Neurodevelopmental retardation, as assessed clinically and with magnetoencephalography and electroencephalography, associated with perinatal dioxin exposure.

UNLABELLED: In 1980s Western Europe, human perinatal exposure to background levels of dioxins was rather high. We therefore evaluated the neurodevelopment of our cohort during the prepubertal period and in adolescence. At prepubertal age (7-12 years) 41 children were tested. Both neuromotor functioning and psychological testing were performed (Dutch version of the Wechsler Intelligence Scale for Children (WISC-R) and the Dutch version of the Child Behavior Checklist for ages 4-18 years (CBCL 4-18) and the Teacher Report Form (TRF)). Neurophysiological tests were performed using magnetoencephalography and electroencephalography. In adolescence (14-18 years) the behavior of 33 children was studied again (CBCL and TRF). And the levels of dioxins and dioxin-like PCBs (dl-PCBs) were measured in serum. RESULTS: At prepubertal age no association was found between perinatal dioxin exposure and verbal, performal and total IQ or with the Touwen's test for neuromotor development. There were behavioral problems associated with both prenatal and postnatal dioxin exposure. In adolescence there were problems associated with the current dioxin levels and dioxin-like-PCBs. Neurophysiological tests revealed clear negative dysfunction. An increase in latency time after a motion stimulus (N2b) of 13 ms (= a delay of 10%) is associated with the higher prenatal dioxin exposure. A similar delay was measured in testing cognitive ability by analyzing the odd ball measurements, N200 and P300, together with an amplitude decrease of 12 %. The delay is indicative of a defective myelinisation and the decrease in amplitude of a loss of neurons. CONCLUSION: We found effects on behavior in association with the perinatal dioxin exposure and in adolescence in association with the current dioxin levels. Neurophysiological testing is instrumental in the detection of effects of perinatal background levels of chemicals on brain development in normal, healthy children. The clinical, neurological and psychological tests commonly used are not sensitive enough to detect important effects.

[University teaching hospitals should no longer hold primacy in graduate medical education]. / Niet langer behoren de universitaire medische centra het primaat te hebben bij de opleiding van specialisten.

Historically, the training of specialist registrars, graduate medical education (GME) has been the responsibility of university teaching hospitals. Recent reforms of GME curricula and the increase in the size of district general hospitals (DGH) require a shift of the primacy of GME to the DGHs. The DGH will accept the challenge to fulfil this educational mission.

Dutch medical oath.

In the first part of this article, the booklet Dutch Medical Oath is reviewed. The content of the new oath is discussed as are the reasons for revision of the previous version of the oath. This is followed by a short history of the oath. In the second part of the article the oath is compared with the seven competencies of a medical specialist. The new oath contains elements of six of these seven competencies. This demonstrates that the oath is in keeping with the new medical educational demands.

[Uterine hyperstimulation following cervix ripening with dinoprostone in a vaginal insert system]. / Weeënstorm na cervixrijping met dinoproston in een vaginaal afgiftesysteem.

Three women, aged 28, 29 and 31 years, primigravidae, with an unripe cervix and an indication for induction of labour, were administered dinoprostone in a controlled vaginal insert system (VIS). A few hours after the insertion of the VIS strong, prolonged contractions occurred with bradycardia in the foetus, resulting in an emergency caesarean section. The children and the mothers recovered well. A potential adverse drug reaction of prostaglandins is uterine hyperstimulation. The sustained-release intravaginal dinoprostone was expected to be safer than the intravaginal or intracervical application of a prostaglandin gel. But data from the literature are conflicting. The risk of uterine hyperstimulation by prostaglandins including the sustained-release dinoprostone system necessitates a re-evaluation of the indications for induction of labour and the procedures of cervical priming. Up-to-date guidelines are an essential tool for the safe use of prostaglandins in daily obstetric practice.

Development and evaluation of a follow up assessment of preterm infants at 5 years of age.

