Tallinn Childrens Hospital

Tallinn, Estonia

Tallinn Childrens Hospital

Tallinn, Estonia
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Nielsen S.N.,Copenhagen University | Grell K.,Copenhagen University | Nersting J.,Copenhagen University | Abrahamsson J.,Gothenburg University | And 8 more authors.
The Lancet Oncology | Year: 2017

Background Adjustment of mercaptopurine and methotrexate maintenance therapy of acute lymphoblastic leukaemia by leucocyte count is confounded by natural variations. Cytotoxicity is primarily mediated by DNA-incorporated thioguanine nucleotides (DNA-TGN). The aim of this study was to establish whether DNA-TGN concentrations in blood leucocytes during maintenance therapy are associated with relapse-free survival. Methods In this substudy of the NOPHO ALL2008 phase 3 trial done in 23 hospitals in seven European countries (Denmark, Estonia, Finland, Iceland, Lithuania, Norway, and Sweden), we analysed data from centralised and blinded analyses of 6-mercaptopurine and methotrexate metabolites in blood samples from patients with non-high-risk childhood acute lymphoblastic leukaemia. Eligible patients were aged 1·0–17·9 years; had been diagnosed with non-high-risk precursor B-cell or T-cell leukaemia; had been treated according to the Nordic Society of Pediatric Hematology and Oncology ALL2008 protocol; and had reached maintenance therapy in first remission. Maintenance therapy was (mercaptopurine 75 mg/m2 once per day and methotrexate 20 mg/m2 once per week, targeted to a leucocyte count of 1·5–3·0 × 109 cells per L). We measured DNA-TGN and erythrocyte concentrations of TGN nucleotides, methylated mercaptopurine metabolites, and methotrexate polyglutamates. The primary objective was the association of DNA-TGN concentrations and 6-mercaptopurine and methotrexate metabolites with relapse-free survival. The secondary endpoint was the assessment of DNA-TGN concentration and 6-mercaptopurine and methotrexate metabolites during maintenance therapy phase 2. Findings Between Nov 26, 2008 and June 14, 2016, 1509 patients from the NOPHO ALL2008 study were assessed for eligibility in the DNA-TGN substudy, of which 918 (89%) of 1026 eligible patients had at least one DNA-TGN measurement and were included in the analyses. Median follow-up was 4·6 years (IQR 3·1–6·1). Relapse-free survival was significantly associated with DNA-TGN concentration (adjusted hazard ratio 0·81 per 100 fmol/μg DNA increase, 95% CI 0·67–0·98; p=0·029). In patients with at least five blood samples, erythrocyte concentrations of TGN, methylated mercaptopurine metabolites, and methotrexate polyglutamates were associated with DNA-TGN concentration (all p<0·0001). Interpretation Our results suggest the need for intervention trials to identify clinically applicable strategies for individualised drug dosing to increase DNA-TGN concentration, and randomised studies to investigate whether such strategies improve cure rates compared with current dose adjustments based on white blood cell counts. Funding Danish Cancer Society, Childhood Cancer Foundation (Denmark), Childhood Cancer Foundation (Sweden), Nordic Cancer Union, Otto Christensen Foundation, University Hospital Rigshospitalet, and Novo Nordic Foundation. © 2017 Elsevier Ltd


Lass J.,University of Tartu | Naelapaa K.,Copenhagen University | Shah U.,Medicines for Children Research Network | Kaar R.,Tallinn Childrens Hospital | And 4 more authors.
BMC Pediatrics | Year: 2012

Background: Information on the neonatal exposure to excipients is limited. Our aim was to describe the extent of excipient intake by Estonian neonates; to classify the excipients according to potential neonatal toxicity and thereby to measure the extent of exposure of neonates to potentially harmful excipients.Methods: A prospective cohort study that recorded all medicines prescribed to patients aged below 28 days admitted to Tartu University Hospital from 01.02-01.08 2008 and to Tallinn Children's Hospital from 01.02- 01.08 2009 was conducted. Excipients were identified from Summaries of Product Characteristics and classified according to toxicity following a literature review.Results: 1961 prescriptions comprising 107 medicines were written for 348/490 neonates admitted. A total of 123 excipients were found in 1620 (83%) prescriptions and 93 (87%) medicines. 47 (38%) of these excipients were classified as potentially or known to be harmful to neonates. Most neonates (97%) received at least one medicine (median number 2) with potentially or known to be harmful excipient. Parabens were the most commonly used known to be harmful excipients and sodium metabisulphite the most commonly used potentially harmful excipient, received by 343 (99%) and 297 (85%) of treated neonates, respectively.Conclusions: Hospitalised neonates in Estonia are commonly receiving a wide range of excipients with their medication. Quantitative information about excipients should be made available to pharmacists and neonatologists helping them to take into account excipient issues when selecting medicines and to monitor for adverse effects if administration of medicines containing excipients is unavoidable. © 2012 Lass et al.; licensee BioMed Central Ltd.


