Two-year development of children conceived by IVM: a prospective controlled single-blinded study.

STUDY QUESTION: Is there a difference in mental development of children conceived by IVM in comparison to IVF or ICSI, independently, at the age of 2 years? SUMMARY ANSWER: No differences could be found in mental development of IVM children compared to IVF and IVM children compared to ICSI as well. WHAT IS KNOWN ALREADY: Only few retrospective or non-controlled studies addressed the health of IVM children and did not show a negative impact of the IVM procedure. STUDY DESIGN, SIZE, DURATION: Prospective controlled single-blinded study including 63 pregnancies (21 per IVM, IVF and ICSI groups) with 70 children expected. Examinations of 62 embryos at first trimester screening, of 57 fetuses at 21st week of pregnancy, of 60 children at birth and of 37 children at their second birthday were performed during the study period from January 2009 until October 2016. Bayley score at the age of 2 was the primary outcome parameter. Data of 40 children after spontaneous conception from a previous prospective unrelated study were further used as control at 2 years examination and compared to the pooled ART group (IVM, IVF and ICSI). PARTICIPANTS/MATERIALS, SETTING, METHODS: Twenty-one IVM pregnancies achieved in the study period were included. For each of them, the following IVF- and ICSI pregnancies were recruited as controls. Ultrasound examinations during pregnancy, examinations of newborns and of children around their second birthday were done by blinded prenatal specialists, pediatricians and neuropediatricians, respectively. MAIN RESULTS AND THE ROLE OF CHANCE: Children conceived after IVM did not show differences during embryonic development, at birth nor in their neuropediatric development at the age of 2 compared to their counterparts after IVF and after ICSI (Bayley score 91.3 ± 21.0 for IVM, 96.8 ± 13.2 for IVF and 103.9 ± 13.1 for ICSI) and of the pooled ART group compared to children after spontaneous conception (96.6 ± 16.4 ART and 103.2 ± 9.4 spontaneous conception). When analyzing singleton pregnancies only, again no differences during pregnancy, at birth and at their 2-year evaluation were detected between IVM versus IVF and IVM versus ICSI. LIMITATIONS, REASONS FOR CAUTION: Due to the small sample size data must be interpreted with caution. To allow a confirmative answer that there are no health risks for children conceived by IVM, large multicenter cohort or registry-based studies are urgently needed. WIDER IMPLICATIONS OF THE FINDINGS: The study adds further information to previous uncontrolled or retrospective studies, which were unable to detect risks for the health of IVM children. STUDY FUNDING/COMPETING INTEREST(S): The study was supported by the 'Deutsche Forschungsgemeinschaft' (DFG): STR 387/4-1. G.R. receives royalties from Pearson Assessment Germany (editor fee for Bayley-III). The other authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: Not applicable.

Large neutral amino acids block phenylalanine transport into brain tissue in patients with phenylketonuria.

Large neutral amino acids (LNAAs), including phenylalanine (Phe), compete for transport across the blood-brain barrier (BBB) via the L-type amino acid carrier. Accordingly, elevated plasma Phe impairs brain uptake of other LNAAs in patients with phenylketonuria (PKU). Direct effects of elevated brain Phe and depleted LNAAs are probably major causes for disturbed brain development and function in PKU. Competition for the carrier might conversely be put to use to lower Phe influx when the plasma concentrations of all other LNAAs are increased. This hypothesis was tested by measuring brain Phe in patients with PKU by quantitative 1H magnetic resonance spectroscopy during an oral Phe challenge with and without additional supplementation with all other LNAAs. Baseline plasma Phe was approximately 1,000 micromol/l and brain Phe was approximately 250 micromol/l in both series. Without LNAA supplementation, brain Phe increased to approximately 400 micromol/l after the oral Phe load. Electroencephalogram (EEG) spectral analysis revealed acutely disturbed brain activity. With concurrent LNAA supplementation, Phe influx was completely blocked and there was no slowing of EEG activity. These results are relevant for further characterization of the LNAA carrier and of the pathophysiology underlying brain dysfunction in PKU and for treatment of patients with PKU, as brain function might be improved by continued LNAA supplementation.

