infants are rigid and have severe apnea, before developing hypertonic quadriplegia in infancy.

Short-term and long-term effects of neonatal pain and its analgesic treatment have been topics of translational research over the years. This study aimed to identify the long-term effects of continuous morphine infusion in the neonatal period on thermal pain sensitivity, the incidence of chronic pain, and neurological functioning. Eighty-nine of the 150 participants of a neonatal randomized controlled trial on continuous morphine infusion versus placebo during mechanical ventilation underwent quantitative sensory testing and neurological examination at the age of 8 or 9 years. Forty-three children from the morphine group and 46 children from the placebo group participated in this follow-up study. Thermal detection and pain thresholds were compared with data from 28 healthy controls. Multivariate analyses revealed no statistically significant differences in thermal detection thresholds and pain thresholds between the morphine and placebo groups. The incidence of chronic pain was comparable between both groups. The neurological examination was normal in 29 (76%) of the children in the morphine group and 25 (61%) of the children in the control group ( P = .14). We found that neonatal continuous morphine infusion (10 μg/kg/h) has no adverse effects on thermal detection and pain thresholds, the incidence of chronic pain, or overall neurological functioning 8 to 9 years later. Perspective This unique long-term follow-up study shows that neonatal continuous morphine infusion (10 μg/kg/h) has no long-term adverse effects on thermal detection and pain thresholds or overall neurological functioning. These findings will help clinicians to find the most adequate and safe analgesic dosing regimens for neonates and infants.

Polychlorinated biphenyls (PCBs) and dioxins are known as neurotoxic compounds that may modulate sex steroid hormones. Steroid hormones play a mediating role in brain development and may influence behaviors that show sex differences, such as childhood play behavior. Inthis study we evaluated the effects of perinatal exposure to environmental levels of PCBs and dioxins on chilhood play behavior and whether the effects showed sex differences. As part of the follow-up to the Dutch PCB/dioxin study at school age, we used the Pre-School Activity Inventory (PSAI) to assess play behavior in the Rotterdam cohort (n - 207). The PSAI assesses masculine or femine play behavior scored on three subscales: masculine, feminine, and composite. Prenatal exposure to PCBs was defined as the sum of PCB 118, 138, 153, and 180 in maternal and cord plasma and breast milk. For breast milk we measured additional PCBs as well as 17 dioxins. Respondents returned 160 questionnaires (age 7.5 years 7.5 years ± 0.4). EFfects of prenatal exposure to PCBs, measured in maternal and cord plasma, on the masculine and composite scales were different for boys and girls (p < .05). In boys, higher prenatal PCB levels were related with less masculinized play, assessed by the masculine scale (Pmaternal = .042; Pcord = .001) and composite scale (Pcord = .011), whereas in girls higher PCB levels were associated with more masculinized play, assessed by the composite scale (PPCBmilk = .028). Higher prenatal dioxin levels were associated with more feminized play in boys as well as girls, assessed by the feminine scale (p = .048). These effects suggest prenatal steroid hormone imbalances caused by prenatal exposure to environmental levels of PCBs, dioxins, and other related organochlorine compounds.

Low-level exposure to polychlorinated biphenyl-153 (PCB-153) and dichlorodiphenyldichloroethylene (p-p′-DDE) can impair fetal growth; however, the exposure–response relationship and effect modifiers of such association are not well established. This study is an extension of an earlier European meta-analysis. Our aim was to explore exposure–response relationship between PCB-153 and p-p′-DDE and birth outcomes; to evaluate whether any no exposure–effect level and susceptible subgroups exist; and to assess the role of maternal gestational weight gain (GWG). We used a pooled dataset of 9377 mother–child pairs enrolled in 14 study populations from 11 European birth cohorts. General additive models were used to evaluate the shape of the relationships between organochlorine compounds and birth outcomes. We observed an inverse linear exposure–response relationship between prenatal exposure to PCB-153 and birth weight [decline of 194 g (95% CI −314, −74) per 1 μg/L increase in PCB-153]. We showed effects on birth weight over the entire exposure range, including at low levels. This reduction seems to be stronger among children of mothers who were non-Caucasian or had smoked during pregnancy. The most susceptible subgroup was girls whose mothers smoked during pregnancy. After adjusting for absolute GWG or estimated fat mass, a reduction in birth weight was still observed. This study suggests that the association between low-level exposure to PCB-153 and birth weight exists and follows an inverse linear exposure–response relationship with effects even at low levels, and that maternal smoking and ethnicity modify this association. Keywords: Biomarkers of exposure, Persistent organic pollutants, Polychlorinated biphenyls (PCBs), Dichlorodiphenyldichloroethylene (DDE), Birth weight