BACKGROUND: Long term follow up shows a high frequency of developmental disturbances in preterm survivors of neonatal intensive care formerly considered non-disabled. AIMS: To develop and validate an assessment tool that can help paediatricians to identify before 6 years of age which survivors have developmental disturbances that may interfere with normal education and normal life. METHODS: A total of 431 very premature infants, mean gestational age 30.2 weeks, mean birth weight 1276 g, were studied at age 5 years. Children with severe handicaps were excluded. The percentage of children with a correctly identified developmental disturbance in the domains cognition, speech and language development, neuromotor development, and behaviour were determined. RESULTS: The follow up instrument classified 67% as optimal and 33% as at risk or abnormal. Of the children classified as at risk or abnormal, 60% had not been identified at earlier follow up assessments. The combined set of standardised tests identified a further 30% with mild motor, cognitive, or behavioural disturbances. The paediatrician's assessment had a specificity of 88% (95% CI 83-93%), a sensitivity of 48% (95% CI 42-58%), a positive predictive value of 85% (95% CI 78-91%), and a negative predictive value of 55% (95% CI 49-61%). CONCLUSIONS: Even after standardised and thorough assessment, paediatricians may overlook impairments for cognitive, motor, and behavioural development. Long term follow up studies that do not include detailed standardised tests for multiple domains, especially fine motor domain, may underestimate developmental problems.

Neonatal thyroxine supplementation in very preterm children: developmental outcome evaluated at early school age.

OBJECTIVE: Transient hypothyroxinemia in very premature infants is associated with developmental problems. A randomized, placebo-controlled trial of thyroxine (T(4)) supplementation was conducted in a group of 200 infants <30 weeks' gestation. T(4) supplementation improved mental outcome at 2 years old in children of 25/26 weeks' gestation only. The effect of T(4) supplementation beyond 2 years of age is unknown. We present the effects of neonatal T(4) supplementation on outcome at early school age. METHODS: Standardized measurements were used to assess cognitive, behavioral, and motor outcome, as well as a qualitative assessment of neurologic functioning. Survivors of the T(4) trial were assessed at the age of 5.7 years. RESULTS: Ninety-nine percent of the 157 survivors participated. Outcome on all domains was comparable between the T(4) group and placebo group. In children <27 weeks' gestation, a 10 IQ point difference was found in favor of the T(4) group, whereas in children of 29 weeks' gestation, a difference of 15 IQ points was found in favor of the placebo group. Teachers' reports showed less behavioral problems in the T(4)-treated children of 25/26 weeks' gestation, but more behavioral problems in the T(4)-treated children of 27 weeks' gestation. Differences in motor outcome and neurologic outcome were in favor of the T(4)-treated children <29 weeks' gestation, but not of the T(4)-treated children of 29 weeks' gestation. CONCLUSIONS: We found benefits of T(4) supplementation for children <29 weeks' gestation, and especially in children of 25/26 weeks' gestation. However, in children of 29 weeks' gestation T(4) supplementation is associated with more developmental problems.

Late onset of discordant growth in a monochorionic twin pregnancy: vascular anastomoses determine fetal growth pattern and not placental sharing.

Twin-twin transfusion syndrome in monochorionic twin pregnancies has a complex and variable clinical presentation. We present the first documented case where two unidirectional arteriovenous anastomoses connecting the donor twin's larger with the recipient's smaller placental part produce late onset of discordant growth and subsequent twin-twin transfusion syndrome. We conclude that the haemodynamic effects of the anastomoses caused the observed discordant fetal development and not the unequally shared placenta.

Postnatal thyroid hormone replacement in very preterm infants.

Transient hypothyroxinemia occurs frequently in very preterm infants and is caused by a combination of factors as immaturity of the hypothalamo-pituitary-thyroid system, loss of the maternal thyroxine (T4) contribution, immaturity of thyroid hormone metabolism, and neonatal illness. Thyroid hormone is important in maturation of the brain, but also of heart and lungs. Low neonatal T4 concentrations in plasma are related to worse clinical and neurodevelopmental outcome. Despite these relationships, only few randomized clinical trials have been performed to find out whether T4 supplementation can improve clinical and/or neurodevelomental outcome of preterm infants. The currently available evidence does not support use of supplemental T4 in all preterm infants. There are, however, indications that T4 might improve neurodevelopmental outcome in infants born before 27 to 29 weeks of gestation. Therefore, it is necessary that new trials are set up to further study the benefits of thyroid hormones given in the neonatal period of very preterm infants.

Neurologic development of the newborn and young child in relation to maternal thyroid function.