Variability of blood-brain ratios of phenylalanine in typical patients with phenylketonuria.

Blood-brain ratios (BBR) of phenylalanine (Phe) were determined by quantitative in vivo 1H magnetic resonance spectroscopy (1H-MRS) in 17 adult patients with early-treated phenylketonuria who were randomly selected from a sample of 75 adults. Measurements were performed in all patients during steady-state conditions. The BBR showed a unimodal distribution with a mean of 4.0 (range 3.3 to 4.5). Blood-brain ratios were comparable for subgroups of patients with genotypes classified as severe, moderate, or mild and for patients on different types of diets. Brain Phe concentrations showed a strong linear correlation with blood Phe values (r = 0.93, P < 0.001). There were no saturation effects for blood Phe values up to 1.8 mmol/L, and a local regression analysis did not confirm increasing BBR for increasing blood Phe values. The intellectual outcome (Wechsler Adult Intelligence Scale) was correlated with long-term dietary control (r = -0.65, P < 0.05), fluctuation of blood Phe values during treatment (r = -0.60, P < 0.05), and concurrent blood and brain Phe concentration. The severity of white matter changes visible on magnetic resonance images (MRI) was increased with high blood and brain Phe concentrations but failed to reach statistical significance. No correlation was found between BBR values, intelligence quotient, and MRI grade. Based on the assumption that BBR show intraindividual stability, the current data do not support the hypothesis that blood-brain barrier transport of Phe is a key explanatory factor for outcome variability in the vast majority of "typical" patients with phenylketonuria.

Hypoxanthine: a marker for asphyxia.

It has been hypothesized that hypoxanthine concentrations in the blood of newborn infants are a marker of asphyxia. To test this hypothesis, we measured serum hypoxanthine levels in relationship to perinatal and neonatal asphyxia, and compared arterial hypoxanthine levels with arterial pH and base deficit. We also compared hypoxanthine levels of survivors with those of asphyxiated non-survivors. Forty-two newborns were classified as asphyxiated by either of two methods: 1) Infants from whom umbilical cord hypoxanthine levels were taken were classified as asphyxiated if they had an Apgar score of 6 or less at 1 or 5 minutes, fetal heart rate below 100 beats per minute, or meconium-stained amniotic fluid; and 2) infants from whom peripheral arterial hypoxanthine samples were taken were classified by clinical assessment, whereby one author, blinded to the infants' hypoxanthine levels, prospectively assessed each patient's condition for evidence of asphyxia. Hypoxanthine levels correlated with increased base deficit (P less than .001; r = 0.8) and with decreased pH (P less than .001; r = -0.5). By both of our asphyxia classification methods, hypoxanthine levels were significantly higher (P less than .002) in the asphyxiated groups. We also noted a higher hypoxanthine level in asphyxiated non-survivors as compared with all survivors (P less than .02). We propose that serum hypoxanthine levels may help define asphyxia. Because hypoxanthine, when metabolized by xanthine oxidase, generates oxygen radicals that are highly destructive to tissue, hypoxanthine levels may have important therapeutic implications for asphyxiated patients.

Quantitation of localized (31)P magnetic resonance spectra based on the reciprocity principle.

There is a need for absolute quantitation methods in (31)P magnetic resonance spectroscopy, because none of the phosphorous-containing metabolites is necessarily constant in pathology. Here, a method for absolute quantitation of in vivo (31)P MR spectra that provides reproducible metabolite contents in institutional or standard units is described. It relies on the reciprocity principle, i.e., the proportionality between the B(1) field map and the map of reception strength for a coil with identical relative current distributions in receive and transmit mode. Cerebral tissue contents of (31)P metabolites were determined in a predominantly white matter-containing location in healthy subjects. The results are in good agreement with the literature and the interexamination coefficient of variance is better than that in most previous studies. A gender difference found for some of the (31)P metabolites may be explained by different voxel composition.

Propionic acidemia without acidemia: a case report.

Propionic acidemia is a recessively inherited disorder of organic acid metabolism characterized by a spectrum of clinical and biochemical findings. Metabolic acidosis is a key feature of this disease and is useful in differentiating it from nonketotic hyperglycinemia. This case report is presented because significant metabolic acidosis was not a prominent or persistent finding in this patient.