Prenatal exposure to polychlorinated biphenyls (PCBs) and dioxins is associated with changes in the T-cell lymphocyte population in healthy Dutch infants. We investigated whether these changes persist into later childhood and whether background exposure to PCBs and dioxins is associated with the prevalence of infectious or allergic diseases and humoral immunity at preschool age. The total study group consisted of 207 healthy mother-infant pairs. We estimated prenatal exposure to PCBs and dioxins by the sum of PCBs 118, 138, 153, and 180 (sigmaPCB) in maternal and cord plasma and in breast-fed infants by the dioxin, planar, and mono-ortho PCB toxic equivalent (TEQ) levels in human milk. At 42 months of age, current body burden was estimated by the PCB in plasma. We assessed the prevalence of infectious and allergic diseases by parent questionnaire, and measured humoral immunity by antibody levels for mumps, measles, and rubella after primary vaccination. We performed immunologic marker analyses of lymphocytes in a subgroup of 85 children. Prenatal PCB exposure was associated with an increased number of lymphocytes, T-cells, and CD3CD8(+) (cytotoxic), CD4(+)CD45RO(+) (memory), T-cell receptor (TcR) [alpha]ss(+), and CD3(+)HLA-DR(+) (activated) T cells and lower antibody levels to mumps and measles at preschool age. Adjusted for confounders, prenatal PCB exposure was associated with less shortness of breath with wheeze, and current PCB body burden was associated with a higher prevalence of recurrent middle-ear infections and of chicken pox and a lower prevalence of allergic reactions. A higher dioxin TEQ was associated with a higher prevalence of coughing, chest congestion, and phlegm. We conclude that in Dutch preschool children the effects of perinatal background exposure to PCBs and dioxins persist into childhood and might be associated with a greater susceptibility to infectious diseases. Common infections acquired early in life may prevent the development of allergy, so PCB exposure might be associated with a lower prevalence of allergic diseases.

Lower birth weight and growth retardation has been found in studies with laboratory animals, in children born of mothers exposed to accidental high levels of polychlorinated biphenyls (PCBs) and related compounds, and in children born of mothers who consumed PCB-contaminated fish. The effect of background exposure to PCBs and dioxins on birth size and growth in human newborns, however, is still unknown. This study examined birth size and postnatal growth of term newborns in relation to their background PCB and dioxin exposure. Birth weight and weight, length, and head circumference were measured at 10 d and 3, 7, 18, and 42 mo of age in 207 children, of whom 105 were breast-fed and 102 were formula-fed during infancy. The effect of in utero exposure to PCBs on birth size, assessed by cord and maternal plasma PCB levels, was investigated in the whole group. The effect of prenatal PCB exposure on postnatal growth was studied in the formula-fed group, whereas the effect of prenatal as well as lactational exposure to PCBs and dioxins on postnatal growth was studied in the breast-fed group. After adjustment for covariates, cord and maternal plasma PCB levels where both negatively associated with birth weight. Infants with high cord plasma PCB levels (P90 = 0.80 microL) weighed 165 g less compared with infants with low cord plasma PCB levels (P10 = 0.20 microg/L). Cord and maternal plasma PCB levels where both significantly associated with lower growth rate, defined as change in SD score (SDS) of weight, length, and head circumference from birth to 3 mo in the formula-fed group (all p values

Adverse neurological effects of exposure to PCBs have been found up to 18 months of age. Now we report on the effect of pre- and postnatal exposure to PCBs and dioxins on the neurological condition at 42 months of age. For this purpose, PCB levels were determined in cord and maternal plasma, and used as a measure of prenatal exposure. Breast milk was analyzed for PCBs and dioxins. In addition, PCBs were determined in plasma sampled from the child at 42 months of age. We evaluated the neurological condition of 394 children using the Touwen/Hempel method. After adjustment for covariates, neither prenatal PCB exposure nor postnatal exposure to PCBs and dioxins was found to be related to the neurological condition at 42 months of age.