A prospective observational study was performed in pregnant women with known thyroid disease. We studied the effect of maternal thyroid function in the first half of pregnancy on the neurologic development of the infant in the first 2 y of life. Clinical and thyroid function data were collected from 20 pregnant women with known thyroid disease and their newborn children. Infants were divided into three groups according to their maternal thyroid function within the first half of pregnancy: Group A (n = 7): maternal subclinical hypothyroidism, Group B (n = 6): maternal euthyroidism, and Group C (n = 7): maternal hyperthyroidism or subclinical hyperthyroidism. Neurophysiologic, i.e. motor nerve conduction velocity and somatosensory evoked potentials and neurologic and developmental (Bayley scales) assessments were done. One infant, born to a mother with Graves' disease, developed transient hyperthyroidism. At the age of 6 and 12 mo, the mean mental developmental index (MDI) score was 16 points lower for infants in Group A than for those in Group B (p = 0.03 and 0.02, respectively). At the age of 24 mo, the mean MDI score was 6 points lower, which was not statistically significant. Neurophysiologic and neurologic assessments and the mean Psychomotor Developmental scores did not differ among the three groups. In conclusion, maternal subclinical hypothyroidism in the first half of pregnancy was associated with a lower mean MDI score in their infants during the first year of life.

The discrepancy between maturation of visual-evoked potentials and cognitive outcome at five years in very preterm infants with and without hemodynamic signs of fetal brain-sparing.

OBJECTIVE: After intrauterine growth restriction we found at the age of 6 months an acceleration of neurophysiologic maturation. However, at later ages impaired cognitive outcome has been reported. Therefore, we investigated in children with and without fetal hemodynamic adaptation to intrauterine growth restriction whether the accelerated neurophysiologic maturation in infancy might be associated with impaired cognitive outcome at preschool age. DESIGN: At 5 years of age cognitive function was assessed using the Revision of the Amsterdam Children's Intelligence Test in 73 preterm infants (26-33 weeks) who were prospectively followed from the antenatal period up to the age of 5 years. Maternal educational level was used as a background variable to estimate the confounding effects of socioeconomic status on cognitive function. Fetal Doppler studies were performed and the umbilical artery pulsatility index (PI) divided by the middle cerebral artery PI ratio (U/C ratio) was calculated. A U/C ratio >0.725 was considered as an indication of fetal cerebral hemodynamic adaptation to a compromised placental perfusion, ie, fetal brain-sparing. Visual-evoked potentials (VEPs) were recorded at 6 months and 1 year of age. In addition, data on neurologic status at 3 years were available. RESULTS: Mean IQ score was significantly lower for children born with a raised U/C ratio (87 +/- 16) compared with children with a normal U/C ratio (96 +/- 17). VEP latencies decreased significantly in infants with a normal U/C ratio, whereas no decrease was found in infants with a raised U/C ratio. Variables contributing significantly to the variance of cognitive function were: U/C group, VEP latency maturation, level of maternal education, and neurodevelopmental outcome at 3 years. The linear regression model explained 33% of the variance in cognitive function. CONCLUSIONS: Both being born with a raised U/C ratio and an acceleration of VEP latencies are negatively associated with cognitive outcome at 5 years of age. Fetal brain-sparing, although a seemingly beneficial adaptive mechanism for intact neurologic survival, is, however, later associated with a poorer cognitive outcome.

Transfer of 4'-chloro-2,2':6',2"-terpyridine platinum(II) between human serum albumin, glutathione and other thiolate ligands. A possible selective natural transport mechanism for the delivery of platinum(II) drugs to tumour cells.

The antitrypanosomal and antitumour activities of (2,2':6',2"-terpyridine)platinum(II) complexes have been postulated to be due to their ability to inhibit irreversibly the NADPH/FAD redox enzymes trypanothione reductase and human thioredoxin reductase respectively. Here we show that these platinum(II) complexes metallate recombinant human albumin (rHA) at the single free thiol group (Cys-34). Moreover, the (2,2':6',2"-terpyridine)platinum(II) complex can be transferred from rHA to other thiols, such as 2-hydroxyethanethiol or glutathione. Human serum albumin could therefore provide a natural transport mechanism for the selective delivery of these agents to tumor cells by the enhanced permeability and retention (EPR) mechanism.

Evaluation of the effect of thyroxine supplementation on behavioural outcome in very preterm infants.