Continuous negative pressure in the treatment of infants with pulmonary hypertension and respiratory failure.

We report the successful use of continuous negative pressure (CNP) with standard intermittent mandatory ventilation (IMV) in five patients suffering from respiratory failure and persistent pulmonary hypertension of the newborn (PPHN). These infants all fulfilled criteria for use of extracorporeal membrane oxygenation (ECMO) with PaO2 less than 40 torr, alveolar-arterial oxygen difference (AaDO2) greater than 620 mm Hg, and oxygenation index (OI) greater than 50. Despite a considerable amount of conventional ventilation with mean airway pressures (PAW) between 14 and 26 cm water, none of these patients were able to improve oxygenation. All infants demonstrated significant improvement in ventilation requirements after initiation of CNP as reflected by a decrease in PAW, proximal inspiratory pressure (PIP), and IMV. Oxygenation dramatically improved in all infants. All five patients survived without any pulmonary or neurological complications at discharge. Availability of CNP may circumvent the need for ECMO in infants with severe lung disease and PPHN.

Interpeduncular heterotopia in Joubert syndrome: a previously undescribed MR finding.

The so-called molar tooth sign is the radiologic hallmark of JSRD. Joubert syndrome is a rare, most often autosomal-recessive disorder with a characteristic malformation of the midhindbrain. We describe 3 patients with JSRD and the additional MR finding of tissue resembling heterotopia in the interpeduncular fossa, which in one patient was combined with a more extensive intramesencephalic heterotopia. Interpeduncular heterotopia has not been reported previously, either in the context of JSRD or as a separate entity. This new imaging feature enlarges the spectrum of brain stem abnormalities in JSRD. In view of the underlying ciliopathy, it seems likely that the interpeduncular heterotopia results from misdirected migration.

Region- and pattern-specific effects of glutamate uptake blockers on epileptiform activity in rat brain slices.

Many epileptic syndromes develop into pharmaco-resistant forms, calling for the development of new anticonvulsant strategies. The transmitter glutamate serves a double role as excitatory transmitter and as precursor for GABA, thus interfering with glutamate uptake may therefore exert complex effects on excitation-inhibition-balance in epileptic networks. In the present study we tested the effect of two different glutamate uptake blockers on acutely induced epileptiform activity in hippocampal-entorhinal cortex slices from adult rats: dihydrokainate (DHK) which blocks predominantly glial glutamate uptake, and threo-beta-benzyloxyaspartic acid (TBOA) which blocks both glial and neuronal glutamate uptake. Three different models were used to induce epileptiform discharges: (i) increasing NMDA receptor-mediated excitation by omitting Mg(2+)-ions; (ii) blocking potassium channels by 4-aminopyridine; (iii) reducing GABA(A) receptor-mediated inhibition by penicillin. Application of DHK or TBOA markedly reduced the frequency of epileptiform discharges in CA1 in the low magnesium and the 4-AP model while pathological activity was increased in the penicillin-model. In contrast, frequency of epileptiform discharges in EC was consistently increased by DHK and TBOA. Effects of DHK were more easily reversible than those of TBOA. Thus glutamate uptake blockers exert variable effects on epileptiform activity, depending on brain region and on the mechanism of ictogenesis.

Quantitative score for the evaluation of kinematic recordings in neuropediatric diagnostics. Detection of complex patterns in spontaneous limb movements.

OBJECTIVE: Evaluation of spontaneous infant movements is an important tool for the detection of neurological impairments. One important aspect of this evaluation is the observation of movements which exhibit certain complex properties. This article presents a method to automatically extract segments which contain such complex patterns in order to quantitatively assess them. METHODS: Expert knowledge is represented in a principal component model which captures the term complexity as the multivariate interactions in the kinematic chains of the upper and the lower limb. A complexity score is introduced which is used to quantify the similarity of new movements to this model. It was applied to the recordings of 53 infants which were diagnosed by physicians as normal or pathologic. RESULTS: Time segments marked as complex (from five infants) by physicians could be detected with a mean accuracy of 0.77 by the automated approach. The median of the best complexity scores of the pathologic group (n = 21) is significantly lower (p = 0.001) than the median of the normal group (n = 27). CONCLUSION: Using the complexity score we were able to quantify movement complexity in regard of the understanding of physicians. This could be useful for clinical applications.