The neurological optimality of 418 Dutch children was evaluated at the age of 18 months, in order to determine whether prenatal and breast milk mediated exposure to polychlorinated biphenyls (PCBs) and dioxins affected neurological development. Half of the infants were breast-fed, the other half were formula-fed. PCB concentrations in cord and maternal plasma were used as a measure of prenatal exposure to PCBs. To measure postnatal exposure, PCB and dioxin congeners were determined in human milk and in formula milk. After adjusting for covariates, transplacental PCB exposure was negatively related to the neurological condition at 18 months. Although greater amounts of PCBs and dioxins are transferred via nursing than via placental passage, an effect of lactational exposure to PCBs and dioxins could not be detected. We even found a beneficial effect of breast-feeding on the fluency of movements. We conclude that transplacental PCB passage has a small negative effect on the neurological condition in 18-month-old toddlers.

Aim To examine neonatal and parental predictors of executive function in very preterm (gestational age ≤30 weeks) children aged 4.0–12.0 years. Methods Two-hundred very preterm (mean age 8.2 ± 2.5 years) children without severe disabilities, born between 1996 and 2004, were assessed with measures of executive function including working memory, verbal fluency, planning and inhibitory control. Neonatal predictors were obtained from clinical records. Parental predictors included parental education, which was derived from questionnaires. Multiple linear regression analyses identified associations between neonatal and parental predictors and executive function in very preterm children. Results Better postnatal growth at 6 weeks of corrected age-predicted better spatial span (R² = 0.03, β = 0.17, p = 0.02) and planning (R² = 0.03, β = 0.16, p = 0.04). A higher level of parental education predicted better verbal fluency (R² = 0.02, β = 0.12, p = 0.02). Verbal working memory was not predicted by neonatal risk factors or by parental education (βs 0.20). Conclusions Executive function in very preterm children is associated with early postnatal growth and level of parental education but not with neonatal complications.

Bei Fruh- und Neugeborenen wiesen Daten aus Tierversuchen auf mogliche negative Folgen einer fruhen und chronischen Exposition mit Morphin hin. Vor diesem Hintergrund wurde von 2000–2002 eine Studie durchgefuhrt, die 150 Sauglinge und Fruhgeborene aufnahm, die in den ersten Lebenswochen auf einer Intensivstation kunstlich beatmet wurden und entweder eine Morphindauerinfusion oder eine Placeboinfusion erhielten. In der vorliegenden Arbeit werden Langzeitdaten der mittlerweile 8–9 Jahre alten Kinder veroffentlicht, die jetzt auch eine quantitative sensorische Testung beinhalten.

Polychlorinated biphenyls (PCBs) and dioxins are potentially toxic compounds which occur widely in the environment. Their effects on the growth and development of infants at the levels currently found in highly industrialised western countries is not well known. This Dutch multicenter study, combining animal and human studies, tries to answer this question. Animal studies showed that PCB 169, given once during pregnancy at a dose of 1.8 g kg-1 bodyweight, has an effect on developmental parameters, dopamine regulation and fertility. Effects on thyroid hormones were also found in animals, probably due to both a competitive binding of PCB metabolites to the thyroxine binding protein and increased glucuronidation, Perhaps to compensate for this, an increased diodase activity in the brain was found. Human studies involved 400 mother-infant pairs, half of them being breast-fed, the other half were fed a formula devoid of PCBs and dioxins. PCB levels were measured in serum and dioxin and PCB levels in breastmilk. Levels were found to be as high as previously found in highly industrialised countries. Growth and development were carefully documented, but no data are as yet available. In pregnant women, a significant negative correlation was found between some dioxin and PCB congeners in milk and plasma thyroid hormones, while newborn infants showed higher thyroid stimulating hormone (TSH) at higher levels of dioxin exposure. In summary, data from this combined multicenter study involving animals and humans increases our insight into the potentially negative effects of PCBs and dioxins on growth and development.

