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Background: Data on the efficacy and safety of long-acting β2-agonists (LABA) in children are limited, and current guidelines recommend that LABA always be used with inhaled corticosteroids (ICS).Objective: To compare asthma control, assessed by rescue medications use, in children prescribed LABA and ICS as a fixed-dose combination (LABA/ICS) or concurrently via separate inhalers (LABA+ICS).Methods: Retrospective observational study of asthma medication prescribed to children aged 0-18 years registered with 40 primary care practices for the years 2002-6. Asthma control, reflected by requirement for oral corticosteroids (OCS) and/or six or more short-acting β2-agonist (SABA) canisters per year, was assessed for children prescribed LABA/ICS or LABA+ICS.Results: 10,454 (8%) of all registered children received at least one prescription for asthma medication over the study period. Prescribing of LABA/ICS increased significantly, with a concomitant decrease in prescribing of LABA+ICS. Use of OCS increased by 60%, with the lowest use in children prescribed only SABA and highest use in those prescribed LABA. Children prescribed LABA/ICS were significantly less likely than those prescribed LABA+ICS to require OCS rescue therapy and or >6 SABA inhalers a year (OR 1.6; 95% CI 1.1 to 2.2; p=0.04 and OR 1.7; 95% CI 1.1 to 2.5; p=0.005, respectively, for the years 2005-6).Conclusions: The results of this retrospective observational study suggest that children prescribed fixed-dose LABA-and-ICS combination devices achieve better asthma control, as reflected in reduced requirements for SABA and reduced courses of OCS than equivalent doses in separate devices. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To assess current attitudes of hospital based paediatricians to off label prescribing, and the performance of clinical trials in children. DESIGN: A prospective, questionnaire based study. SETTING: 257 hospital based consultants and specialist registrars in paediatric practice in Scotland during 2003-2004. RESULTS: A 25 item questionnaire was sent to 257 hospital based paediatricians and 151 (59%) were returned completed. Over 90% of responders were familiar with the concept of, and knowingly prescribed, off label drugs; 55% of responders stated that such prescribing disadvantaged children, and 47% expressed concerns about the efficacy of off label medicines. Although 70% of responders expressed concerns about safety, only 17% had observed an adverse event, and 47% a treatment failure, while 69% did not obtain informed consent or tell parents they were prescribing off label, and 67% did not inform the family's general practitioner. Many respondents did not believe it was necessary to carry out clinical trials in children for new (46%) or generic (64%) medicines. However, 52% of respondents stated that they would be willing to undertake clinical studies and recruit their own patients (61%) or children (73%) to take part in such studies. CONCLUSIONS: Among Scottish paediatricians there is concern about off label prescribing, although the majority do not consider it necessary to inform parents or GP colleagues. The need for clinical trials in children was recognised but there was a less than wholehearted acceptance of the need for such studies, at variance with the current drive to promote clinical trials in this age group. [ABSTRACT FROM AUTHOR]

Background: Previous studies suggest an association between age within schoolyear and attention-deficit hyperactivity disorder (ADHD). Scotland and Wales have different school entry cut-off dates (six months apart) and policies on holding back children. We aim to investigate the association between relative age and treated attention deficit hyperactivity disorder (ADHD) in two countries, accounting for held-back children., Methods: Routine education and health records of 1,063,256 primary and secondary schoolchildren in Scotland (2009-2013) and Wales (2009-2016) were linked. Logistic regression was used to examine the relationships between age within schoolyear and treated ADHD, adjusting for child, maternity and obstetric confounders., Results: Amongst children in their expected school year, 8,721 (0.87%) had treated ADHD (Scotland 0.84%; Wales 0.96%). In Wales, ADHD increased with decreasing age (youngest quartile, adjusted OR 1.32, 95% CI 1.19-1.46) but, in Scotland, it did not differ between the youngest and oldest quartiles. Including held-back children in analysis of their expected year, the overall prevalence of treated ADHD was 0.93%, and increased across age quartiles in both countries. More children were held back in Scotland (57,979; 7.66%) than Wales (2,401; 0.78%). Held-back children were more likely to have treated ADHD (Scotland OR 2.18, 95% CI 2.01-2.36; Wales OR 1.70, 95% CI 1.21-2.31) and 81.18% of held-back children would have been in the youngest quartile of their expected year., Conclusions: Children younger within schoolyear are more likely to be treated for ADHD, suggesting immaturity may influence diagnosis. However, these children are more likely to be held back in countries that permit flexibility, attenuating the relative age effect., (© 2022. The Author(s).)

