Pharmacokinetics of oral spironolactone in infants up to 2 years of age.

PURPOSE: Spironolactone is a potassium sparing diuretic used for decades. Until now, pharmacokinetic (PK) studies of spironolactone have not been conducted in infants and therefore pediatric dosing is based on expert opinion. We aimed to describe the PK profiles of spironolactone and its main metabolites (7alpha-thiomethylspironolactone (TMS) and canrenone (CAN)) in infants up to two years of age. METHODS: The PK of spironolactone and its main metabolites were evaluated following an oral administration of spironolactone (1 mg/kg/dose) to pediatric patients with chronic heart failure, ascites, and/or oedema. The plasma concentration of spironolactone and metabolites (TMS and CAN) was determined using an ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS). Based on rich sampling PK data, the estimation of population PK parameters was performed using nonlinear mixed-effects modelling software Monolix 2018R2. RESULTS: A total of 150 spironolactone, 158 TMS, and 158 CAN concentrations from 23 patients (ages: 3 days-21 months; median weight 4.3 kg (2.2-12.6)) were available for PK analysis. A one-compartment model for spironolactone, TMS, and CAN best fitted the data. The median (range) of individual estimated apparent clearance values were 47.7 (11.9-138.1) L/h for spironolactone, 9.7 (1.5-66.9) L/h for TMS, and 1.0 (0.2-5.9) L/h for CAN. The disposition of spironolactone and metabolites was mainly affected by size of the patient: body weight explained 22% of inter-individual variability of spironolactone clearance. None of the undesirable effects of spironolactone was documented during the study period. CONCLUSION: The pharmacokinetics of spironolactone and its metabolites was highly variable between patients below 2 years of age. Body weight explained a significant part of this variability; this highlights the need to take it into account for dosing prescription in this population. (Clinical trial Registration Number 2013-001189-40).

Risk factors for cerebral palsy and movement difficulties in 5-year-old children born extremely preterm.

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.

Variation in delivery room management of preterm infants across Europe: a survey of the Union of European Neonatal and Perinatal Societies.

The aim of the present study, endorsed by the Union of European Neonatal and Perinatal Societies (UENPS) and the Italian Society of Neonatology (SIN), was to analyze the current delivery room (DR) stabilization practices in a large sample of European birth centers that care for preterm infants with gestational age (GA) < 33 weeks. Cross-sectional electronic survey was used in this study. A questionnaire focusing on the current DR practices for infants < 33 weeks' GA, divided in 6 neonatal resuscitation domains, was individually sent to the directors of European neonatal facilities, made available as a web-based link. A comparison was made between hospitals grouped into 5 geographical areas (Eastern Europe (EE), Italy (ITA), Mediterranean countries (MC), Turkey (TUR), and Western Europe (WE)) and between high- and low-volume units across Europe. Two hundred and sixty-two centers from 33 European countries responded to the survey. At the time of the survey, approximately 20,000 very low birth weight (VLBW, < 1500 g) infants were admitted to the participating hospitals, with a median (IQR) of 48 (27-89) infants per center per year. Significant differences between the 5 geographical areas concerned: the volume of neonatal care, ranging from 86 (53-206) admitted VLBW infants per center per year in TUR to 35 (IQR 25-53) in MC; the umbilical cord (UC) management, being the delayed cord clamping performed in < 50% of centers in EE, ITA, and MC, and the cord milking the preferred strategy in TUR; the spotty use of some body temperature control strategies, including thermal mattress mainly employed in WE, and heated humidified gases for ventilation seldom available in MC; and some of the ventilation practices, mainly in regard to the initial FiO2 for < 28 weeks' GA infants, pressures selected for ventilation, and the preferred interface to start ventilation. Specifically, 62.5% of TUR centers indicated the short binasal prongs as the preferred interface, as opposed to the face mask which is widely adopted as first choice in > 80% of the rest of the responding units; the DR surfactant administration, which ranges from 44.4% of the birth centers in MC to 87.5% in WE; and, finally, the ethical issues around the minimal GA limit to provide full resuscitation, ranging from 22 to 25 weeks across Europe. A comparison between high- and low-volume units showed significant differences in the domains of UC management and ventilation practices.    Conclusion: Current DR practice and ethical choices show similarities and divergences across Europe. Some areas of assistance, like UC management and DR ventilation strategies, would benefit of standardization. Clinicians and stakeholders should consider this information when allocating resources and planning European perinatal programs. What is Known: • Delivery room (DR) support of preterm infants has a direct influence on both immediate survival and long-term morbidity. • Resuscitation practices for preterm infants often deviate from the internationally defined algorithms. What is New: • Current DR practice and ethical choices show similarities and divergences across Europe. Some areas of assistance, like UC management and DR ventilation strategies, would benefit of standardization. • Clinicians and stakeholders should consider this information when allocating resources and planning European perinatal programs.