Dioxins [polychlorinated dibenzo-p-dioxins (PCDD), dibenzofurans (PCDF)] and polychlorinated biphenyls (PCB) are potentially hazardous compounds. Animal studies have demonstrated that PCDD, PCDF, and PCB can alter thyroid hormone homeostasis. We investigated thyroid hormone levels in 105 mother-infant pairs. To estimate maternal and infant exposure, four nonplanar PCB congeners were measured in maternal plasma during the last month of pregnancy and in umbilical cord plasma. Seventeen PCDD and PCDF congeners, three planar PCB congeners, and 23 nonplanar PCB congeners were measured in human milk. Higher PCDD, PCDF, and PCB levels in human milk, expressed as toxic equivalents, correlated significantly with lower plasma levels of maternal total triiodothyronine and total thyroxine, and with higher plasma-levels of TSH in the infants in the 2nd wk and 3rd mo after birth. Infants exposed to higher toxic equivalents levels had also lower plasma free thyroxine and total thyroxine levels in the 2nd wk after birth. We conclude that elevated levels of dioxins and PCB can alter the human thyroid hormone status.

To examine executive functioning in very preterm (gestational age ≤30 wks) children at 4 to 12 years of age.Two-hundred very preterm (106 males, 94 females; mean gestational age 28.1wks, SD 1.4; mean age 8y 2mo, SD 2y 6mo) and 230 term children (106 males, 124 females; mean gestational age 39.9wks, SD 1.2; mean age 8y 4mo, SD 2y 3mo) without severe disabilities, born between 1996 and 2004, were assessed on an executive function battery comprising response inhibition, interference control, switching, verbal fluency, verbal and spatial working memory, and planning. Multiple regression analyses examined group differences while adjusting for effects of parental education, age, sex, and speed indices.Relative to children born at term, very preterm children had significant (p(s)0.02; where p(s) represents p-values) deficits in verbal fluency (0.5 standardized mean differences [SMD]), response inhibition (0.4 SMD), planning (0.4 SMD), and verbal and spatial working memory (0.3 SMD), independent of slow and highly fluctuating processing speed. A significant group by age interaction indicated that group differences for response inhibition decreased between 4 and 12 years.Very preterm birth is associated with a profile of affected and non-affected executive functions independent of impaired speed. Deficits are of small to moderate magnitude and persist over time, except for response inhibition for which very preterm children catch up with peers.

Newborns on ventilatory support often receive morphine to induce analgesia. Animal experiments suggest that this may impair subsequent cognitive and behavioral development. There are sparse human data on long-term effects of neonatal morphine. We aimed to investigate the effects of continuous morphine administered in the neonatal period on the child's functioning. We conducted a follow-up study among 5-year-olds who, as mechanically ventilated neonates, had participated in a placebo-controlled trial on effects of morphine administration on pain and neurologic outcome. They were now tested on intelligence, visual motor integration, behavior, chronic pain, and health-related quality of life. Univariate analyses showed significantly lower overall intelligence quotient (IQ) scores for children who earlier had received morphine, that is, mean 94 (SD 14.5) versus 100 (SD 12.9) for those who received placebo (P = 0.049). Other between-group differences in outcomes were not found. The statistical difference disappeared after correction for treatment condition, open-label morphine consumption over the first 28 days, and a propensity score for clinically relevant co-variables in multiple regression analyses. However, scores on one IQ subtest, "visual analysis," were significantly negatively related to having received morphine and to open-label morphine consumption the first 28 days. The finding of a significant effect of morphine on the "visual analysis" IQ subtest calls for follow-up at a later age focusing on the higher-order neurocognitive functions. Morphine received in the neonatal period has negative effects on the child's cognitive functioning at the age of 5 years which warrants follow-up at a later age.