Parent based language intervention for 2-year-old children with specific expressive language delay: a randomised controlled trial.

OBJECTIVE: The aim of this randomised controlled trial was to evaluate the effectiveness of a short, highly structured parent based language intervention group programme for 2-year-old children with specific expressive language delay (SELD, without deficits in receptive language). METHODS: 61 children with SELD (mean age 24.7 months, SD 0.9) were selected between October 2003 and February 2006 during routine developmental check-ups in general paediatric practices, using a German parent-report screening questionnaire (adapted from the MacArthur Communicative Development Inventories). Standardised instruments were used to assess the language and non-verbal cognitive abilities of these children and of 36 other children with normal language development (reference group; mean age 24.6 months, SD 0.8). 58 children with SELD were sequentially randomly assigned to an intervention group (n = 29) or a 12-month waiting group (n = 29). In the intervention group, mothers participated in the 3-month Heidelberg Parent-based Language Intervention (HPLI). All children were reassessed 6 and 12 months after pretest. Assessors were blind to allocation and previous results. RESULTS: 47 children were included in the analysis. At the age of 3 years, 75% of the children in the intervention group showed normal expressive language abilities in contrast to 44% in the waiting group. Only 8% of the children in the intervention group versus 26% in the waiting group met the criteria for specific language impairment (t score < or =35). CONCLUSIONS: By applying the short, highly structured HPLI in children with SELD, the rate of treatment for language impairment at the age of 3 years can be significantly reduced.

Neurological aspects of adult phenylketonuria.

Phenylketonuria, an autosomal recessively transmitted disorder of amino acid metabolism, is caused by a deficiency of hepatic phenylalanine hydroxylase converting phenylalanine to tyrosine. Thus, phenylalanine accumulates to plasma levels exceeding 1200 mumol/l. Untreated phenylketonuria is characterized by microcephaly, epilepsy, severe mental retardation and, in some cases, progressive supranuclear motor disturbances. These symptoms can largely be prevented by the early start of a phenylalanine-restricted diet. Neurological investigations of treated patients reveal only minor neurological signs, such as tremor or brisk deep tendon reflexes. Magnetic resonance imaging shows white matter abnormalities. However, in single patients, progressive neurological symptoms occurred. Thus, the long-term prognosis of treated phenylketonuria is still under discussion.

Adult care in phenylketonuria and hyperphenylalaninaemia: the relevance of neurological abnormalities.

UNLABELLED: Neurological abnormalities in phenylketonuria were described before dietary treatment became possible. These included tremor, clumsiness, epilepsy, spastic paraparesis and occasionally extrapyramidal features. Neurological deterioration after childhood was recognised. Patients with neurological deterioration described recently have been late diagnosed or intellectually impaired or both. No early diagnosed patient who was well treated and of good intellectual outcome has yet shown neurological deterioration after stopping diet but it may happen. CONCLUSION: The fascinating links between pathology, magnetic resonance imaging appearances, magnetic resonance spectroscopy results and clinical features are not yet clearly understood. Patients must understand the possible risks of stopping diet and make their choice. All patients need help, support and follow-up regardless of the choices they make over continuing diet.

Visual evoked potentials of mildly mentally retarded and control children.

Visual evoked potentials (VEPs) were recorded from 25 10- to 13-year-old mildly mentally retarded children and compared with those from 31 control children of the same age-range. Correlations of VEPs with age were weak, but a relationship between VEPs and IQ was demonstrated for the control group. The retarded group had significantly longer latencies and higher amplitude peaks than the control group, with the differences occurring primarily over non-specific cortex and for secondary components. Analysis also showed that the retarded group were neurophysiologically heterogeneous. Since the same children had been analyzed earlier by quantitative EEG methods, comparisons are made with respect to these two methods of investigating brain function.

Pharmacological closure of the patent ductus arteriosus.

