Heili Varendi

Hospitalised neonates in Estonia commonly receive potentially harmful excipients

BackgroundInformation 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.MethodsA prospective cohort study that recorded all medicines prescribed to patients aged below 28u2009days 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.Results1961 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.ConclusionsHospitalised 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.

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

BackgroundAntibiotic 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.MethodsA 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.ResultsIn 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, 5th 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.ConclusionsThe 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.

Potentially harmful excipients in neonatal medicines: a pan-European observational study

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.

An Observational Study of Blood Concentrations and Kinetics of Methyl- and Propyl-Parabens in Neonates

ABSTRACTPurposeSystemic exposure to parabens in the neonatal population, in particular propyl-parabens (PPB), remains a concern. Blood concentrations and kinetics of methyl-parabens (MPB) and PPB were therefore determined in neonates receiving medicines containing these excipients.MethodsA multi-centre, non-interventional, observational study of excipient-kinetics in neonates. ‘Dried Blood Spot’ samples were collected opportunistically at the same time as routine samples and the observations modelled using a non-linear mixed effects approach.ResultsA total of 841 blood MPB and PPB concentration data were available for evaluation from 181 pre- and term-neonates. Quantifiable blood concentrations of MPB and PPB were observed in 99% and 49% of patients, and 55% and 25% of all concentrations were above limit of detection (10xa0ng/ml), respectively. Only MPB data was amenable to modelling. Oral bioavailability was influenced by type of formulation and disposition was best described by a two compartment model with clearance (CL) influenced by post natal age (PNA); CLPNA<21 days 0.57 versus CLPNA>21days 0.88xa0L/h.ConclusionsDaily repeated administration of parabens containing medicines can result in prolonged systemic exposure to the parent compound in neonates. Animal toxicology studies of PPB that specifically address the neonatal period are required before a permitted daily exposure for this age group can be established.

Observational infant exploratory [14C]‐paracetamol pharmacokinetic microdose/therapeutic dose study with accelerator mass spectrometry bioanalysis

AIMSnThe 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.nnnMETHODSn[(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.nnnRESULTSnThirty-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).nnnCONCLUSIONSnAll 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.

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.

Use of magnesium sulfate before 32 weeks of gestation: a European population-based cohort study

Objectives The use of magnesium sulfate (MgSO4) in European obstetric units is unknown. We aimed to describe reported policies and actual use of MgSO4 in women delivering before 32u2005weeks of gestation by indication. Methods We used data from the European Perinatal Intensive Care in Europe (EPICE) population-based cohort study of births before 32u2005weeks of gestation in 19 regions in 11 European countries. Data were collected from April 2011 to September 2012 from medical records and questionnaires. The study population comprised 720 women with severe pre-eclampsia, eclampsia or HELLP and 3658 without pre-eclampsia delivering from 24 to 31u2005weeks of gestation in 119 maternity units with 20 or more very preterm deliveries per year. Results Among women with severe pre-eclampsia, eclampsia or HELLP, 255 (35.4%) received MgSO4 before delivery. 41% of units reported use of MgSO4 whenever possible for pre-eclampsia and administered MgSO4 more often than units reporting use sometimes. In women without pre-eclampsia, 95 (2.6%) received MgSO4. 9 units (7.6%) reported using MgSO4 for fetal neuroprotection whenever possible. In these units, the median rate of MgSO4 use for deliveries without severe pre-eclampsia, eclampsia and HELLP was 14.3%. Only 1u2005unit reported using MgSO4 as a first-line tocolytic. Among women without pre-eclampsia, MgSO4 use was not higher in women hospitalised before delivery for preterm labour. Conclusions Severe pre-eclampsia, eclampsia or HELLP are not treated with MgSO4 as frequently as evidence-based medicine recommends. MgSO4 is seldom used for fetal neuroprotection, and is no longer used for tocolysis. To continuously lower morbidity, greater attention to use of MgSO4 is needed.

Parent and nurse perceptions on the quality of family-centred care in 11 European NICUs

BACKGROUNDnFamily-centred care (FCC) is a state-of-the-art practice in neonatal intensive care units (NICU) based on its shown benefits on the well-being of both infants and parents. However, there is no systematic knowledge about how FCC is implemented in different European contexts.nnnOBJECTIVESnTo describe parents presence and the quality of FCC from the perspectives of mothers, fathers and nurses in 11 European NICUs.nnnMETHODSnA prospective survey was conducted in Finland, Sweden, Norway, Estonia, Spain and Italy. The perceived quality of FCC was measured using 8 text-message questions sent to the parents mobile phones, one question each day, during the infants hospital stay. Nurses answered corresponding questions through a Web questionnaire during a 3-month period. The responses were rated on a 7-point Likert scale. Parents who were not present in the unit during the day used a 0 response.nnnRESULTSnA total of 262 families of preterm infants born before 35 gestational weeks participated in the study. Mothers gave 5045 responses, fathers gave 3971 responses and nurses gave 11,132 answers. The mothers were present during 92.7% and the fathers during 77.9% of the study days. The mothers rated the quality of FCC slightly higher than the fathers did (5.8 [95% CI 5.7-5.9] vs. 5.7 [95% CI 5.6-5.8], mean difference of 0.12 [95% CI 0.05-0.2], p<0.001). There was wide variation in the parents presence and the quality of FCC between the units. The weakest aspects of FCC were emotional support, parents participation in decision-making and fathers participation in infant care. The perceived quality of FCC between the nurses and parents were comparable.nnnCONCLUSIONSnThis study showed a high perceived quality of FCC in 11 European units, as indicated by both parents and nurses. The innovative data-collection method and instrument successfully quantified each units FCC profile for further quality improvement and should be trialled in other NICUs and countries.

Evidence-based neonatal unit practices and determinants of Postnatal corticosteroid-use in preterm births below 30 weeks ga in Europe. A population-based cohort study

Background Postnatal corticosteroids (PNC) were widely used to treat and prevent bronchopulmonary dysplasia in preterm infants until studies showed increased risk of cerebral palsy and neurodevelopmental impairment. We aimed to describe PNC use in Europe and evaluate the determinants of their use, including neonatal characteristics and adherence to evidence-based practices in neonatal intensive care units (NICUs). Methods 3917/4096 (95,6%) infants born between 24 and 29 weeks gestational age in 19 regions of 11 European countries of the EPICE cohort we included. We examined neonatal characteristics associated with PNC use. The cohort was divided by tertiles of probability of PNC use determined by logistic regression analysis. We also evaluated the impact of the neonatal unit’s reported adherence to European recommendations for respiratory management and a stated policy of reduced PNC use. Results PNC were prescribed for 545/3917 (13.9%) infants (regional range 3.1–49.4%) and for 29.7% of infants in the highest risk tertile (regional range 5.4–72.4%). After adjustment, independent predictors of PNC use were a low gestational age, small for gestational age, male sex, mechanical ventilation, use of non-steroidal anti-inflammatory drugs to treat persistent ductus arteriosus and region. A stated NICU policy reduced PNC use (odds ratio 0.29 [95% CI 0.17; 0.50]). Conclusion PNC are frequently used in Europe, but with wide regional variation that was unexplained by neonatal characteristics. Even for infants at highest risk for PNC use, some regions only rarely prescribed PNC. A stated policy of reduced PNC use was associated with observed practice and is recommended.

Variability in very preterm stillbirth and in-hospital mortality across Europe

An exploration of the demographic and case-mix factors accounting for the regional variation in stillbirth and in-hospital very preterm mortality rates 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.