Very-low-birthweight (VLBW; birthweight1500 g and/or gestational age32 wks) children are at risk for speech problems. However, there are few studies on speech development in VLBW children at an early age. The aim of this study was to investigate phonological development in 2-year-old VLBW children.Twenty VLBW children without major neurosensory impairment (7 males, 13 females; mean birthweight 971 g, SD 315; mean gestational age 28 wks, SD 1.81) and 20 term children (7 males, 13 females; mean birthweight 3503 g, SD 416; mean gestational age 40 wks, SD 1.26) were compared on measures of phonological development derived from 20-minute spontaneous speech samples of standardized mother-child play interaction as well as on standardized tests of cognitive and psychomotor development, language, and behaviour.VLBW children had significantly fewer acquired consonants (median 9, p=0.02) and a significantly lower phonological mean length of utterance (pMLU; median 4.1, p0.01) than term children (median acquired consonants 10, median pMLU 5.0).This study provides evidence for poor phonological development in even healthy VLBW children, compared with term-matched children, independent of their cognitive, psychomotor, and language development, and their behavioural functioning.

We examined whether very preterm (a parts per thousand currency sign30 weeks gestation) children at early school age have impairments in executive function (EF) independent of IQ and processing speed, and whether demographic and neonatal risk factors were associated with EF impairments. A consecutive sample of 50 children (27 boys and 23 girls) born very preterm (mean age = 5.9 years, SD = 0.4, mean gestational age = 28.0 weeks, SD = 1.4) was compared to a sample of 50 age-matched full-term controls (23 girls and 27 boys, mean age = 6.0 years, SD = 0.6) with respect to performance on a comprehensive EF battery, assessing the domains of inhibition, working memory, switching, verbal fluency, and concept generation. The very preterm group demonstrated poor performance compared to the controls on all EF domains, even after partialing out the effects of IQ. Processing speed was marginally related to EF. Analyses with demographic and neonatal risk factors showed maternal education and gestational age to be related to EF. This study adds to the emerging body of literature showing that very preterm birth is associated with EF impairments

Perinatal exposure to PCBs and dioxins is associated with immune changes in healthy Dutch preschool children. To examine whether such effects persist into later childhood, we here report on the immunological effects of perinatal exposure to PCBs and dioxins in 167 Dutch children at school age. A higher postnatal PCB exposure was associated with a higher prevalence of recurrent middle ear infections and a higher prenatal PCB exposure with less shortness of breath with wheeze, as assessed by parent questionnaire. Our data indicate that, at environmental levels of these man made chemicals, subtle health effects may occur.

Objective To investigate the chance of detecting hearing loss with neonatal hearing screening in relation to exposure to tobramycin and vancomycin. Study design Automated auditory brainstem response (A-ABR) hearing screening was performed in all neonates with at least one risk factor. Data on drug administration were abstracted from patient files. Exposure to these drugs was related to the result of hearing screening. In patients failing hearing screening, exposure to ototoxic medication was assessed in the light of other risk factors for hearing loss. Results Six hundred twenty-five patients were analyzed; 45 neonates failed hearing screening. Tobramycin, vancomycin, and furosemide were used in 508, 130, and 174 patients, respectively. Exposure to vancomycin, tobramycin, or furosemide or a combination, defined in terms of treatment duration, total dose, or serum concentrations of antibiotics, was not related to failure to pass A-ABR screening. Ototoxic medication was not the most probable risk factor in any of the patients with serum concentrations outside the therapeutic range. Conclusions Routine therapeutic drug monitoring of vancomycin and tobramycin in neonates for ototoxicity reasons is not helpful in detecting patients at risk for clinically important hearing loss in the 2- to 4-kHz range. A longer period of audiometric follow-up is needed to determine any long-term effects. ( J Pediatr 2003;142:41-6 )

Objective: Our purpose was to evaluate whether effects of exposure to environmental levels of PCBs and dioxins on development in the Dutch cohort persist until school age. Study design: In the Dutch PCB/dioxin study, cognitive and motor abilities were assessed with the McCarthy Scales of Children's Abilities in children at school age. During infancy, half of this population was fully breast-fed for at least ≥6 weeks and the other half formula fed. Prenatal exposure to PCBs was defined as the sum of PCB118, 138, 153, and 180 in maternal and cord plasma. In breast milk, additional measurements of 17 dioxins, 6 dioxin-like PCBs, and 20 nondioxin-like PCBs were done. Results: Negative effects of prenatal PCB and dioxin exposure on cognitive and motor abilities were seen when parental and home characteristics were less optimal. These effects were not measurable in children raised in more optimal environments. Concluslons: Neurotoxic effects of prenatal PCB and dioxin exposure may persist into school age, resulting in subtle cognitive and motor developmental delays. More optimal intellectual stimulation provided by a more advantageous parental and home environment may counteract these effects of prenatal exposure to PCBs and dioxins on cognitive and motor abilities. Chemicals/CAS: Dioxins; Environmental Pollutants; Polychlorinated Biphenyls