Background: Looked after children are defined as children who are in the care of their local authority. Previous studies have reported that looked after children have poorer mental and physical health, increased behavioural problems, and increased self-harm and mortality compared to peers. They also experience poorer educational outcomes, yet population-wide research into the latter is lacking, particularly in the United Kingdom. Education and health share a bidirectional relationship; therefore, it is important to dually investigate both outcomes. Our study aimed to compare educational and health outcomes for looked after children with peers, adjusting for sociodemographic, maternity, and comorbidity confounders., Methods and Findings: Linkage of 9 Scotland-wide databases, covering dispensed prescriptions, hospital admissions, maternity records, death certificates, annual pupil census, examinations, school absences/exclusions, unemployment, and looked after children provided retrospective data on 715,111 children attending Scottish schools between 2009 and 2012 (13,898 [1.9%] looked after). Compared to peers, 13,898 (1.9%) looked after children were more likely to be absent (adjusted incidence rate ratio [AIRR] 1.27, 95% confidence interval [CI] 1.24 to 1.30) and excluded (AIRR 4.09, 95% CI 3.86 to 4.33) from school, have special educational need (SEN; adjusted odds ratio [AOR] 3.48, 95% CI 3.35 to 3.62) and neurodevelopmental multimorbidity (AOR 2.45, 95% CI 2.34 to 2.57), achieve the lowest level of academic attainment (AOR 5.92, 95% CI 5.17 to 6.78), and be unemployed after leaving school (AOR 2.12, 95% CI 1.96 to 2.29). They were more likely to require treatment for epilepsy (AOR 1.50, 95% CI 1.27 to 1.78), attention deficit hyperactivity disorder (ADHD; AOR 3.01, 95% CI 2.76 to 3.27), and depression (AOR 1.90, 95% CI 1.62 to 2.22), be hospitalised overall (adjusted hazard ratio [AHR] 1.23, 95% CI 1.19 to 1.28) for injury (AHR 1.80, 95% CI 1.69 to 1.91) and self-harm (AHR 5.19, 95% CI 4.66 to 5.78), and die prematurely (AHR 3.21, 95% CI 2.16 to 4.77). Compared to children looked after at home, children looked after away from home had less absenteeism (AIRR 0.35, 95% CI 0.33 to 0.36), less exclusion (AIRR 0.63, 95% CI 0.56 to 0.71), less unemployment (AOR 0.53, 95% CI 0.46 to 0.62), and better attainment (AIRR 0.31, 95% CI 0.23 to 0.40). Therefore, among those in care, being cared for away from home appeared to be a protective factor resulting in better educational outcomes. The main limitations of this study were lack of data on local authority care preschool or before 2009, total time spent in care, and age of first contact with social care., Conclusions: Looked after children had poorer health and educational outcomes than peers independent of increased neurodevelopmental conditions and SEN. Further work is required to understand whether poorer outcomes relate to reasons for entering care, including maltreatment and adverse childhood events, neurodevelopmental vulnerabilities, or characteristics of the care system., Competing Interests: The authors have declared that no competing interests exist

Background: Hypertensive disorders during pregnancy are an important risk to mother and fetus, frequently necessitating antihypertensive treatment. Data describing the safety of in-utero exposure to antihypertensive treatment is conflicting with many studies suffering from significant methodological issues., Method: We conducted a retrospective cohort study using linked routinely collected healthcare records for 268 711 children born 2010-2014 in Scotland to assess outcomes following in-utero exposure to antihypertensive medication., Results: We identified a cohort of 265 488 eligible mother-child pairs born over the study period; of which, 2433 were exposed in utero to antihypertensive medication, 4391 exposed to treated late-onset hypertension and 6066 exposed to untreated hypertension during pregnancy. In-utero antihypertensive exposure was associated with an increased risk of circulatory defects (aOR 2.29; 99% CI 1.14-4.59) compared with normal controls and the untreated hypertensive group. We report no increased odds of any developmental outcomes at 2.5 years of age following exposure to antihypertensive medication during pregnancy, untreated hypertension or late-onset hypertension., Conclusion: Although circulatory defects may be associated with antihypertensive medication exposure during pregnancy, the mechanisms underlying this process are unclear., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background: To compare health, educational and employment outcomes of schoolchildren receiving medication for a skin disorder with peers., Methods: This retrospective population cohort study linked eight Scotland-wide databases, covering dispensed prescriptions, hospital