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Background: Motor impairment is common after extremely preterm (EPT, <28 weeks' gestational age (GA)) birth, with cerebral palsy (CP) affecting about 10% of children and non-CP movement difficulties (MD) up to 50%. This study investigated the sociodemographic, perinatal and neonatal risk factors for CP and non-CP MD., Methods: Data come from a European population-based cohort of children born EPT in 2011-2012 in 11 countries. We used multinomial logistic regression to assess risk factors for CP and non-CP MD (Movement Assessment Battery for Children - 2nd edition ≤5th percentile) compared to no MD (>15th percentile) among 5-year-old children., Results: Compared to children without MD (n = 366), young maternal age, male sex and bronchopulmonary dysplasia were similarly associated with CP (n = 100) and non-CP MD (n = 224) with relative risk ratios (RRR) ranging from 2.3 to 3.6. CP was strongly related to severe brain lesions (RRR >10), other neonatal morbidities, congenital anomalies and low Apgar score (RRR: 2.4-3.3), while non-CP MD was associated with primiparity, maternal education, small for GA (RRR: 1.6-2.6) and severe brain lesions, but at a much lower order of magnitude., Conclusion: CP and non-CP MD have different risk factor profiles, with fewer clinical but more sociodemographic risk factors for non-CP MD., Impact: Young maternal age, male sex and bronchopulmonary dysplasia similarly increased risks of both cerebral palsy and non-cerebral palsy movement difficulties. Cerebral palsy was strongly related to clinical risk factors including severe brain lesions and other neonatal morbidities, while non-cerebral palsy movement difficulties were more associated with sociodemographic risk factors. These results on the similarities and differences in risk profiles of children with cerebral palsy and non-cerebral palsy movement difficulties raise questions for etiological research and provide a basis for improving the identification of children who may benefit from follow-up and early intervention., (© 2023. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Background: Cryptorchidism is one of the most common urogenital malformations. Cryptorchidism prevalence varies greatly in different countries and populations. The aim of the current study was to determine and analyse cryptorchidism prevalence in Estonia., Materials and Methods: During 2012-2015, all consecutively born 5014 boys at Tartu University Hospital were examined for cryptorchidism. All the subjects with cryptorchidism were followed up for at least 6 months to assess spontaneous testicular descent., Results: Note that 2.1% cases had one or both testicles undescended at birth, 1.6% cases at expected date of birth, 1% cases at 3 months of age, and 0.8% cases at the age of 6 months had cryptorchidism. Cryptorchidism prevalence at birth was higher in preterm boys (11.9%), boys of low birth weight (16.7%) and boys small for gestational age (14%) but was lower in full-term newborn boys (1.1%). During follow-up, testes descended spontaneously in 61.6% of boys, more commonly in prematurely born boys (92%) and boys with low gestational weight (93%) as compared to full-term cryptorchid boys (29.2%) and cryptorchid boys with normal birth weight (34%). At the age of 6 months, cryptorchidism prevalence was equalized in preterm boys (0.9%) and boys with low birth weight (1%) as compared to full-term boys (0.7%) and boys with normal birth weight (0.7%). Boys SGA required surgical intervention more commonly than boys with normal birth weight. Ethnically, cryptorchidism prevalence at birth was similar among Estonians and non-Estonians., Conclusion: Our data revealed that cryptorchidism prevalence, especially in full-term boys, is lower in Estonia than reported in the other Nordic-Baltic countries and worldwide., (© 2021 American Society of Andrology and European Academy of Andrology.)