Polychlorinated biphenyls (PCBs) are persistent pollutants that are ubiquitous in the food chain, and detectable amounts are in the blood of almost every person in most populations that have been examined. Extensive evidence from animal studies shows that PCBs are neurotoxins, even at low doses. Interpretation of human data regarding low-level, early-life PCB exposure and subsequent neurodevelopment is problematic because levels of exposure were not similarly quantified across studies. We expressed the exposure levels from 10 studies of PCB and neurodevelopment in a uniform manner using a combination of data from original investigators, laboratory reanalyses, calculations based on published data, and expert opinion. The mainstay of our comparison was the median level of PCB 153 in maternal pregnancy serum. The median concentration of PCB 153 in the 10 studies ranged from 30 to 450 ng/g serum lipid, and the median of the 10 medians was 110 ng/g. We found that a) the distribution of PCB 153 exposure in most studies overlapped substantially, b) exposure levels in the Faroe Islands study were about 3-4-fold higher than in most other studies, and c) the exposure levels in the two recent U.S. studies were about one-third of those in the four earlier U.S. studies or recent Dutch, German, and northern Quebec studies. Our results will facilitate a direct comparison of the findings on PCBs and neurodevelopment when they are published for all 10 studies.

To study possible adverse effects of environmental exposure to polychlorinated biphenyls (PCB) and dioxins on cognitive functioning in young children.In a follow-up of the Dutch PCB/Dioxin study, cognitive abilities were assessed with the Kaufman Assessment Battery for Children in 42-month-old children (n = 395). In a subgroup (n = 193) verbal comprehension was assessed with the Reynell Language Developmental Scales. Prenatal PCB exposure was estimated from the sum of PCBs 118, 138, 153, and 180 (SigmaPCB) in maternal plasma. Lactational exposure was assessed from breast milk PCB and dioxin concentrations, multiplied by the number of weeks of breast-feeding. Current PCB body burden was estimated from SigmaPCB in 42-month-old plasma samples.After adjustment was done for covariables, maternal SigmaPCB was associated with lower scores on the overall cognitive and sequential and simultaneous processing scales of the Kaufman Assessment Battery for Children (all P.05). The highest exposed group (SigmaPCB/= 3 microg/L) scored 4 points lower on all 3 scales of the K-ABC when compared with the lowest exposed group (SigmaPCB1.5 microg/L). Both lactational exposure and current exposure to PCBs and dioxins were not related to 42-month cognitive performance.In utero exposure to "background" PCB concentrations is associated with poorer cognitive functioning in preschool children. Children of mothers at the upper end of exposure are especially at risk. Therefore maternal PCB body burden should be reduced, and breast-feeding should not be discouraged.

Food is the major source for polychlorinated biphenyl (PCB) and dioxin accumulation in the human body. Therefore, investigating food habits from early ages until reproductive age (25 years) is important in order to assess exposure risk for the next generation. The objective of this study was to assess the PCB/dioxin exposure and the relative contribution of different foods to total exposure during preschool age. Particularly, the importance of lactational PCB/dioxin exposure vs. dietary exposure until adulthood was investigated. A cohort of 207 children was studied from birth until preschool age. Based on 3 planar PCBs and 17 2,3,7,8-substituted dibenzo-para-dioxins (PCDDs) and dibenzofurans (PCDFs) measured in breast milk, a model was developed to calculate the cumulative toxic equivalent (TEQ) intake during breast-feeding (0-1 year). In 3. 5-year-old children, daily dietary intake of planar PCB-TEQ and dioxin-TEQ was measured with a validated food questionnaire. Cumulative TEQ intake from 1 to 5 years was estimated using the PCB- and dioxin-TEQ intake measured with the food questionnaire. Cumulative TEQ intake from 6 to 25 years was estimated using national food consumption and contamination data of PCB- and dioxin-TEQ intake. In toddlers, dairy products contributed 43% to PCB-TEQ and 50% to dioxin-TEQ intake. Meat and meat products contributed 14% and 19%, respectively, and processed foods 23% and 15%, respectively. Breast-feeding for 6 months contributed to the cumulative PCB/dioxin TEQ intake until 25 years of age, 12% in boys and 14% in girls. The daily TEQ intake per kilogram body weight is 50 times higher in breast-fed infants and three times higher in toddlers than in adults. Long-term dietary exposure to PCBs and dioxins in men and women is partly due to breast-feeding (12 and 14%, respectively). After weaning, dairy products, processed foods, and meat are major contributors of PCB and dioxin accumulation until reproductive age. Instead of discouraging breast-feeding, maternal transfer of PCBs and dioxins to the next generation must be avoided by enforcement of strict regulations for PCB and dioxin discharge and by reducing consumption of animal products and processed foods in all ages.