admissions, maternity records, death certificates, annual pupil census, school examinations, school absences/exclusions and unemployment to investigate educational (absence, exclusion, special educational need, academic attainment), employment, and health (admissions and mortality) outcomes of 766,244 children attending local authority run primary, secondary and special schools in Scotland between 2009 and 2013., Results: After adjusting for sociodemographic and maternity confounders the 130,087 (17.0%) children treated for a skin disorder had increased hospitalisation, particularly within one year of commencing treatment (IRR 1.38, 95% CI 1.35-1.41, p<0.001) and mortality (HR 1.50, 95% CI 1.18-1.90, p<0.001). They had greater special educational need (OR 1.19, 95% CI 1.17-1.21, p<0.001) and more frequent absences from school (IRR 1.07, 95% CI 1.06-1.08, p<0.001) but did not exhibit poorer exam attainment or increased post-school unemployment. The associations remained after further adjustment for comorbid chronic conditions., Conclusions: Despite increased hospitalisation, school absenteeism, and special educational need, children treated for a skin disorder did not have poorer exam attainment or employment outcomes. Whilst findings relating to educational and employment outcomes are reassuring, the association with increased risk of mortality is alarming and merits further investigation., Competing Interests: The authors have declared that no competing interests exist.

Background: Neurodevelopmental conditions commonly coexist in children, but compared to adults, childhood multimorbidity attracts less attention in research and clinical practice. We previously reported that children treated for attention deficit hyperactivity disorder (ADHD) and depression have more school absences and exclusions, additional support needs, poorer attainment, and increased unemployment. They are also more likely to have coexisting conditions, including autism and intellectual disability. We investigated prevalence of neurodevelopmental multimorbidity (≥2 conditions) among Scottish schoolchildren and their educational outcomes compared to peers., Methods and Findings: We retrospectively linked 6 Scotland-wide databases to analyse 766,244 children (390,290 [50.9%] boys; 375,954 [49.1%] girls) aged 4 to 19 years (mean = 10.9) attending Scottish schools between 2009 and 2013. Children were distributed across all deprivation quintiles (most to least deprived: 22.7%, 20.1%, 19.3%, 19.5%, 18.4%). The majority (96.2%) were white ethnicity. We ascertained autism spectrum disorder (ASD) and intellectual disabilities from records of additional support needs and ADHD and depression through relevant encashed prescriptions. We identified neurodevelopmental multimorbidity (≥2 of these conditions) in 4,789 (0.6%) children, with ASD and intellectual disability the most common combination. On adjusting for sociodemographic (sex, age, ethnicity, deprivation) and maternity (maternal age, maternal smoking, sex-gestation-specific birth weight centile, gestational age, 5-minute Apgar score, mode of delivery, parity) factors, multimorbidity was associated with increased school absenteeism and exclusion, unemployment, and poorer exam attainment. Significant dose relationships were evident between number of conditions (0, 1, ≥2) and the last 3 outcomes. Compared to children with no conditions, children with 1 condition, and children with 2 or more conditions, had more absenteeism (1 condition adjusted incidence rate ratio [IRR] 1.28, 95% CI 1.27-1.30, p < 0.001 and 2 or more conditions adjusted IRR 1.23, 95% CI 1.20-1.28, p < 0.001), greater exclusion (adjusted IRR 2.37, 95% CI 2.25-2.48, p < 0.001 and adjusted IRR 3.04, 95% CI 2.74-3.38, p < 0.001), poorer attainment (adjusted odds ratio [OR] 3.92, 95% CI 3.63-4.23, p < 0.001 and adjusted OR 12.07, 95% CI 9.15-15.94, p < 0.001), and increased unemployment (adjusted OR 1.57, 95% CI 1.49-1.66, p < 0.001 and adjusted OR 2.11, 95% CI 1.83-2.45, p < 0.001). Associations remained after further adjustment for comorbid physical conditions and additional support needs. Coexisting depression was the strongest driver of absenteeism and coexisting ADHD the strongest driver of exclusion. Absence of formal primary care diagnoses was a limitation since ascertaining depression and ADHD from prescriptions omitted affected children receiving alternative or no treatment and some antidepressants can be prescribed for other indications., Conclusions: Structuring clinical practice and training around single conditions may disadvantage children with neurodevelopmental multimorbidity, who we observed had significantly poorer educational outcomes compared to children with 1 condition and no conditions., Competing Interests: The authors have declared that no competing interests exist.