Background: Studies are sparse and inconclusive about the association between maternal education and cognitive development among children born very preterm (VPT). Although this association is well established in the general population, questions remain about its magnitude among children born VPT whose risks of medical and developmental complications are high. We investigated the association of maternal education with cognitive outcomes in European VPT birth cohorts., Methods: We used harmonized aggregated data from 15 population-based cohorts of children born at <32 weeks of gestational age (GA) or <1500 g from 1985 to 2013 in 13 countries with information on maternal education and assessments of general development at 2-3 years and/or intelligence quotients between 4 and 15 years. Term-born controls (≥37 weeks of GA) were available in eight cohorts. Maternal education was classified as: low (primary/lower secondary); medium (upper secondary/short tertiary); high (bachelor's/higher). Pooled standardized mean differences (SMDs) in cognitive scores were estimated (reference: high educational level) for children assessed at ages 2-3, 4-7 and 8-15 years., Results: The study included 10 145 VPT children from 12 cohorts at 2-3 years, 8829 from 12 cohorts at 4-7 years and 1865 children from 6 cohorts at 8-15 years. Children whose mothers had low, compared with high, educational attainment scored lower on cognitive measures [pooled unadjusted SMDs: 2-3 years = -0.32 (95% confidence intervals: -0.43 to -0.21); 4-7 years = -0.57 (-0.67; -0.47); 8-15 years = -0.54 (-0.72; -0.37)]. Analyses by GA subgroups (<27 vs ≥27 weeks) in children without severe neonatal morbidity and term controls yielded similar results., Conclusions: Across diverse settings and regardless of the degree of prematurity, low maternal education was associated with lower cognition., (© The Author(s) 2021; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Background: We aimed to evaluate the policies and practices about neonatal resuscitation in a large sample of European hospitals., Methods: This was a cross-sectional electronic survey. A 91-item questionnaire focusing on the current delivery room practices in neonatal resuscitation domains was individually sent to the directors of 730 European neonatal facilities or (in 5 countries) made available as a Web-based link. A comparison was made between hospitals with ≤2,000 and those with >2,000 births/year and between hospitals in 5 European areas (Eastern Europe, Italy, Mediterranean countries, Turkey, and Western Europe)., Results: The response rate was 57% and included participants from 33 European countries. In 2018, approximately 1.27 million births occurred at the participating hospitals, with a median of 1,900 births/center (interquartile range: 1,400-3,000). Routine antenatal counseling (p < 0.05), the presence of a resuscitation team at all deliveries (p < 0.01), umbilical cord management (p < 0.01), practices for thermal management (p < 0.05), and heart rate monitoring (p < 0.01) were significantly different between hospitals with ≤2,000 births/year and those with >2,000 births/year. Ethical and educational aspects were similar between hospitals with low and high birth volumes. Significant variance in practice, ethical decision-making, and training programs were found between hospitals in 5 different European areas., Conclusions: Several recommendations about available equipment and clinical practices recommended by the international guidelines are already implemented by centers in Europe, but a large variance still persists. Clinicians and stakeholders should consider this information when allocating resources and planning European perinatal programs., (© 2022 S. Karger AG, Basel.)

Objectives: To compare mortality, morbidity and neurodevelopment by mode of delivery (MOD) for very preterm births with low prelabour risk of caesarean section (CS)., Methods: The study was a population-based prospective cohort study in 19 regions in 11 European countries. Multivariable mixed effects models and weighted propensity score models were used to estimate adjusted odds ratios (aOR) by observed MOD and the unit's policy regarding MOD. Population: Singleton vertex-presenting live births at 24 + 0 to 31 + 6 weeks of gestation without serious congenital anomalies, preeclampsia, HELLP or eclampsia, antenatal detection of growth restriction and prelabour CS for fetal or maternal indications., Results: Main outcome measures: A composite of in-hospital mortality and intraventricular haemorrhage (grade III/IV) or periventricular leukomalacia. Secondary outcomes were components of the primary outcome, 5 min Apgar score <7 and moderate to severe neurodevelopmental impairment at two years of corrected age. The rate of CS was 29.6% but varied greatly between countries (8.0-52.6%). MOD was not associated with the primary outcome (aOR for CS 0.99; 95% confidence interval [CI] 0.65-1.50) when comparing units with a systematic policy of CS or no policy of MOD to units with a policy of vaginal delivery (aOR 0.88; 95% CI 0.59-1.32). No association was observed for two-year neurodevelopment impairment for CS (aOR 1.15; 95% CI 0.66-2.01) or unit policies (aOR 1.04; 95% CI 0.63-1.70)., Conclusions: Among singleton vertex-presenting live births without medical complications requiring a CS at 24 + 0 to 31 + 6 weeks of gestation, CS was not associated with improved neonatal or long-term outcomes., (© 2021 Walter de Gruyter GmbH, Berlin/Boston.)

