Margot van de Bor

Indomethacin-induced changes in renal blood flow velocity waveform in premature infants investigated with color Doppler imaging

Renal dysfunction has been recognized as an adverse effect of indomethacin treatment and is probably secondary to impairment of renal blood flow. We therefore evaluated renal artery blood flow velocity in 15 premature infants with a symptomatic ductus arteriosus before and during the first 12 hours after a single intravenous dose of 0.1 mg/kg of indomethacin. Renal artery blood flow velocity was measured serially by color-Doppler flow imaging and used as a qualitative measure of true renal blood flow. Indomethacin administration led to a sharp decrease in peak systolic flow velocity and temporal mean flow velocity of the renal artery. This effect was maximal at 10 minutes after indomethacin dosing; the flow velocities showed a slow recovery, reaching baseline values again at 2 hours after indomethacin dosing. We conclude that indomethacin can affect renal blood supply in the premature infant for a period of at least 1 hour after indomethacin treatment.

Prenatal Exposure to Perfluoroalkyl Substances and Behavioral Development in Children

Background: In recent years, prevalence rates of behavioral disorders in children have increased. One factor possibly implied in the etiology of behavioral disorders is exposure to perfluoroalkyl substances (PFASs). The use of PFASs is highly integrated into everyday life, and exposure is ubiquitous. Exposure to PFASs during early life may be particularly harmful, as it represents a critical time window for brain development. However, research in the area is limited, especially among preschool children. The objective of the current study was to explore the relationship between prenatal exposure to several PFASs and behavioral development at the age of 18 months. Methods: Data from the Dutch cohort LINC (Linking Maternal Nutrition to Child Health) were used. Perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) were measured in cord plasma. The total exposure of PFASs was also calculated (ΣPFASs). Behavioral development was assessed with the Child Behavior Checklist 1.5–5 (CBCL 1.5–5). The CBCL scales “Attention Deficit Hyperactivity Disorder” (ADHD) and “Externalizing problems” were used for further analysis. Separate regression models were composed for each combination, in which exposure levels were classified in tertiles. Both whole population and sex-stratified analyses were performed. A family history of ADHD, the educational level, smoking or using alcohol or illicit drugs during pregnancy were considered as confounders. In total, data from 76 mother-child pairs was included. Results: No significant associations were found between prenatal PFAS exposure and ADHD scores in the whole population and in the sex-stratified analyses. With regard to externalizing behavior, a significant negative association was found between the highest levels of ΣPFAS exposure and externalizing problem behavior in the whole population, but only in the crude model. After stratifying for sex, boys in the second and third tertile of exposure to PFOA presented significantly lower scores on the Externalizing Problem Scale than boys with the lowest exposure levels in the adjusted model. Girls exposed to higher levels of ΣPFAS exposure (T2) showed significantly lower scores on the Externalizing Problem Scale, in both crude and adjusted models. No significant associations with PFOS were found. Conclusions: Results from the current study show that prenatal exposure to PFOA was negatively related to externalizing behavior in boys. Results were different for boys and girls, emphasizing that mechanisms at work might be sex-dependent. However, results should be interpreted with caution as the sample size was small.

Does perinatal exposure to endocrine disruptors induce autism spectrum and attention deficit hyperactivity disorders? Review

Aim:  To provide an overview of studies on perinatal exposure in humans to endocrine disrupting chemicals (EDCs) in relation to autism spectrum (ASD) and attention deficit hyperactivity (ADHD) disorders.