Polychlorinated biphenyls (PCBs) and dioxins (polychlorinated dibenzo-p-dioxins (PCDDs), and dibenzofurans (PCDFs)) are widespread environmental contaminants which are neurotoxic in animals. Perinatal exposure to PCBs, PCDDs, and PCDFs occurs prenatally via the placenta and postnatally via breast milk. To investigate whether such an exposure affects the neonatal neurological condition, the neurological optimality of 418 Dutch newborns was evaluated with the Prechtl neurological examination. Half of the infants were breast-fed, the other half were formula-fed, representing a relatively high against a relatively low postnatally exposed group, respectively. As an index of prenatal exposure, four non-planar PCBs in cord and maternal plasma were used. These PCB levels were not related to neurological function. As measures of combined pre- and early neonatal exposure, 17 dioxin congeners, three planar, and 23 non-planar PCB congeners were determined in human milk in the second week after delivery. Higher levels of PCBs, PCDDs, and PCDFs in breast milk were related to reduced neonatal neurological optimality. Higher levels of planar PCBs in breast milk were associated with a higher incidence of hypotonia. This study confirms previous reports about the neurotoxic effects of these compounds on the developing brain of newborn infants.

Background and Aim To determine the prevalence of sensorineural hearing loss (SNHL) measured by auditory brainstem response (ABR) at 2 years of corrected age in very preterm (VPT) infants with normal neonatal hearing screening (NHS). Methods 85 VPT infants (gestational age 20 dB for at least one ear, after correction for possible conductive hearing loss. Univariate analyses were performed to identify risk factors associated with SNHL. Results Bilateral pass AABR shortly after birth was found in 81 (95%) VPT infants. In spite of bilateral pass AABR, 23 (29%) out of 78 VPT infants had hearing loss, defined as an estimated hearing loss >20 dB HL for at least one ear, measured by ABR at 2 years of corrected age. Of these VPT infants, 5 (6%) had SNHL. Proven sepsis was found in 4 (80%) VPT infants with SNHL compared to 23 (32%) VPT infants without SNHL (P Conclusions SNHL could be identified in 6% of 2-year-old VPT infants in spite of normal NHS shortly after birth. Follow-up audiometric testing after normal NHS is recommended for VPT infants who had proven sepsis in the neonatal period.

Dioxins and polychlorinated biphenyls (PCBs) are ubiquitous toxic compounds in the environment. Negative influences of these compounds on the health status of human beings have been described. Especially susceptible might be the fetus, which is exposed in utero, and the newborn breast-fed infant, since both are exposed to relatively high levels of dioxins and PCBs during a critical period of organ growth and development. We investigated PCB levels in 406 maternal plasma samples as well as PCB and dioxin levels in 172 human milk samples with relation to living area of women living for at least five years in the western industrialized part of the Netherlands or the northern more rural part. The western part was further subdivided into one urban and two highly industrialized areas. After correction for covariates, we found significantly higher levels of PCB 118 in maternal plasma as well as significantly higher levels of the dioxin-TEQ and of ten individual dioxin and PCB congener levels in human milk in the western more industrialized areas of the Netherlands compared to the northern more rural part. We did not find significant differences in planar, mono-ortho or di-ortho PCB-TEQ levels in human milk between all different areas. We conclude that significantly higher levels of a number of dioxin and PCB congeners are found in women living in industrialized areas compared to women living in rural areas in the Netherlands.