Purpose: To date, there are contradictory findings concerning if, at which age, and to what extent children's language development is affected by prematurity at birth. The objective was to compare language skills of extremely preterm (EPT) and very preterm (VPT) girls and boys at 24 months corrected for gestational age (GA) at birth with those of full-term (FT) girls and boys, and to explore the effect of perinatal and demographic factors., Method: Parents of 138 preterm (PT) children born <32 weeks' gestation (48 EPT with GA below 28 weeks, 90 VPT with GA 28-31 weeks) and of 150 FT controls completed the short Estonian version of the MacArthur-Bates Communicative Development Inventory: Words and Sentences (ECDI-II SF). Language skills of PT children were also assessed with the Bayley-III Language Scale (BSID-III), and compared with data from 152 FT controls., Results: Mean scores of all language measurements were significantly lower in boys (not girls) from both PT groups compared to FT girls and boys, while no significant differences were found between PT groups. Across groups, girls obtained significantly better language scores than boys. In PT children, being a girl, and attending day care at corrected age (CA) 2;0 years, predicted a larger expressive vocabulary (measured by the ECDI-II SF). Bayley language composite scores (sum of expressive and receptive language) were higher in PT girls than in boys, and the scores were negatively affected by the number of severe neonatal morbidities., Conclusions: The findings highlight the importance of systematic language-focused assessments (using parents and trained examiners) of EPT and VPT boys, as well as the need to support their development., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objectives: To develop research priorities on the consequences of very preterm (VPT) birth for the RECAP Preterm platform which brings together data from 23 European VPT birth cohorts., Design and Setting: This study used a two-round modified Delphi consensus process. Round 1 was based on 28 research themes related to childhood outcomes (<12 years) derived from consultations with cohort researchers. An external panel of multidisciplinary stakeholders then ranked their top 10 themes and provided comments. In round 2, panel members provided feedback on rankings and on new themes suggested in round 1., Results: Of 71 individuals contacted, 64 (90%) participated as panel members comprising obstetricians, neonatologists, nurses, general and specialist paediatricians, psychologists, physiotherapists, parents, adults born preterm, policy makers and epidemiologists from 17 countries. All 28 initial themes were ranked in the top 10 by at least six panel members. Highest ranking themes were: education (73% of panel members' top 10 choices); care and outcomes of extremely preterm births, including ethical decisions (63%); growth and nutrition (60%); emotional well-being and social inclusion (55%); parental stress (55%) and impact of social circumstances on outcomes (52%). Highest ranking themes were robust across panel members classified by background. 15 new themes had at least 6 top 10 endorsements in round 2., Conclusions: This study elicited a broad range of research priorities on the consequences of VPT birth, with good consensus on highest ranks between stakeholder groups. Several highly ranked themes focused on the socioemotional needs of children and parents, which have been less studied., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Objective: To determine whether the variation in neurodevelopmental disability rates between populations persists after adjustment for demographic, maternal and infant characteristics for an international very preterm (VPT) birth cohort using a standardised approach to neurodevelopmental assessment at 2 years of age., Design: Prospective standardised cohort study., Setting: 15 regions in 10 European countries., Patients: VPT births: 22 +0 -31 +6 weeks of gestation., Data Collection: Standardised data collection tools relating to pregnancy, birth and neonatal care and developmental outcomes at 2 years corrected age using a validated parent completed questionnaire., Main Outcome Measures: Crude and standardised prevalence ratios calculated to compare rates of moderate to severe neurodevelopmental impairment between regions grouped by country using fixed effects models., Results: Parent reported rates of moderate or severe neurodevelopmental impairment for the cohort were: 17.3% (ranging 10.2%-26.1% between regions grouped by country) with crude standardised prevalence ratios ranging from 0.60 to 1.53. Adjustment for population, maternal and infant factors resulted in a small reduction in the overall variation (ranging from 0.65 to 1.30)., Conclusion: There is wide variation in the rates of moderate to severe neurodevelopmental impairment for VPT cohorts across Europe, much of which persists following adjustment for known population, maternal and infant factors. Further work is needed to investigate whether other factors including quality of care and evidence-based practice have an effect on neurodevelopmental outcomes for these children., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background Hospitalized neonates receive the highest number of drugs compared to all other age groups, but consumption rates vary between studies depending on patient characteristics and local practices. There are no large-scale international studies on drug use in neonatal units. Objective We aimed to describe drug use in European neonatal units and characterize its associations with geographic region and gestational age. Setting A one-day point prevalence study was performed as part of the European Study of Neonatal Exposure to Excipients from January to June 2012. Method All neonatal prescriptions and demographic data were registered in a web-based database. The impact of gestational age and region on prescription rate were analysed with logistic regression. Main outcome measure The number and variety of drugs prescribed to hospitalized neonates in different gestational age groups and geographic regions. Results In total, 21 European countries with 89 neonatal units participated. Altogether 2173 prescriptions given to 726 neonates were registered. The 10 drugs with the highest prescription rate were multivitamins, vitamin D, caffeine, gentamicin, amino acids for parenteral nutrition, phytomenadione, ampicillin, benzylpenicillin, fat emulsion for parenteral nutrition and probiotics. The six most commonly prescribed ATC groups (alimentary tract and metabolism, blood and blood-forming organs, systemic anti-infectives, nervous, respiratory and cardiovascular system) covered 98% of prescriptions. Gestational age significantly affected the use of all commonly used drug groups. Geographic region influenced the use of alimentary tract and metabolism, blood and blood-forming organs, systemic anti-infectives, nervous and respiratory system drugs. Conclusion While gestational age-dependent differences in neonatal drug use were expected, regional variations (except for systemic anti-infectives) indicate a need for cooperation in developing harmonized evidence-based guidelines and suggest priorities for collaborative work.