Depressive symptoms in mothers of preterm infants before and during COVID-19 restrictions in neonatal intensive care units.

AIM: Little is known about the specific restriction measures used in intensive care units (NICUs) during the COVID-19 pandemic and their impact on parental well-being. Hence, this study aimed to assess the association between restriction measures and mothers' post-partum depressive symptoms. METHODS: This comparative cohort study included mothers who gave birth before 35 weeks of gestation in Estonia. The outcome measure was mothers' post-partum depressive symptoms at the time of infant discharge, evaluated using the Edinburgh Postnatal Depression Scale (EPDS). In addition to the pandemic itself, the number of restriction measures in the NICUs was analysed as a potential explanatory factor for depressive symptoms. RESULTS: The study included 55 mothers before the pandemic in 2018-2019 and 54 mothers during the COVID-19 pandemic in 2021. No significant difference was found in the median EPDS scores between the cohorts: 7.0 [interquartile range (IQR): 4.0-12.0] and 8.0 (IQR: 5.0-12.8) respectively. The number of restriction measures was not associated with mothers' EPDS scores in either unadjusted or adjusted models. CONCLUSION: The COVID-19 pandemic or the number of restriction measures used in Estonian NICUs did not associate with mothers' post = partum depressive symptoms.

Mode of delivery and adverse short- and long-term outcomes in vertex-presenting very preterm born infants: a European population-based prospective cohort study.

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.

Signal Enhancement in the HPLC-ESI-MS/MS analysis of spironolactone and its metabolites using HFIP and NH4F as eluent additives.

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.

Observational infant exploratory [(14)C]-paracetamol pharmacokinetic microdose/therapeutic dose study with accelerator mass spectrometry bioanalysis.

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.

High variability in the dosing of commonly used antibiotics revealed by a Europe-wide point prevalence study: implications for research and dissemination.

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.

Comparison of two alternative study designs in assessment of medicines utilisation in neonates.

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.

The effects of olfactory stimulation and gender differences on pain responses in full-term infants.

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.

A Survey of the Union of European Neonatal and Perinatal Societies on Neonatal Respiratory Care in Neonatal Intensive Care Units.

(1) Background: Our survey aimed to gather information on respiratory care in Neonatal Intensive Care Units (NICUs) in the European and Mediterranean region. (2) Methods: Cross-sectional electronic survey. An 89-item questionnaire focusing on the current modes, devices, and strategies employed in neonatal units in the domain of respiratory care was sent to directors/heads of 528 NICUs. The adherence to the "European consensus guidelines on the management of respiratory distress syndrome" was assessed for comparison. (3) Results: The response rate was 75% (397/528 units). In most Delivery Rooms (DRs), full resuscitation is given from 22 to 23 weeks gestational age. A T-piece device with facial masks or short binasal prongs are commonly used for respiratory stabilization. Initial FiO2 is set as per guidelines. Most units use heated humidified gases to prevent heat loss. SpO2 and ECG monitoring are largely performed. Surfactant in the DR is preferentially given through Intubation-Surfactant-Extubation (INSURE) or Less-Invasive-Surfactant-Administration (LISA) techniques. DR caffeine is widespread. In the NICUs, most of the non-invasive modes used are nasal CPAP and nasal intermittent positive-pressure ventilation. Volume-targeted, synchronized intermittent positive-pressure ventilation is the preferred invasive mode to treat acute respiratory distress. Pulmonary recruitment maneuvers are common approaches. During NICU stay, surfactant administration is primarily guided by FiO2 and SpO2/FiO2 ratio, and it is mostly performed through LISA or INSURE. Steroids are used to facilitate extubation and prevent bronchopulmonary dysplasia. (4) Conclusions: Overall, clinical practices are in line with the 2022 European Guidelines, but there are some divergences. These data will allow stakeholders to make comparisons and to identify opportunities for improvement.

Laryngeal Mask Airway in Neonatal Resuscitation: A Survey of the Union of European Neonatal and Perinatal Societies.