Background: Preterm children have more language problems than term children. However, it is unknown whether the language problems in these children worsen, are stable, or improve over time. We aimed to determine the developmental course of language function in preterm children in comparison to term children during childhood.

Background and Aims: Perinatal asphyxia is an important cause of permanent brain injury in term infants. An important neuroimaging indicator of neurodevelopmental prognosis following perinatal asphyxia is the extent of thalamic involvement. However the different patterns of injury seen within thalamus remain unclear. We used diffusion tensor imaging to study these patterns. Methods: In this retrospective study, we analysed DTI scans of 24 patients diagnosed with perinatal asphyxia, scanned between day 4-7 after birth. Images were acquired using a GE 1.5 Tesla system. Regions of interest were manually placed in four different thalamic regions (ventrolateral, medial, anterior and posterior region) and four localisations in cortex (prefrontal, parietal (post S1), occipital and temporal). ADC values were calculated using ‘DTI-studio’. Pearson's correlation coefficient and a multiple regression analysis were used (SPSS 17.0) to study relations between cortical and thalamic values. Results: We found significant correlations between prefrontal cortical ADC values and (connected) anterior- and medial thalamic regions. Temporal ADC values were correlated to Posterior thalamic regions. Occipital and parietal cortex showed highest correlation with posterior thalamic regions. Conclusions: Our study reveals significant correlations between the decrease of ADC values of thalamic nuclei and their anatomically corresponding cortical areas in perinatal asphyxia. These findings help explain different injury patterns seen within the asphyxiated thalamus. Unravelling these thalamic injury patterns using DTI could provide insights needed to improve our prognostication following perinatal asphyxia.

Objective. To investigate the effects of biological and social factors on the cognitive development of very low birth weight children, a longitudinal follow-up study was conducted from birth to 3.6 years of age. Methodology. The study group consisted of a cohort of 79 surviving high-risk, very low birth weight infants. Neonatal cerebral ultrasonographic findings and a neurological score were used as indicators of biological risk. A sociodemographic risk score and the Home Observation for Measurement of the Environment inventory were used as indicators of social risk. Cognitive development was assessed at ages 1 and 2 years by the Mental scale of the Bayley Scales of Infant Development and at age 3.6 years by the Kaufman Assessment Battery for Children. Results. The mean mental index at 1 year of age was 96 (SD 19), at 2 years of age 86 (SD 26), and at 3.6 years of age for intelligence 87 (SD 13) and for achievement 86 (SD 14). In a stepwise multiple regression analysis of biological as well as social factors, the neurological score alone was the best predictor for cognitive development at 1 year of age, explaining 46% of the variance. From 2 years of age onward, the best predictors for cognitive development were the neurological score together with the home environment, explaining 46% of the variance for the Mental Developmental Index at age 2, 34% for intelligence, and 56% for achievement at age 3.6. Conclusions. Children at high biological risk were able to catch up on their cognitive delay in a highly stimulating home environment. Children at low as well as high biological risk in a less stimulating home environment showed a decline in cognitive development. For these children, early intervention programs might be important in the prevention of cognitive disabilities.

To determine the assessments before discharge from the intensive care unit, that will predict outcome most accurately, a prospective longitudinal study in a cohort of 79 high risk VLBW children was conducted from birth to 3.6 years of age. Birthweight, gestational age, obstetrical and neonatal optimality, neonatal neurological examinations and neonatal cerebral ultrasound were studied in relation to outcome. The best predictor for outcome was a simple cerebral ultrasound classification according to the presence or absence of ventriculomegaly and intraparenchymal damage of any cause. Infants with normal neonatal cerebral scans or abnormal scans without ventriculomegaly almost invariably had a normal neurological outcome. In infants with cerebral lesions with ventriculomegaly the incidence of normal neurological outcome decreased to less than 50%. Intraparenchymal damage was associated with cerebral palsy as well as other (mental and sensori) handicaps in over 85% of the cases. Neonatal neurological examinations at preterm age had additional value in predicting neurological outcome especially in the group with ventriculomegaly. Neither birthweight, nor gestational age, obstetrical or neonatal optimality were independent variables in the prediction of outcome in high risk VLBW children at 3.6 years of age.