Objective: Caesarean section (CS) may reduce mortality and morbidity for very preterm breech infants, but evidence is inconclusive. We evaluated neonatal outcomes for singleton breech infants by mode of delivery in a European cohort., Study Design: Data come from the EPICE population-based cohort of very preterm births in 19 regions in 11 European countries (7770 live births). The study population was singleton spontaneous-onset breech births at 24-31 weeks gestational age (GA) without antenatal medical complications requiring caesarean delivery (N = 572). Mixed-effects regression models adjusting for maternal and pregnancy covariates and propensity score matching was used to examine the effect of (1) CS and (2) a unit policy of systematic CS for breech presentation by GA. The primary outcome was a composite of in-hospital mortality, intraventricular haemorrhage grades III & IV or cystic periventricular leukomalacia. Secondary outcomes were each component separately, five minute Apgar score below seven and mortality within six hours of delivery., Results: 64.4% of infants were delivered by CS with a range across regions from 41% to 100%; these infants had higher GA and were more likely to be small for gestational age, receive antenatal steroids, and have mothers who were hospitalised for more than one day before delivery compared to those delivered vaginally. CS was associated with lower risks of all outcomes in mixed-effects adjusted models (odds ratio (OR) for the composite outcome: 0.50, 95% confidence interval (CI): 0.30-0.81), but not in propensity score matched models (OR: 0.72, 95% CI: 0.41; 1.29). A systematic CS policy was associated with lower mortality and morbidity in unadjusted, but not adjusted models (OR for composite outcome: 0.76, 95% CI: 0.44; 1.28). 35% of births 24-25 weeks were delivered by CS and protective effects were consistently stronger, but not statistically significant., Conclusions: Point estimates indicated protective effects of caesarean delivery for very preterm breech infants in conventional statistical models. However, analyses using propensity scores and based on unit policies did not confirm statistically significant associations. Prospective large-scale studies are needed to establish best practice and could be implemented in European regions where vaginal delivery remains an option., (Copyright © 2019. Published by Elsevier B.V.)

Objective: To investigate the variation in severe neonatal morbidity among very preterm (VPT) infants across European regions and whether morbidity rates are higher in regions with low compared with high mortality rates., Design: Area-based cohort study of all births before 32 weeks of gestational age., Setting: 16 regions in 11 European countries in 2011/2012., Patients: Survivors to discharge from neonatal care (n=6422)., Main Outcome Measures: Severe neonatal morbidity was defined as intraventricular haemorrhage grades III and IV, cystic periventricular leukomalacia, surgical necrotizing enterocolitis and retinopathy of prematurity grades ≥3. A secondary outcome included severe bronchopulmonary dysplasia (BPD), data available in 14 regions. Common definitions for neonatal morbidities were established before data abstraction from medical records. Regional severe neonatal morbidity rates were correlated with regional in-hospital mortality rates for live births after adjustment on maternal and neonatal characteristics., Results: 10.6% of survivors had a severe neonatal morbidity without severe BPD (regional range 6.4%-23.5%) and 13.8% including severe BPD (regional range 10.0%-23.5%). Adjusted inhospital mortality was 13.7% (regional range 8.4%-18.8%). Differences between regions remained significant after consideration of maternal and neonatal characteristics (P<0.001) and severe neonatal morbidity rates were not correlated with mortality rates (P=0.50)., Conclusion: Severe neonatal morbidity rates for VPT survivors varied widely across European regions and were independent of mortality rates., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2019. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Importance: Administration-to-birth intervals of antenatal corticosteroids (ANS) vary. The significance of this variation is unclear. Specifically, to our knowledge, the shortest effective administration-to-birth interval is unknown., Objective: To explore the associations between ANS administration-to-birth interval and survival and morbidity among very preterm infants., Design, Setting, and Participants: The Effective Perinatal Intensive Care in Europe (EPICE) study, a population-based prospective cohort study, gathered data from 19 regions in 11 European countries in 2011 and 2012 on 4594 singleton infants with gestational ages between 24 and 31 weeks, without severe anomalies and unexposed to repeated courses of ANS. Data were analyzed November 2016., Exposure: Time from first injection of ANS to delivery in hours and days., Main Outcomes and Measures: Three outcomes were studied: in-hospital mortality; a composite of mortality or severe neonatal morbidity, defined as an intraventricular hemorrhage grade of 3 or greater, cystic periventricular leukomalacia, surgical necrotizing enterocolitis, or stage 3 or greater retinopathy of prematurity; and severe neonatal brain injury, defined as an intraventricular hemorrhage grade of 3 or greater or cystic periventricular leukomalacia., Results: Of the 4594 infants included in the cohort, 2496 infants (54.3%) were boys, and the mean (SD) gestational age was 28.5 (2.2) weeks and mean (SD) birth weight was 1213 (400) g. Mortality for the 662 infants (14.4%) unexposed to ANS was 20.6% (136 of 661). Administration of ANS was associated with an immediate and rapid decline in mortality, reaching a plateau with more than 50% risk reduction after an administration-to-birth interval of 18 to 36 hours. A similar pattern for timing was seen for the composite mortality or morbidity outcome, whereas a significant risk reduction of severe neonatal brain injury was associated with longer administration-to-birth intervals (greater than 48 hours). For all outcomes, the risk reduction associated with ANS was transient, with increasing mortality and risk for severe neonatal brain injury associated with administration-to-birth intervals exceeding 1 week. Under the assumption of a causal relationship between timing of ANS and mortality, a simulation of ANS administered 3 hours before delivery to infants who did not receive ANS showed that their estimated decline in mortality would be 26%., Conclusions and Relevance: Antenatal corticosteroids may be effective even if given only hours before delivery. Therefore, the infants of pregnant women at risk of imminent preterm delivery may benefit from its use.