Pharmacological closure by indomethacin is customary if symptoms of PDA are not controlled adequately with fluid restriction and diuretics. Its use, however, requires a comprehensive clinical assessment of all the vital perinatal factors and a vigilant monitoring of the sick infant. Prophylactic use of indomethacin is discouraged. The decision to use pharmacological versus surgical treatment or both should be individualized based on evidence-based research and clinician's own experience. Surgical ligation remains the primary mode of therapy in cases of pharmacological treatment failure or recurrence.

Magnetic resonance imaging of the brain in adolescents with phenylketonuria and in one case of 6-pyruvoyl tetrahydropteridine synthase deficiency.

White matter abnormalities on MRI have been observed in phenylketonuria (PKU) patients with late onset neurological symptoms as well as in neurologically inconspicious patients. We investigated 14 early treated adolescents at an age between 12 and 17 years (mean age 14.3 years) with classical PKU as well as one retarded patient with atypical PKU by cranial MRI with spinecho T1-, T2- and proton density sequences. Clinical examination was normal. Visual evoked potential (VEP) examination showed a prolonged latency of peak P100 (mean 122.6 ms; control mean 115.9) and IQ testing showed a mean IQ of 101.1. To investigate the influence of plasma phenylalanine (Phe) levels three approaches were used: Phe was determined for the day of MRI, for a period of 6 months prior to MRI and for lifetime up to 12 years. MRI scans revealed areas of abnormally increased signal intensity on T2-weighted and proton density images in 12 (86%) patients, preferably involving the parieto-occipital lobes. MRI of the patient with atypical PKU was normal. MRI findings correlated most strongly to long-term dietary control up to 12 years. We found no correlation with the other parameters of biochemical control, IQ or VEP latency. The nature and prognosis of MRI abnormalities in neurologically normal PKU patients remain unclear although abnormalities in VEPs which were not associated with the degree of MRI abnormalities in our sample indicate a disturbance in myelination along the visual pathways.

Intelligence and professional career in young adults treated early for phenylketonuria.

The intellectual status and professional careers of 51 young adults with phenylketonuria whose treatment started before 3 months of age are described. Their mean IQ was 97 (SD = 16). Of the IQs, 4% were more than 2 SD below the norm. The distribution of types of schooling of the patients was comparable to that in the German population. The professional careers of nearly all the patients were according to their educational level. Within the sample the outcome was significantly correlated with phenylalanine (Phe) control, even when the patients' social background was statistically taken into account. The main influence of Phe on intelligence seems to occur during the first decade of life since IQ data remain stable even after Phe levels increased during adolescence.

EEGs in phenylketonuria. I: Follow-up to adulthood; II: Short-term diet-related changes in EEGs and cognitive function.

The authors report the results of two EEG studies on adult patients with phenylketonuria (PKU) who had been treated early. Part I: the authors followed the EEGs of 34 PKU patients from birth to age 21. The frequency of abnormal EEG findings (especially epileptiform activity) steadily increased until age 12, then decreased. IQ correlated significantly with quality of dietary control during follow-up. Part II: frequency analysis of the EEG and neuropsychological testing were performed on eight adult patients after periods of four weeks with low and high levels of phenylalanine. Only five patients followed the strict dietary regulations. With high levels of phenylalanine, the dominant peak of EEG background activity shifted to the slower frequency spectrum in all patients; in addition, neuropsychological testing revealed impairment of cognitive function. The significance of different approaches of EEG examinations is discussed with respect to the problems of monitoring PKU patients and the pathogenic mechanisms of CNS damage in phenylketonuria.

High-dose intravenous gammaglobulin for neonatal alloimmune thrombocytopenia in twins.

We report the successful treatment of neonatal alloimmune thrombocytopenia with repeated infusions of high-dose immunoglobulin G (400 mg/kg/d for 5 days) in twins. Platelet counts increased within 3 days from less than 20 x 10(9)/l to more than 70 x 10(9)/l. The first twin survived without neurological or other sequelae. The second twin had probably developed intracranial hemorrhage (ICH) in utero. This infant developed long-term neurological sequelae with blindness, cerebral palsy and infantile spasms. Implications of the therapeutic approach and prevention of severe complications in pregnancies with known risk for neonatal alloimmune thrombocytopenia are discussed.