Raja R.A.,Copenhagen University | Schmiegelow K.,Copenhagen University | Albertsen B.K.,Aarhus University Hospital | Prunsild K.,Tallinn Childrens Hospital | And 8 more authors.
British Journal of Haematology | Year: 2014

L-asparaginase is an important drug in the treatment of childhood acute lymphoblastic leukaemia (ALL). Treatment is associated with several toxicities, including acute pancreatitis. Clinical course, presentation, re-exposure to L-asparginase after pancreatitis and risk of recurrent pancreatitis within an asparaginase-intensive protocol has been poorly reported. Children (1-17 years) on the ongoing Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL2008 protocol with asparaginase-associated pancreatitis (AAP) diagnosed between 2008 and 2012 were identified through the online NOPHO ALL toxicity registry. NOPHO ALL2008 includes eight or 15 doses of intramuscular pegylated L-asparginase (PEG-asparaginase) 1000 iu/m2/dose at 2-6 weeks intervals, with a total of 30 weeks of exposure to PEG-asparaginase (clinicaltrials.gov no: NCT00819351). Of 786 children, 45 were diagnosed with AAP with a cumulative risk of AAP of 5·9%. AAP occurred after a median of five doses (range 1-13), and 11 d (median) from the latest administration of PEG-Asparaginase. Thirteen patients developed pseudocysts (30%) and 11 patients developed necrosis (25%). One patient died from pancreatitis. Twelve AAP patients were re-exposed to L-asparginase, two of whom developed mild AAP once more, after four and six doses respectively. In conclusion, re-exposure to PEG-asparaginase in ALL patients with mild AAP seems safe. © 2014 John Wiley & Sons Ltd.


Soeorg H.,University of Tartu | Huik K.,University of Tartu | Parm U.,University of Tartu | Ilmoja M.-L.,Tallinn Childrens Hospital | And 3 more authors.
Pediatric Infectious Disease Journal | Year: 2013

Background: Coagulase-negative staphylococci (CoNS) are the first colonizers of gastrointestinal tract (GIT) and the commonest cause of late-onset sepsis (LOS) in preterm neonates. Intravascular catheters are considered a major source of CoNS bacteremia. However, several cases of LOS remain without an identified source. To elucidate whether GIT could be a potential source of invasive strains, we aimed to assess the molecular similarity between CoNS from blood and GIT in preterm neonates with LOS. Methods: Altogether 22 blood and 53 GIT isolates collected from 22 neonates with LOS caused by CoNS {Staphylococcus haemolyticus in 13, Staphylococcus epidermidis in 7 and Staphylococcus hominis in 2 patients) were included. Rectal swabs were collected twice weekly from birth, but only isolates obtained before LOS were analyzed. S. epidermidis isolates were typed by multilocus variable number of tandem repeats analysis and multilocus sequence typing, S. haemolyticus by pulsed-field gel electrophoresis. Results: Eighteen of 22 neonates had the same CoNS species in GIT and bloodstream; all these isolates from them (altogether 18 blood and 28 GIT isolates) underwent typing. The genotypic similarity between bloodstream and ≥1 antecedent GIT isolates was observed in 13 of 18 patients-3 of 7 with S. epidermidis and 10 of 11 with S. haemolyticus infection. The concordant GIT isolates were collected 0-7 days before the positive blood culture. Conclusions: The similarity between CoNS from GIT and bloodstream indicates that preterm neonates harbour invasive strains in GIT before LOS. Whether there is a causal relationship between GIT colonization and LOS remains to be elucidated in further studies. Copyright © 2013 by Lippincott Williams & Wilkins.