Background: In 2017, the World Health Organization published "Medication Without Harm, WHO Global Patient Safety Challenge," to reduce patient harm caused by unsafe medication use practices. While the five objectives emphasise the need to create a framework for action, engaging key stakeholders and others, most published research has focused on the perspectives of health professionals. The aim was to explore the views and experiences of decision-makers in Qatar on organisational safety culture, medication errors and error reporting., Method: Qualitative, semi-structured interviews were conducted with healthcare decision-makers (policy-makers, professional leaders and managers, lead educators and trainers) in Qatar. Participants were recruited via purposive and snowball sampling, continued to the point of data saturation. The interview schedule focused on: error causation and error prevention; engendering a safety culture; and initiatives to encourage error reporting. Interviews were digitally recorded, transcribed and independently analysed by two researchers using the Framework Approach., Results: From the 21 interviews conducted, key themes were the need to: promote trust within the organisation through articulating a fair blame culture; eliminate management, professional and cultural hierarchies; focus on team building, open communication and feedback; promote professional development; and scale-up successful initiatives. There was recognition that the current medication error reporting processes and systems were suboptimal, with suggested enhancements in themes of promoting a fair blame culture and open communication., Conclusion: These positive and negative aspects of organisational culture can inform the development of theory-based interventions to promote patient safety. Central to these will be the further development and sustainment of a "fair" blame culture in Qatar and beyond., (© 2020 The Authors. International Journal of Clinical Practice published by John Wiley & Sons Ltd.)

Background: Childhood depression is relatively common, under-researched and can impact social and cognitive function and self-esteem., Methods: Record linkage of routinely collected Scotland-wide administrative databases covering prescriptions [prescribing information system (PIS)], hospitalizations (Scottish Morbidity Records 01 and 04), maternity records (Scottish Morbidity Records 02), deaths (National Records of Scotland), annual pupil census, school absences/exclusions, special educational needs (Scottish Exchange of Educational Data; ScotXed), examinations (Scottish Qualifications Authority) and (un)employment (ScotXed) provided data on 766 237 children attending Scottish schools between 2009 and 2013 inclusively. We compared educational and health outcomes of children receiving antidepressant medication with their peers, adjusting for confounders (socio-demographic, maternity and comorbidity) and explored effect modifiers and mediators., Results: Compared with peers, children receiving antidepressants were more likely to be absent [adjusted incidence rate ratio (IRR) 1.90, 95% confidence interval (CI) 1.85-1.95] or excluded (adjusted IRR 1.48, 95% CI 1.29-1.69) from school, have special educational needs [adjusted odds ratio (OR) 1.77, 95% CI 1.65-1.90], have the lowest level of academic attainment (adjusted OR 3.00, 95% CI 2.51-3.58) and be unemployed after leaving school (adjusted OR 1.88, 95% CI 1.71-2.08). They had increased hospitalization [adjusted hazard ratio (HR) 2.07, 95% CI 1.98-2.18] and mortality (adjusted HR 2.73, 95% CI 1.73-4.29) over 5 years' follow-up. Higher absenteeism partially explained poorer attainment and unemployment. Treatment with antidepressants was less common among boys than girls (0.5% vs 1.0%) but the associations with special educational need and unemployment were stronger in boys., Conclusions: Children receiving antidepressants fare worse than their peers across a wide range of education and health outcomes. Interventions to reduce absenteeism or mitigate its effects should be investigated., (© The Author(s) 2020. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Hypertensive disorders during pregnancy are an important risk to mother and fetus, frequently necessitating antihypertensive treatment. Data describing the safety of in utero exposure to antihypertensive treatment is conflicting, with many studies suffering from significant methodological issues, such as inappropriate study design, small sample sizes, and no untreated control group. We conducted a retrospective cohort study using linked routinely collected healthcare records for 268 711 children born 2010-2014 in Scotland to assess outcomes following in utero exposure to antihypertensive medication. We identified a cohort of 265 488 eligible children born over the study