INTRODUCTION: Laryngeal mask airway (LMA) use in neonatal resuscitation is limited despite existing evidence and recommendations. This survey investigated the knowledge and experience of healthcare providers on the use of the LMA and explored barriers and solutions for implementation. METHODS: This online, cross-sectional survey on LMA in neonatal resuscitation involved healthcare professionals of the Union of European Neonatal and Perinatal Societies (UENPS). RESULTS: A total of 858 healthcare professionals from 42 countries participated in the survey. Only 6% took part in an LMA-specific course. Some delivery rooms were not equipped with LMA (26.1%). LMA was mainly considered after the failure of a face mask (FM) or endotracheal tube (ET), while the first choice was limited to neonates with upper airway malformations. LMA and FM were considered easier to position but less effective than ET, while LMA was considered less invasive than ET but more invasive than FM. Participants felt less competent and experienced with LMA than FM and ET. The lack of confidence in LMA was perceived as the main barrier to its implementation in neonatal resuscitation. More training, supervision, and device availability in delivery wards were suggested as possible actions to overcome those barriers. CONCLUSION: Our survey confirms previous findings on limited knowledge, experience, and confidence with LMA, which is usually considered an option after the failure of FM/ET. Our findings highlight the need for increasing the availability of LMA in delivery wards. Moreover, increasing LMA training and having an LMA expert supervisor during clinical practice may improve the implementation of LMA use in neonatal clinical practice.

Follow-up study of 2-year-olds born at very low gestational age in Estonia.

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.

Apgar Score and Neurodevelopmental Outcomes at Age 5 Years in Infants Born Extremely Preterm.

Importance: The Apgar score is used worldwide as an assessment tool to estimate the vitality of newborns in their first minutes of life. Its applicability to estimate neurodevelopmental outcomes in infants born extremely preterm (EPT; <28 weeks' gestation) is not well established. Objective: To investigate the association between the Apgar score and neurodevelopmental outcomes in infants born EPT. Design, Setting, and Participants: This cohort study was conducted using data from the Effective Perinatal Intensive Care in Europe-Screening to Improve Health in Very Preterm Infants in Europe (EPICE-SHIPS) study, a population-based cohort in 19 regions of 11 European countries in 2011 to 2012. Clinical assessments of cognition and motor function at age 5 years were performed in infants born EPT and analyzed in January to July 2023. Exposures: Apgar score at 5 minutes of life categorized into 4 groups (0-3, 4-6, 7-8, and 9-10 points). Main Outcomes and Measures: Cognitive and motor outcomes were assessed using the Wechsler Preschool and Primary Scale of Intelligence test of IQ derived from locally normed versions by country and the Movement Assessment Battery for Children-Second Edition. Parents additionally provided information on communication and problem-solving skills using the Ages and Stages Questionnaire, third edition (ASQ-3). All outcomes were measured as continuous variables. Results: From the total cohort of 4395 infants born EPT, 2522 infants were live born, 1654 infants survived to age 5 years, and 996 infants (478 females [48.0%]) followed up had at least 1 of 3 outcome measures. After adjusting for sociodemographic variables, perinatal factors, and severe neonatal morbidities, there was no association of Apgar score with IQ, even for scores of 3 or less (ß = -3.3; 95% CI, -10.5 to 3.8) compared with the score 9 to 10 category. Similarly, no association was found for ASQ-3 (ß = -2.1; 95% CI, -24.6 to 20.4). Congruent results for Apgar scores of 3 or less were obtained for motor function scores for all children (ß = -4.0; 95% CI, -20.1 to 12.1) and excluding children with a diagnosis of cerebral palsy (ß = 0.8, 95% CI -11.7 to 13.3). Conclusions and Relevance: This study found that low Apgar scores were not associated with longer-term outcomes in infants born EPT. This finding may be associated with high interobserver variability in Apgar scoring, reduced vitality signs and poorer responses to resuscitation after birth among infants born EPT, and the association of more deleterious exposures in the neonatal intensive care unit or of socioeconomic factors with greater changes in outcomes during the first 5 years of life.

Hospitalised neonates in Estonia commonly receive potentially harmful excipients.

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.

Changes in care and short-term outcome for very preterm infants in Estonia.

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.

Prevalence of congenital cryptorchidism in Estonia.

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.

Neonatal Resuscitation Practices in Europe: A Survey of the Union of European Neonatal and Perinatal Societies.

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.

Maternal education and cognitive development in 15 European very-preterm birth cohorts from the RECAP Preterm platform.

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.