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.

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).

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.

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.

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.

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.

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.

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.

Language skills at corrected age 2;0 are poorer in extremely and very preterm boys but not girls compared with their full-term peers.

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.

Priorities for collaborative research using very preterm birth cohorts.

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.

EPICE cohort: two-year neurodevelopmental outcomes after very preterm birth.

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.

Medicines prescription patterns in European neonatal units.

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.

Mode of delivery and mortality and morbidity for very preterm singleton infants in a breech position: A European cohort study.

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.

Wide variation in severe neonatal morbidity among very preterm infants in European regions.

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.

Association of Short Antenatal Corticosteroid Administration-to-Birth Intervals With Survival and Morbidity Among Very Preterm Infants: Results From the EPICE Cohort.

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.

Variability in Very Preterm Stillbirth and In-Hospital Mortality Across Europe.

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.

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.