This paper describes an LC-MS/MS method to determine the concentration of spironolactone and its metabolites 7-alpha-methylthiospironolactone and canrenone in blood plasma samples. The resulting assay is simple (using protein precipitation for sample preparation) and sensitive (the lower limit of quantification is close to 0.5 ng/ml) while requiring only 50 μl of plasma, making it especially suitable for analyzing samples obtained from pediatric and neonatal patients where sample sizes are limited. The sensitivity is achieved by using ammonium fluoride as an eluent additive, which in our case amplifies the signal from our analytes in the plasma solution on average about 70 times. The method is fully validated according to the European Medicines Agency's guideline and used for the measurement of pediatric patients' samples in clinical trials for evaluating oral spironolactone's and its metabolites' pharmacokinetics in children up to 2 years of age.

Background and Objective: Stillbirth and in-hospital mortality rates associated with very preterm births (VPT) vary widely across Europe. International comparisons are complicated by a lack of standardized data collection and differences in definitions, registration, and reporting. This study aims to determine what proportion of the variation in stillbirth and in-hospital VPT mortality rates persists after adjusting for population demographics, case-mix, and timing of death., Methods: Standardized data collection for a geographically defined prospective cohort of VPTs (22 +0 -31 +6 weeks gestation) across 16 regions in Europe. Crude and adjusted stillbirth and in-hospital mortality rates for VPT infants were calculated by time of death by using multinomial logistic regression models., Results: The stillbirth and in-hospital mortality rate for VPTs was 27.7% (range, 19.9%-35.9% by region). Adjusting for maternal and pregnancy characteristics had little impact on the variation. The addition of infant characteristics reduced the variation of mortality rates by approximately one-fifth (4.8% to 3.9%). The SD for deaths <12 hours after birth was reduced by one-quarter, but did not change after risk adjustment for deaths ≥12 hours after birth., Conclusions: In terms of the regional variation in overall VPT mortality, over four-fifths of the variation could not be accounted for by maternal, pregnancy, and infant characteristics. Investigation of the timing of death showed that these characteristics only accounted for a small proportion of the variation in VPT deaths. These findings suggest that there may be an inequity in the quality of care provision and treatment of VPT infants across Europe., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2017 by the American Academy of Pediatrics.)

Objectives: Our objectives were to explore the possibility of avoiding neonatal exposure to potentially harmful excipients of interest (EOI)-parabens, polysorbate 80, propylene glycol, benzoates, saccharin sodium, sorbitol and ethanol-through product substitution in Europe., Methods: We performed a 3-day service evaluation survey and a 1-day point prevalence study in 20 and 21 European countries, respectively. Analysis included active pharmaceutical ingredients (APIs) used in ≥10 % of units. We calculated the potential reduction in number of products with EOI through substitution in three stages: (1) similar API and route of administration, (2) plus similar dosage form and (3) plus similar strength. The reduction of individual exposure was analysed according to the second-stage criteria., Results: We identified 137 products for 25 APIs that contained EOI. Substitution with EOI-free product(s) was available for 88 % (n = 120), 66 % (n = 91) and 31 % (n = 42) of products according to the first-, second- and third-stage criteria, respectively. Overall, 456 (63 % of 726) neonates received products containing EOI. Substitution of the products that had alternatives with similar API and dosage form would reduce the number of exposed neonates from 456 to 257 (44 % reduction)., Conclusions: EOI-free formulations are available for a substantial number of products currently used in European neonates. Replacement of only the most frequently used products may spare almost half of neonates from unnecessary exposure to EOI.