Aetiological rôle of cerebral blood-flow alterations in development and extension of peri-intraventricular haemorrhage

The aetiology and extension of peri‐intraventricular haemorrhage (PIVH) are thought to be related to cerebral blood‐flow alterations, and especially to increased cerebral blood‐flow and fluctuating velocity of blood‐flow. Using transcutaneous Doppler technique, the authors investigated cerebral blood‐flow in 60 infants with gestations of less than 34 weeks. Pulsatility index (PI) and area under the velocity curve (AUVC) of the anterior cerebral arteries (ACA) were used as qualitative measures of cerebral blood‐flow, and the coefficient of variation of PI and AUVC as indicators of fluctuations in blood‐flow velocity. A reasonable correlation was found between PI and AUVC and their coefficients of variation in the ACA. First onset of PIVH was related to fluctuating blood‐flow velocity, and extension of PIVH with both increased velocity (indicating increased blood‐flow) and fluctuating velocity. Increased cerebral blood‐flow and its fluctuating pattern were positively correlated with arterial carbon dioxide tension.

Incidence and prediction of periventricular-intraventricular hemorrhage in very preterm infants

During a prospective national survey of mortality and morbidity in infants born before 32 weeks gestation in the Netherlands in 1983, the incidence of periventricular-intraventricular hemorrhage (PIVH) was studied with ultrasound, in 484 of those infants. Stepwise logistic regression analyses were used to examine the predictive value of several maternal, prenatal and postnatal factors for the development of neonatal PIVH. PIVH was detected in 140 infants (28.9%); of these, 36 were grade I, 39 grade II, 22 grade III and 43 grade IV. The mortality rate increased from 3 to 84% with increasing severity of PIVH. Gestational age appeared to be the strongest predictive factor for both incidence and severity of PIVH, followed by idiopathic respiratory distress syndrome (IRDS), prolonged rupture of membranes and birth weight. Of the maternal and prenatal factors studied, only prolonged rupture of membranes (greater than 24 hours) and preeclampsia appeared to influence the risk of developing PIVH. Both were associated with a 50% reduction in the incidence of PIVH. None of the intrapartum factors studied showed a significant association with subsequent development of PIVH. Development of IRDS appeared to result in a twofold increase in the incidence of PIVH.

The OBELIX project: early life exposure to endocrine disruptors and obesity

The hypothesis of whether early life exposure (both pre- and early postnatal) to endocrine-disrupting chemicals (EDCs) may be a risk factor for obesity and related metabolic diseases later in life will be tested in the European research project OBELIX (OBesogenic Endocrine disrupting chemicals: LInking prenatal eXposure to the development of obesity later in life). OBELIX is a 4-y project that started in May 2009 and which has the following 5 main objectives: 1) to assess early life exposure in humans to major classes of EDCs identified as potential inducers of obesity (ie, dioxin-like compounds, non-dioxin-like polychlorinated biphenyls, organochlorine pesticides, brominated flame retardants, phthalates, and perfluorinated compounds) by using mother-child cohorts from 4 European regions with different food-contaminant exposure patterns; 2) to relate early life exposure to EDCs with clinical markers, novel biomarkers, and health-effect data related to obesity; 3) to perform hazard characterization of early life exposure to EDCs for the development of obesity later in life by using a mouse model; 4) to determine mechanisms of action of obesogenic EDCs on developmental programming with in vivo and in vitro genomics and epigenetic analyses; and 5) to perform risk assessments of prenatal exposure to obesogenic EDCs in food by integrating maternal exposure through food-contaminant exposure and health-effect data in children and hazard data in animal studies.

OUTCOME OF PERIVENTRICULAR-INTRAVENTRICULAR HAEMORRHAG FIVE YEARS OF AGE

The authors studied the relationship between periventricular‐intraventricular haemorrhage in infants of <32 weeks gestation who had undergone routine cranial ultrasound scanning in the neonatal period, and neurodevelopmental outcome at the age of five years. Of 484 infants enrolled into the study, all 304 survivors were available for follow‐up at the age of five years. 85 children had a disability; in 50 of these, the disability caused a handicap. Three children with dilated lateral ventricles and no periventricular‐intraventricular haemorrhage were excluded from further analyses. 26 per cent of the infants with severe (grades III/IV) haemorrhage and 67 per cent of the infants with mild (grades 1/11) haemorrhage survived the neonatal period. Children with mild haemorrhage had a significantly increased risk of disability (including handicap) at the age of five years.