period; of which, 2350 were exposed to in utero antihypertensive medication, 4391 exposed to treated late-onset hypertension, and 7971 exposed to untreated hypertension during pregnancy. Untreated hypertension was associated with increased risk of preterm birth (adjusted risk ratio [aRR], 1.15 [99% CI, 1.01-1.30]), low birth weight (aRR, 2.01 [99% CI, 1.72-2.36]) and being small for gestational age (aRR, 1.50 [99% CI, 1.35-1.66]), while in utero antihypertensive exposure was also associated with preterm birth (aRR, 3.12 [99% CI, 2.68-3.64]), low birth weight (aRR, 2.23 [99% CI, 1.79-2.78]), and being small for gestational age (aRR, 2.13 [99% CI, 1.81-2.52]). Late-onset hypertension was also associated with preterm birth (aRR, 2.21 [99% CI, 1.86-2.62]), low birth weight (aRR, 2.06 [99% CI, 1.74-2.43]), and being small for gestational age (aRR, 1.90 [99% CI, 1.68-2.16]). Our results suggest that hypertension is a key risk factor for low birth weight and preterm birth. Although preterm birth may be associated with antihypertensive medication exposure during pregnancy, these associations may reflect increasing hypertension severity necessitating treatment.

Objective: The aim of this study is to systematically review published studies, reporting outcomes to offspring following in utero exposure to antidepressant medications, which used an untreated depressed comparison group., Methods: OVID, Scopus, EBSCO Collections, the Cochrane Library and Web of Science databases were searched for relevant publications published between January 1950 and May 2018 and a total of 188 potentially eligible studies were identified., Results: Following review, 16 primary studies were eligible for inclusion. Antidepressant exposure was associated with an increased risk of lower gestational age, preterm birth, but not low birthweight or being small for gestational age compared to untreated depression. There is some evidence that congenital defects are associated with antidepressant use, particularly between cardiac defects and paroxetine use. There is conflicting evidence regarding neurodevelopment in offspring, with some reports of increased incidence of autistic spectrum disorders and depression, but also reports of no problems when measuring emotional symptoms, peer problems, conduct problems and hyperactivity-inattention scores., Conclusion: When compared with an untreated depressed group, antidepressant exposure was associated with adverse outcomes at birth, while there is insufficient data to determine whether the association between antidepressants and congenital defects or developmental disorders is a true association. However, although we compared treated vs. untreated depression there still may be residual confounding as an untreated depressed group is likely to have less severe depression., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: The global prevalence of childhood asthma is increasing. The condition impacts physical and psychosocial morbidity; therefore, wide-ranging effects on health and education outcomes are plausible., Methods: Linkage of eight Scotland-wide databases, covering dispensed prescriptions, hospital admissions, maternity records, death certificates, annual pupil census, examinations, school absences/exclusions and unemployment, provided data on 683 716 children attending Scottish schools between 2009 and 2013. We compared schoolchildren on medication for asthma with peers, adjusting for sociodemographic, maternity and comorbidity confounders, and explored effect modifiers and mediators., Results: The 45 900 (6.0%) children treated for asthma had an increased risk of hospitalisation, particularly within the first year of treatment (incidence rate ratio 1.98, 95% CI 1.93-2.04), and increased mortality (HR 1.77, 95% CI 1.30-2.40). They were more likely to have special educational need for mental (OR 1.76, 95% CI 1.49-2.08) and physical (OR 2.76, 95% CI 2.57-2.95) health reasons, and performed worse in school exams (OR 1.11, 95% CI 1.06-1.16). Higher absenteeism (incidence rate ratio 1.25, 95% CI 1.24-1.26) partially explained their poorer attainment., Conclusions: Children with treated asthma have poorer education and health outcomes than their peers. Educational interventions that mitigate the adverse effects of absenteeism should be considered., Competing Interests: Conflict of interest: M. Fleming has nothing to disclose. Conflict of interest: C.A. Fitton has nothing to disclose. Conflict of interest: M.F.C. Steiner has nothing to disclose. Conflict of interest: J.S. McLay has nothing to disclose. Conflict of interest: D. Clark has nothing to disclose. Conflict of interest: A. King has nothing to disclose. Conflict of interest: D.F. Mackay has nothing to disclose. Conflict of interest: J.P. Pell has nothing to disclose., (Copyright ©ERS 2019.)