Lass J.,University of Tartu | Kaar R.,Tallinn Childrens Hospital | Jogi K.,University of Tartu | Varendi H.,University of Tartu | And 2 more authors.
European Journal of Clinical Pharmacology | Year: 2011

Objectives: To characterise neonatal hospital drug use and to compare the availability of drug information between Estonian Summaries of Product Characteristics (SPCs) and other sources. Study design: This was a prospective cohort study in which pharmacotherapy information on neonates admitted to Tartu University Clinics between 1 February and 1 August 2008 and to Tallinn Children's Hospital between 1 February and 1 August 2009 was collected. Drug labelling status was determined according to Estonian SPCs, and neonatal information was compared with the British National Formulary for Children (BNFC) and the Thomson Micromedex database. Results: Of 490 hospitalised neonates, 71% received pharmacotherapy. Within the entire study period, there were 1981 prescriptions for 115 products, with a median of four (interquartile range 2-7) products per child. Antibacterial, cardiovascular and central nervous system drugs were the most commonly prescribed. All treated preterm neonates received at least one unlicensed or age-related off-label prescription. All prescriptions for alimentary, genitourinary, musculoskeletal and sensory system drugs were off-label. There were large differences in the neonatal information provided by the different sources, with the largest differences found for term neonates, for whom the information was available for 67, 38 and 24% of prescriptions according to the BNFC, Micromedex and Estonian SPC, respectively. Conclusions: The high rate of age-related off-label prescribing for neonates calls for urgent action from medical professionals and others to reinforce effective and safe pharmacotherapy for this age group. The existing SPCs should be regularly updated and more closely harmonised to each other. © 2011 Springer-Verlag.


Parm U.,University of Tartu | Metsvaht T.,University of Tartu | Sepp E.,University of Tartu | Ilmoja M.-L.,Tallinn Childrens Hospital | And 3 more authors.
Early Human Development | Year: 2011

Aim: To characterize dynamics of mucosal colonization of neonates by common aerobic Gram negative species and Candida spp. and to identify independent perinatal, neonatal, and environmental factors influencing the colonization process. Study design: The nasopharyngeal (n = 1145) and rectal (n = 1242) swabs were collected on admission and thereafter twice a week in neonates with risk factors of early onset sepsis (n = 276) admitted within the first 72. h of life. The association between colonization by different microbes and a total of 22 predefined risk factors was assessed using univariate and multiple logistic regression analyses. Results: Throughout the study about half of the patients had rectal (55.8%) or nasopharyngeal colonization (42.8%) with common Gram-negative microorganisms. Colonization dynamics and risk factors were in general similar for a given bacterial species in both mucosal sites; nonfermentative microbes more often found in nasopharyngeal swabs and Enterobacteriaceae in rectal swabs. All organisms except Escherichia coli were influenced by the duration of intensive care unit stay but other risk factors were species specific, perhaps reflecting their mode of acquisition. While colonization by E. coli and Candida albicans was associated with perinatal factors like term birth, vaginal delivery, and breast milk feeding; colonization by Klebsiella pneumoniae, Enteribacter cloacae, Acinetobacter spp. and non-albicans Candida spp. were mostly determined by hospital environment (treatment unit and period, artificial interventions and their duration) and gestation age ≤ 28. weeks. Conclusions: The knowledge of risk factor profiles may permit the development of strategies to prevent heavy colonization and subsequent invasive disease in high risk infants. © 2011 Elsevier Ireland Ltd.


Heidmets L.-T.,University of Tartu | Metsvaht T.,University of Tartu | Ilmoja M.-L.,Tallinn Childrens Hospital | Pisarev H.,University of Tartu | And 2 more authors.
Neonatology | Year: 2011

Background: The amount of blood that can be safely drawn from a preterm neonate for scientific purposes is poorly established. Objectives: To provide scientific evidence on the amount of blood that can be drawn from very low birth weight (VLBW) neonates for study purposes. Methods: We performed a post-hoc analysis of a pharmacokinetic (PK) study of penicillin-G, enrolling 18 neonates with a birth weight of <1,200 g, gestational age of <28 weeks and postnatal age of <5 days, with a risk of early onset sepsis. A median of 2.3 ml/kg of blood was collected from each neonate for the PK analysis. Hemoglobin (Hgb), hematocrit (Ht), basic hemodynamic parameters, total fluid intake, number of blood component transfusions and number of blood analysis for clinical indications were recorded. The control group consisted of 35 gestational age-, postnatal age- and birth weight-matched neonates who had not participated in a PK study. Results: We did not observe significant differences in any studied safety parameter, including Hgb and Ht values, between the two groups. Median number of blood component transfusions (n = 2 in both groups), median volume of transfused red blood cells (22 vs. 24 ml/kg in study vs. control group) and total daily fluid requirement were similar. The median calculated blood loss on clinical indications was 1.9 ml/24 h in the control group and 1.66 ml/24 h in the study group. Conclusions: In VLBW neonates, up to 2.3 ml/kg of blood (corresponding to 2.4% of calculated circulating blood volume) can be drawn for scientific purposes without compromising basic hemodynamic parameters, Hgb and Ht values, blood component transfusions or fluid requirements. Copyright © 2011 S. Karger AG, Basel.