Aims: The aims of the study were to compare [(14)C]-paracetamol ([(14)C]-PARA) paediatric pharmacokinetics (PK) after administration mixed in a therapeutic dose or an isolated microdose and to develop further and validate accelerator mass spectrometry (AMS) bioanalysis in the 0-2 year old age group., Methods: [(14)C]-PARA concentrations in 10-15 µl plasma samples were measured after enteral or i.v. administration of a single [(14)C]-PARA microdose or mixed in with therapeutic dose in infants receiving PARA as part of their therapeutic regimen., Results: Thirty-four infants were included in the PARA PK analysis for this study: oral microdose (n = 4), i.v. microdose (n = 6), oral therapeutic (n = 6) and i.v. therapeutic (n = 18). The respective mean clearance (CL) values (SDs in parentheses) for these dosed groups were 1.46 (1.00) l h(-1), 1.76 (1.07) l h(-1), 2.93 (2.08) l h(-1) and 2.72 (3.10) l h(-1), t(1/2) values 2.65 h, 2.55 h, 8.36 h and 7.16 h and dose normalized AUC(0-t) (mg l(-1) h) values were 0.90 (0.43), 0.84 (0.57), 0.7 (0.79) and 0.54 (0.26)., Conclusions: All necessary ethical, scientific, clinical and regulatory procedures were put in place to conduct PK studies using enteral and systemic microdosing in two European centres. The pharmacokinetics of a therapeutic dose (mg kg(-1)) and a microdose (ng kg(-1)) in babies between 35 to 127 weeks post-menstrual age. [(14)C]-PARA pharmacokinetic parameters were within a two-fold range after a therapeutic dose or a microdose. Exploratory studies using doses significantly less than therapeutic doses may offer ethical and safety advantages with increased bionalytical sensitivity in selected exploratory paediatric pharmacokinetic studies., (© 2015 The British Pharmacological Society.)

Objectives: We aimed to describe administration of eight potentially harmful excipients of interest (EOI)-parabens, polysorbate 80, propylene glycol, benzoates, saccharin sodium, sorbitol, ethanol and benzalkonium chloride-to hospitalised neonates in Europe and to identify risk factors for exposure., Methods: All medicines administered to neonates during 1 day with individual prescription and demographic data were registered in a web-based point prevalence study. Excipients were identified from the Summaries of Product Characteristics. Determinants of EOI administration (geographical region, gestational age (GA), active pharmaceutical ingredient, unit level and hospital teaching status) were identified using multivariable logistical regression analysis., Results: Overall 89 neonatal units from 21 countries participated. Altogether 2095 prescriptions for 530 products administered to 726 neonates were recorded. EOI were found in 638 (31%) prescriptions and were administered to 456 (63%) neonates through a relatively small number of products (n=142; 27%). Parabens, found in 71 (13%) products administered to 313 (43%) neonates, were used most frequently. EOI administration varied by geographical region, GA and route of administration. Geographical region remained a significant determinant of the use of parabens, polysorbate 80, propylene glycol and saccharin sodium after adjustment for the potential covariates including anatomical therapeutic chemical class of the active ingredient., Conclusions: European neonates receive a number of potentially harmful pharmaceutical excipients. Regional differences in EOI administration suggest that EOI-free products are available and provide the potential for substitution to avoid side effects of some excipients., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background: Antibiotic dosing in neonates varies between countries and centres, suggesting suboptimal exposures for some neonates. We aimed to describe variations and factors influencing the variability in the dosing of frequently used antibiotics in European NICUs to help define strategies for improvement., Methods: A sub-analysis of the European Study of Neonatal Exposure to Excipients point prevalence study was undertaken. Demographic data of neonates receiving any antibiotic on the study day within one of three two-week periods from January to June 2012, the dose, dosing interval and route of administration of each prescription were recorded. The British National Formulary for Children (BNFC) and Neofax were used as reference sources. Risk factors for deviations exceeding ±25% of the relevant BNFC dosage recommendation were identified by multivariate logistic regression analysis., Results: In 89 NICUs from 21 countries, 586 antibiotic prescriptions for 342 infants were reported. The twelve most frequently used antibiotics - gentamicin, penicillin G, ampicillin, vancomycin, amikacin, cefotaxime, ceftazidime, meropenem, amoxicillin, metronidazole, teicoplanin and flucloxacillin - covered 92% of systemic prescriptions. Glycopeptide class, GA <32 weeks, 5(th) minute Apgar score <5 and geographical region were associated with deviation from the BNFC dosage recommendation. While the doses of penicillins exceeded recommendations, antibiotics with safety concerns followed (gentamicin) or were dosed below (vancomycin) recommendations., Conclusions: The current lack of compliance with existing dosing recommendations for neonates needs to be overcome through the conduct of well-designed clinical trials with a limited number of antibiotics to define pharmacokinetics/pharmacodynamics, efficacy and safety in this population and by efficient dissemination of the results.