Obesogenic effects of endocrine disruptors, what do we know from animal and human studies?

BACKGROUND Hormonal actions and activation of receptors involved in adipogenesis and brain development during the prenatal period may be affected by exposure to certain chemicals. Experimental studies have shown that amongst others polychlorinated biphenyl (PCB)-153 and dichlorodiphenyltrichloroethane (DDT) may have obesogenic effects in prenatally exposed mice. OBJECTIVE To provide an overview of five classes of chemicals which have frequently been indicated as potential obesogens, and to discuss the evidence available regarding early life exposure to these compounds and overweight later in life. METHODS Pubmed was systematically searched for publications which related early life exposure to endocrine disrupting chemicals (EDCs) to growth parameters later in life. We included 19 studies, which were published from 1995 and onwards. RESULTS Both positive and negative associations are observed between early life exposure and weight or height at various ages, including as early as 14 months, as well as until 20 years of age. In none of the included studies negative associations between perinatal exposure to EDCs and body mass index (BMI) were found and in several studies a positive association was observed. Dose-response relations appear to be non-monotonic. CONCLUSION For certain EDCs, early life exposure may be associated with weight homeostasis later in life, however not necessarily in an obesogenic direction. More sensitive measures of adiposity as well as long-term follow-up are warranted for future studies.

The Dynamics of Autism Spectrum Disorders: How Neurotoxic Compounds and Neurotransmitters Interact

In recent years concern has risen about the increasing prevalence of Autism Spectrum Disorders (ASD). Accumulating evidence shows that exposure to neurotoxic compounds is related to ASD. Neurotransmitters might play a key role, as research has indicated a connection between neurotoxic compounds, neurotransmitters and ASD. In the current review a literature overview with respect to neurotoxic exposure and the effects on neurotransmitter systems is presented. The aim was to identify mechanisms and related factors which together might result in ASD. The literature reported in the current review supports the hypothesis that exposure to neurotoxic compounds can lead to alterations in the GABAergic, glutamatergic, serotonergic and dopaminergic system which have been related to ASD in previous work. However, in several studies findings were reported that are not supportive of this hypothesis. Other factors also might be related, possibly altering the mechanisms at work, such as time and length of exposure as well as dose of the compound. Future research should focus on identifying the pathway through which these factors interact with exposure to neurotoxic compounds making use of human studies.

Cerebral and aortic blood flow velocity patterns in preterm infants receiving prophylactic surfactant treatment

Blood velocity in the internal carotid artery (ICA) and in the descending thoracic aorta (DAo) was investigated used Duplex‐Doppler ultrasound in 14 infants of <30 weeks gestation, treated prophylactically with surfactant, and in 11 comparable infants with relatively mature lungs who served as controls. After surfactant administration, blood gases, pH or FiO2 were not different between the groups. Temporal mean blood velocity in the ICA was used as a relative measure of cerebral flow (TMFV‐cer), and its coefficient of variation (CV‐cer) was used to assess fluctuations in cerebral blood velocity. The pulsatility index (PI) in the ICA (PI‐cer) and DAo (PI‐DAo) was used to estimate if a left‐to‐right shunt was present. During surfactant instillation TMFV‐cer was abnormally low and CV‐cer indicated a fluctuating cerebral blood velocity. At 10 min after surfactant administration, TMFV‐cer of the treated infants was higher compared to the controls, while CV‐cer was stable in both groups. PI‐cer and PI‐DAo were abnormally high during the first hour of life after surfactant treatment, suggesting a left‐to‐right shunt without, however, clinical signs of a hemodynamically important ductus arteriosus. We suggest that cerebral perfusion is affected during and at 10 min after surfactant instillation. Left‐to‐right shunting appears to be a common event following surfactant treatment.