Metsvaht T.,University of Tartu | Ilmoja M.-L.,Tallinn Childrens Hospital | Parm U.,University of Tartu | Maipuu L.,University of Tartu | And 2 more authors.
Acta Paediatrica, International Journal of Paediatrics | Year: 2010

Aim: We aimed to compare the clinical efficacy of ampicillin (AMP) vs. penicillin (PEN) both combined with gentamicin in the empirical treatment of neonates at risk of early onset neonatal sepsis (EOS). Methods: We performed an open label cluster randomized equivalence study in both Estonian neonatal intensive care units, including neonates with suspected EOS, aged less than 72 h. Primary end-point was clinical failure rate, expressed by need for change of antibiotic regimen within 72 h and/or 7-day all cause mortality. Bowel colonization was followed with biweekly perineal swab cultures. Results: Incidence of proven EOS was 4.9%. Among neonates receiving AMP (n = 142) or PEN (n = 141) change of antibiotic regimen within 72 h (10/142 vs. 10/141; OR 1.02; 95% CI 0.40-2.59), 7-day mortality (11/142 vs. 14/141; OR 0.76; 95% CI 0.33-1.75) and over-all treatment failure (20/142 vs. 20/141; OR 1.01; 95% CI 0.52-1.97) occurred at similar rates. The only differences in gut colonization were lower number of patients colonised with enterococci, S. aureus and AMP resistant Acinetobacter spp. in AMP and lower number of those with S. haemolyticus and S. hominis in PEN arm. Conclusions: AMP and PEN combined with gentamicin have similar effectiveness in the empiric treatment of suspected neonatal EOS. © 2010 Foundation Acta Pædiatrica.


Ress K.,University of Tartu | Luts K.,Tallinn Childrens Hospital | Rago T.,University of Tartu | Pisarev H.,University of Tartu | Uibo O.,University of Tartu
European Journal of Pediatrics | Year: 2012

The aims of the study were to analyze the trends and characteristics of the incidence and clinical presentation of childhood celiac disease (CD) from 1976 to 2010 in Estonia. The study included all children up to 19 years of age diagnosed with small bowel biopsy proven CD. During a 35-year period, CD was diagnosed in 152 children in Estonia (68 boys, median age 2.3 years). From 1976 to 1980, the age-standardized incidence rate of CD was 0.10 per 100,000 person-years. After the introduction of gliadin and endomysium antibody screening (in conjunction with activities directed to increase the physicians awareness), the incidence rate increased from 0.48 in 1986-1990 to 1.55 per 100,000 person-years in 1991-1995. After initiating screening with anti-tissue transglutaminase antibodies in 2003 and routine screening for CD among all children with newly diagnosed type 1 diabetes in 2005, the incidence rate increased from 1.59 in 2001-2005 to 3.14 per 100,000 person-years in 2006-2010 (median age 6.8 years). Our nationwide study demonstrates a more than 30-fold increase in the incidence of childhood CD over a 35-year period in Estonia, along with changing patterns in the presentation of pediatric CD. In addition to the impact of use of novel CD screening methods, active search and rising of the awareness among doctors may have strongest effect. Both environmental and social factors could be also involved in the increase in CD incidence. © 2012 Springer-Verlag.


PubMed | University of Helsinki, University of Tartu and Tallinn Childrens Hospital
Type: | Journal: Neural plasticity | Year: 2017

Perinatal stroke is a leading cause of congenital hemiparesis and neurocognitive deficits in children. Dysfunctions in the large-scale resting-state functional networks may underlie cognitive and behavioral disability in these children. We studied resting-state functional connectivity in patients with perinatal stroke collected from the Estonian Pediatric Stroke Database. Neurodevelopment of children was assessed by the Pediatric Stroke Outcome Measurement and the Kaufman Assessment Battery. The study included 36 children (age range 7.6-17.9 years): 10 with periventricular venous infarction (PVI), 7 with arterial ischemic stroke (AIS), and 19 controls. There were no differences in severity of hemiparesis between the PVI and AIS groups. A significant increase in default mode network connectivity (FDR 0.1) and lower cognitive functions (

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