Aim: Studies have reported conflicting findings on whether different smells can reduce distress when infants undergo painful procedures. Our study assessed the impact of vanilla on infants' responses to a painful toe lance, including possible gender differences., Methods: We measured the pain responses of 69 full-term infants - 34 girls and 35 boys - during toe lance, using two multidimensional scales - the Neonatal Facial Coding System and Behavioural Indicators of Infant Pain - together with crying duration and hand movements. Three sets of data were collected during baseline, toe lance and recovery, while the babies were exposed to the odour of vanilla (n = 39) or odourless water (n = 30)., Results: Pain responses increased significantly during toe lance, then declined during recovery. Crying duration correlated significantly with finger splaying/fisting and both pain scale scores, with boys displaying higher pain scores than girls. Vanilla had no impact on pain levels., Conclusion: Crying and finger splaying/fisting were observable responses that may be useful for screening pain or distress in healthy neonates. Increased pain reactions by boys may reflect higher irritability. Exposure to an unfamiliar odour did not have a calming effect on full-term neonates., (©2014 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Background: Estimates of prevalence are known to be affected by the design of cross-sectional studies. A pan-European study provided an opportunity to compare the effect of two cross-sectional study designs on estimates of medicines use., Methods: A Service evaluation survey (SES) and a web-based point-prevalence study (PPS) were conducted as part of a European study of neonatal exposure to excipients. Neonatal units from all European Union countries plus Iceland, Norway, Switzerland and Serbia were invited to participate. All medicines prescribed to neonates were recorded during three-day and one-day study periods in the SES and PPS, respectively. In the PPS individual demographic and prescription data were also collected.To compare the probabilities that a particular medicine would be reported by each study multilevel mixed effects logistic regression models with crossed random effects were applied. The relationship between medicines exposure at the unit and individual levels in the PPS data was assessed using polynomial regression with square root transformation., Results: Of 31 invited countries 20 and 21 with 115 and 89 units joined the SES and PPS, respectively. Out of 5,572,859 live births in invited countries in 2010 a higher proportion was covered by units participating in the SES compared to the PPS (11% vs 6%, respectively; OR 1.89; 95% CI 1.87-1.89). A greater number of active pharmaceutical ingredients (API), manufacturers and trade names were registered in the SES compared to the PPS. High correlation between the two studies in frequency of use for each specified API was seen (R2 = 0.86). The average probability of a department to use a given API was greater in the SES compared to the PPS (OR 2.36; 95% CI 2.05-2.73) with higher frequency of use and longer average duration of prescription further increasing the difference. The polynomial regression model described the correlation between APIs exposure on unit and individual level well (R2 = 0.93)., Conclusion: The simple data structure and longer study period of the SES resulted in improved recruitment and higher likelihood of capture for a given API. The frequency of use at the unit level appears a good surrogate of individual exposure rates.

Aim: To study very low gestational age (VLGA, <32 weeks) infants at 2 years of age and to identify the predictors of adverse outcomes., Methods: A population-based cohort of 155 surviving VLGA infants born in Estonia in 2007 was followed up and compared with a matched full-term (FT) control group. A logistic regression model was used to test associations between risk factors and adverse outcomes., Results: No impairment was found in 60% of the VLGA infants. Neurodevelopmental impairment was noted in 12% of VLGA infants, with 8% of the infants affected by cerebral palsy without independent walking, 5% with cognitive delay, 10% with language delay and 1% with hearing impairment. The differences between preterm and FT infants in terms of the mean Cognitive, Language, and Motor Composite Scores assessed using the Bayley-III scales were in excess of 0.5 SD. Somatic growth delay was a significant problem among preterm infants. The existence of severe neonatal cerebral lesions was the most significant predictor of adverse outcomes., Conclusion: In all domains studied, adverse conditions were more prevalent among VLGA infants than among the FT control group. Efforts to reduce neonatal morbidity in preterm infants should be a key priority for health care in Estonia., (©2012 The Author(s)/Acta Paediatrica ©2012 Foundation Acta Paediatrica.)