Two-hundred infants of <30 weeks gestational age were included in a randomized double-blind controlled trial to study the effect of thyroxine administration on neurodevelopmental outcome in very preterm children. The infants were given either a fixed dose of thyroxine (8 microg/kg birthweight/day) or placebo for the first 6 weeks of life. This paper evaluates the effect of thyroxine administration on behavioural outcome at the age of 2 years. More externalizing, especially destructive, behaviours were found in the group given thyroxine than in the placebo group. This difference was more pronounced in boys and in children born after 27 weeks' gestation. The thyroxine-treated children with behavioural problems had lower plasma-free thyroxine levels than the thyroxine-treated children without behavioural problems. This finding suggests that the presence of more behavioural problems in the group given thyroxine was not an immediate consequence of the treatment.

Thyroid function in very preterm newborns: possible implications.

Thyroid hormones are essential for brain maturation. Very preterm infants, who are at risk of neurodevelopmental disabilities also have low thyroxine (T4) and free thyroxine (FT4) values in the first weeks after birth. This transient hypothyroxinemia may in part be causal to the neurodevelopmental problems. We have carried out a randomized, double-blind, placebo-controlled trial with T4 in 200 infants less than 30 weeks gestation. T4 (or placebo) was given in fixed dose of 8 microg/kg birth weight per day during the first 6 weeks after birth. It resulted in a significant increase of T4, FT4, and reverse triiodothyronine (rT3). Thyrotropin (TSH) secretion was suppressed, and, probably as a result of TSH suppression, triodothyronine (T3) levels were decreased in the T4 group. Mortality was 14% in the T4 group and 21% in the placebo group (NS). No effect was found on morbidity. Heart rate was significantly higher in T4-treated infants less than 28 weeks gestation, but not in T4-treated infants 28 weeks or more, who had the highest FT4 levels. In the study groups as a whole, no clear effect of T4 administration was found on neurodevelopmental outcome. However, there was a strong trend toward improvement of adverse outcome, defined as death or abnormal developmental outcome at 2 years of age. In addition, mental outcome in a subgroup of T4-treated infants less than 27 weeks' gestation was significantly better than in placebo infants of the same age group. In conclusion, this trial does not clearly have conclusive results. New trials of thyroid hormone treatment should be carried out in preterm infants, in order to investigate whether indeed T4 supplementation is required in preterm infants less than 27 or 28 weeks gestation. Addition of T3 to the treatment schedule needs to be considered.

Diabetes insipidus, Sheehan's syndrome and pregnancy.

OBJECTIVE: To study the role of vasopressin in osmoregulation in two successive pregnancies in a woman with Sheehan's syndrome. STUDY DESIGN: Diabetes insipidus (DI) became manifest during two pregnancies in a woman with postpartum hypopituitarism. RESULTS: Water deprivation-vasopressin administration tests demonstrated partial central DI, corrected with vasopressin in week 12, but only with desmopressin in the third trimester, when placental cystylamino peptidase (vasopressinase) contributes to the severity of the DI. CONCLUSION: If DI occurs during pregnancy it may be the first manifestation of a latent central DI, which is often idiopathic, but rarely the first symptom of a pituitary or hypothalamic abnormality. It may also be part of Sheehan's syndrome.

Effects of thyroxine supplementation on neurologic development in infants born at less than 30 weeks' gestation.

BACKGROUND: Premature infants who have transient hypothyroxinemia in the first weeks of life may have developmental delay and neurologic dysfunction. Whether thyroxine treatment during this period results in improved developmental outcomes is not known. METHODS: We carried out a randomized, placebo-controlled, double-blind trial of thyroxine supplementation in 200 infants born at less than 30 weeks' gestation. Thyroxine (8 microg per kilogram of birth weight) or placebo was administered daily, starting 12 to 24 hours after birth, for six weeks. Plasma free thyroxine concentrations were measured weekly for the first eight weeks after birth. Scores on the Bayley Mental and Psychomotor Development Indexes and neurologic function were assessed at 6, 12, and 24 months of age (corrected for prematurity). RESULTS: Mortality and morbidity up to the time of discharge from the hospital were similar in the study groups. At 24 months of age, 157 infants were evaluated. Overall, neither mental nor psychomotor scores differed significantly between the study groups at any time, nor was the frequency of abnormal neurologic outcome significantly different. In thyroxine-treated infants born at gestational ages of less than 27 weeks, the score on the Bayley Mental Development Index at 24 months of age was 18 points higher than the score for the infants with similar gestational ages at birth in the placebo group (P=0.01); for thyroxine-treated infants born at 27 weeks or later, the mental-development score was 10 points lower than that of their counterparts in the placebo group (P=0.03). There was no relation between the initial plasma free thyroxine concentration and the effect of treatment. CONCLUSIONS: In infants born before 30 weeks' gestation, thyroxine supplementation does not improve the developmental outcome at 24 months.