Objective: This study was conducted to determine the association between childhood type 1 diabetes and educational and health outcomes., Research Design and Methods: Record linkage of nine Scotland-wide databases (diabetes register, dispensed prescriptions, maternity records, hospital admissions, death certificates, annual pupil census, school absences/exclusions, school examinations, and unemployment) produced a cohort of 766,047 singleton children born in Scotland who attended Scottish schools between 2009 and 2013. We compared the health and education outcomes of schoolchildren receiving insulin with their peers, adjusting for potential confounders., Results: The 3,330 children (0.47%) treated for type 1 diabetes were more likely to be admitted to the hospital (adjusted hazard ratio [HR] 3.97, 95% CI 3.79-4.16), die (adjusted HR 3.84, 95% CI 1.98-7.43), be absent from school (adjusted incidence rate ratio [IRR] 1.34, 95% CI 1.30-1.39), and have learning difficulties (adjusted odds ratio [OR] 1.19, 95% CI 1.03-1.38). Among children with type 1 diabetes, higher mean HbA 1c (particularly HbA 1c in the highest quintile) was associated with greater absenteeism (adjusted IRR 1.75, 95% CI 1.56-1.96), increased school exclusion (adjusted IRR 2.82, 95% CI 1.14-6.98), poorer attainment (adjusted OR 3.52, 95% CI 1.72-7.18), and higher risk of unemployment (adjusted OR 2.01, 95% CI 1.05-3.85)., Conclusions: Children with type 1 diabetes fare worse than their peers in respect of education and health outcomes, especially if they have higher mean HbA 1c . Interventions are required to minimize school absence and ensure that it does not affect educational attainment., (© 2019 by the American Diabetes Association.)

Background: Childhood epilepsy can adversely affect education and employment in addition to health. Previous studies are small or highly selective producing conflicting results. This retrospective cohort study aims to compare educational and health outcomes of children receiving antiepileptic medication versus peers., Methods: Record linkage of Scotland-wide databases covering dispensed prescriptions, acute and psychiatric hospitalisations, maternity records, deaths, annual pupil census, school absences/exclusions, special educational needs, school examinations, and (un)employment provided data on 766,244 children attending Scottish schools between 2009 and 2013. Outcomes were adjusted for sociodemographic and maternity confounders and comorbid conditions., Results: Compared with peers, children on antiepileptic medication were more likely to experience school absence (Incidence Rate Ratio [IRR] 1.43, 95% CI: 1.38, 1.48), special educational needs (Odds ratio [OR] 9.60, 95% CI: 9.02, 10.23), achieve the lowest level of attainment (OR 3.43, 95% CI: 2.74, 4.29) be unemployed (OR 1.82, 95% CI: 1.60, 2.07), be admitted to hospital (Hazard Ratio [HR] 3.56, 95% CI: 3.42, 3.70), and die (HR 22.02, 95% CI: 17.00, 28.53). Absenteeism partly explained poorer attainment and higher unemployment. Girls and younger children on antiepileptic medication had higher risk of poor outcomes., Conclusions: Children on antiepileptic medication fare worse than peers across educational and health outcomes. In order to reduce school absenteeism and mitigate its effects, children with epilepsy should receive integrated care from a multidisciplinary team that spans education and healthcare.

Objective: To report the incidence and nature of herbal medicinal products' adverse events and herb-drug interactions used by some pregnant and postnatal women., Data Sources: The Allied and Complementary Medicine Database, the Cumulative Index to Nursing and Allied Health Literature, EMBASE, the Cochrane Library, MEDLINE, Scopus, Web of Science, and ClinicalTrials.gov were searched from inception until August 2018., Methods of Study Selection: Any studies reporting adverse events, herb-drug interactions or absence thereof associated with herbal medicinal products used during pregnancy or the postnatal period were included. Conference abstracts, pilot studies, and nonhuman studies were excluded. All included studies were critically appraised by two independent reviewers., Tabulation, Integration and Results: Database searches retrieved 3,487 citations. After duplicate removal and review of titles, abstracts, and full-text, 115 articles were critically appraised. After excluding irrelevant and low-quality articles, 74 articles were included for data extraction and synthesis. Adverse drug reactions, congenital malformations, fetal growth retardation or herb-drug interactions were the primary study objective reported by 19 of the 74 included studies, 16 cohort studies, one cross-sectional survey, and two randomized controlled trials. A total of 47 herbal medicinal products and 1,067,071 women were included in this review. Use of almond oil was associated with preterm birth (odds ratio 2.09, 95% CI 1.07-4.08), oral raspberry leaf was associated with cesarean delivery (adjusted odds ratio [AOR] 3.47, 95% CI 1.45-8.28); heavy licorice use was associated with early preterm birth by 3.07-fold (95% CI 1.17-8.05). African herbal medicine mwanaphepo was associated with maternal morbidity (AOR 1.28; 95% CI 1.09-1.50), and neonatal death or morbidity. Fourteen studies reported absence of adverse events. Four studies reported herb-drug interactions, but none studied adverse events arising from them., Conclusion: The use of herbal medicinal products during pregnancy and the postnatal period should be discouraged until robust evidence of safety is available., Systematic Review Registration: PROSPERO, CRD42017081058.