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.

Aim: To identify recent changes in short-term outcome and care for very preterm infants in Estonia., Methods: Comparison of two population-based cohort of very preterm infants born alive at 22-31 gestational weeks. In 2007-2008, data were recorded prospectively in a neonatal register. For the cohort born in 2002-2003, the same variables were extracted retrospectively from the hospital records. Infants were followed up to discharge or death., Results: The cohort of 2007-2008 contained a higher proportion of infants born by caesarean section and of infants who received antenatal corticosteroids, maternal antibiotics, or surfactant therapy than the earlier cohort. A higher proportion of infants was admitted for care in 2007-2008 (98% vs. 94%; p = 0.013). During the study period, survival until discharge increased (85% vs. 78%; p = 0.041), although the length of hospital stay was unchanged. The use of mechanical ventilation, inotropes, and postnatal antibiotics decreased. Neonatal morbidity remained unchanged, except for a decrease in severe periventricular/intraventricular haemorrhage., Conclusion: The outcome for very preterm infants in Estonia has improved since 2002. With proactive perinatal management and less invasive neonatal care, survival until discharge increased without concomitant increases in neonatal morbidity and the length of hospital stay., (© 2011 The Author(s)/Acta Paediatrica © 2011 Foundation Acta Paediatrica.)

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.

Thirty-one neonates delivered by cesarean section were exposed to an odor for 30 min shortly after birth. Fifteen births had uterine labor contractions before delivery; 16 were without contractions. All babies were later tested (median age = 80 hr) for their responses to the familiar exposure odor and a novel odor presented on either side of the face. Overall, the babies spent more time turned toward the exposure odor than toward the novel scent. Babies in the labor condition, but not those bom without labor, displayed a significant preference for the exposure odor. Norepinephrine (NE) levels were higher in babies who oriented preferentially toward the exposure odor. Brief exposure immediately after birth is sufficient for the development of olfactory learning. Heightened learning by neonates from births with contractions may reflect locus coeruleus and NE activation. Olfactory learning may therefore be particularly efficient shortly after birth.

Unlabelled: In previous studies, newborn infants placed on their mother's chest grasped a nipple and sucked without assistance. Furthermore, neonates sucked preferentially from an untreated breast rather than the alternative breast that had been washed to eliminate its natural odour. This study investigated the influence of breast odours per se on orientated physical movement of neonates. In total, 22 babies were observed during two trials on a warming bed. In one trial, a pad carrying the mother's breast odour was placed 17 cm in front of the baby's nose; in the other trial a clean pad was used. More babies moved towards and reached the breast pad than the clean pad., Conclusion: Natural breast odous unsupported by other maternal stimuli therefore appear to be sufficient to attract and guide neonates to the odour source.

Newborn young of several mammalian species are attracted to the odor of amniotic fluid (AF); these chemical cues also appear to calm neonates and help them adapt to their novel postnatal environment. AF odor likewise elicits positive (head orientation) responses by human infants. The present study systematically examined whether the odors of AF and mother's breasts influence the crying of the newborn infant, when separated from its mother. The total crying time from 31-90 min postnatal was registered on tapes in 47 healthy fullterm newborns, allocated to one of three conditions; exposure to either AF or breast odor or no exposure (controls). Babies exposed to AF smell cried significantly less (median 29 s) than babies in the two other groups (breast odor--301 s, controls--135 s). The data are consistent with the hypothesis that the fetus may become familiar with chemical cues present in the intrauterine environment. Our data provide new evidence of the human baby's fine olfactory discrimination capacity, and add to the growing body of evidence indicating that naturally occurring odors play an important role in the mediation of infants' early behavior.

At their first sucking contact, neonates prefer an unwashed breast to a washed one, but an amniotic fluid (AF)- treated breast over a "natural odour" breast. We examined the development of these neonatal olfactory preferences. On days 3-4 significantly more babies still selected their mother's unwashed breast (n = 21) than the washed alternative (n = 8). Preferences for natural breast odours were more pronounced for girls than boys. In a subsequent experiment comprising another 28 babies, the number of babies who selected a naturally scented (n = 9) vs an AF-treated breast (n = 19) on days 2-5 were not reliably different. However, babies who selected the natural breast had longer pre-test maternal contact and had spent more time breastfeeding. Ten babies who chose the AF breast in the latter experiment were tested in the same manner several days later; all preferred the naturally smelling breast. While preferences for AF fade after birth, responsiveness to natural breast odours may be enhanced by postnatal experience.