Thyroid function in preterm newborns; is T4 treatment required in infants < 27 weeks' gestational age?

Thyroid hormones are essential for brain maturation. Very preterm infants, who are at risk of neurodevelopmental disabilities also have low T4 and FT4 values in the first weeks after birth. This transient hypothyroxinemia may in part be causal to the neurodevelopmental problems. We have carried out a randomised, double-blind, placebo-controlled trial with T4 in 200 infants < 30 weeks' gestation. In the study groups as a whole (n = 100 in the T4 group, n = 100 in the Placebo group), no clear effect of T4 administration was found. In this study we examined whether gestational age influenced the effect of T4 administration. The T4- and placebo groups were subdivided into 4 groups according to gestational age. FT4-values during the first weeks after birth were lowest in the youngest gestational age group in the T4 as well as in the placebo group. In this group with infants < 27 weeks' gestation mental developmental outcome at 2 years of age was significantly better than in the placebo group of the same gestational age. There was also a trend towards a better psychomotor and neurological outcome. Beyond 27 weeks' gestation, no clear effect of T4 could be found; on the contrary, a possible harmful effect on mental developmental outcome might be the result. In conclusion. T4 treatment possibly improves developmental outcome in infants < 27 weeks' gestation, but seems not necessary beyond this gestational age.

Signs of enhanced neuromotor maturation in children due to perinatal load with background levels of dioxins. Follow-up until age 2 years and 7 months.

We investigated psychomotor development (Bayley-test) and neuromotor functioning (Hempel-test) in a group of children with known perinatal load with background levels of dioxins. Bayley-test (n = 32) at 2 years, and additionally investigated growth, medical history, physical condition, TT4, TT4/TBG, TSH, AST and ALT at the age of 2.5 years did not reveal abnormalities, or differences between the high- and the low-exposure group. Although the Hempel-test was normal in all children (n = 31), we found in 22 out of 29 items less suboptimal scores in the high-exposure group; in five items this difference reached significance (p < 0.05). Total-score and subtotal-score (posture of legs and feet excluded) revealed lower "suboptimality-scores" with a wider range in the high-exposure group in comparison to the low-exposure group (total-score p = 0.008 mean 6.7 SD 3.6 and mean 9.3 SD 1.8 respectively and subtotal-score p = 0.06 mean 4.5 SD 2.9 and mean 6.1 SD 1.6 respectively (Mann-Whitney or Wilcoxon Two-Sample Test). Similar signs of enhanced maturation have been described in the tadpole due to low dosis of TCDD. Reflexes were higher (p = 0.02), with a wider range of findings in the high-exposure group. Our hypothesis is that these findings may be due to thyroxine agonistic action of dioxins, which is in accordance with the earlier described signs of relatively high thyroid function in the first 11 weeks of life in this high-exposure group.

46,XY,dup(10q) in direct CVS preparation and mosaic 48,XXXY,dup(10q) in CVS long-term culture and fetal tissue.

Chorionic villus sampling (CVS) was performed on a 40-year-old woman at 9 1/2 menstrual weeks because of advanced maternal age. The direct preparation showed 46,XY,dup(10)(q11.2q23.2). CVS long-term culture and fetal tissue revealed a rare additional abnormality: 48,XXXY,dup(10)(q11.2q23.2). This abnormality represented the major cell line (> 85 per cent in 691 cells) in an (XY)/XXY/XXXY/(XXXXY) mosaic (all cell lines presumably bearing the dup(10q); the presence of XY and XXXXY cell lines is uncertain). To our knowledge, this is the first report of trisomy 10q11-q23 and of prenatally detected 48,XXXY in chorionic villi. The mosaic could have resulted from early post-zygotic non-disjunctions in a 46,XY,dup(10q) or 47,XXY,dup(10q) zygote. The results from DNA studies of four polymorphisms, mapped to Xp and Xq, support this theory. The literature on prenatally detected cases with sex chromosome tetrasomy and pentasomy and those with additional autosomal abnormalities is reviewed. The reported case underlines the problem of false-negative findings when only direct CVS preparations are karyotyped.