Background: There is a need for theory informed interventions to optimise medication reporting. This study aimed to quantify and explain behavioural determinants relating to error reporting of healthcare professionals in Qatar as a basis of developing interventions to optimise the effectiveness and efficiency of error reporting., Methods: A sequential explanatory mixed methods design comprising a cross-sectional survey followed by focus groups in Hamad Medical Corporation, Qatar. All doctors, nurses and pharmacists were invited to complete a questionnaire that included items of behavioural determinants derived from the Theoretical Domains Framework (TDF), an integrative framework of 33 theories of behaviour change. Principal component analysis (PCA) was used to identify components, with total component scores computed. Differences in total scores among demographic groupings were tested using Mann-Whitney U test (2 groups) or Kruskal-Wallis (>2 groups). Respondents expressing interest in focus group participation were sampled purposively, and discussions based on survey findings using the TDF to provide further insight to survey findings. Ethical approval was received from Hamad Medical Corporation, Robert Gordon University, and Qatar University., Results: One thousand, six hundred and four questionnaires were received (67.9% nurses, 13.3% doctors, 12.9% pharmacists). Questionnaire items clustered into six components of: knowledge and skills related to error reporting; feedback and support; action and impact; motivation; effort; and emotions. There were statistically significant higher scores in relation to age (older more positive, p<0.001), experience as a healthcare professional (more experienced most positive apart from those with the highest level of experience, p<0.001), and profession (pharmacists most positive, p<0.05). Fifty-four healthcare professionals from different disciplines participated in the focus groups. Themes mapped to nine of fourteen TDF domains. In terms of emotions, the themes that emerged as barriers to error reporting were: fear and worry on submitting a report; that submitting was likely to lead to further investigation that could impact performance evaluation and career progression; concerns over the impact on working relationships; and the potential lack of confidentiality., Conclusions: This study has quantified and explained key facilitators and barriers of medication error reporting. Barriers appeared to be largely centred on issues relating to emotions and related beliefs of consequences. Quantitative results demonstrated that while these were issues for all healthcare professionals, those younger and less experienced were most concerned. Qualitative findings highlighted particular concerns relating to these emotional aspects. These results can be used to develop theoretically informed interventions with the aims of improving the effectiveness and efficiency of the medication reporting systems impacting patient safety., Competing Interests: The authors have declared that no competing interests exist.

Background: There is a lack of robust, rigorous mixed methods studies of patient safety culture generally and notably those which incorporate behavioural theories of change. The study aimed to quantify and explain key aspects of patient safety culture which were of most concern to healthcare professionals in Qatar., Methods: A sequential explanatory mixed methods design of a cross-sectional survey followed by focus groups in Hamad Medical Corporation, Qatar. All doctors, nurses and pharmacists were invited to complete the Hospital Survey on Patient Safety Culture (HSOPS). Respondents expressing interest in focus group participation were sampled purposively, and discussions based on survey findings using the Theoretical Domains Framework (TDF) to explain behavioural determinants., Results: One thousand, six hundred and four questionnaires were received (67.9% nurses, 13.3% doctors, 12.9% pharmacists). HSOPS composites with the lowest levels of positive responses were non-punitive response to errors (24.0% positive) and staffing (36.2%). Specific TDF determinants potentially associated with these composites were social/professional role and identity, emotions, and environmental context and resources. Thematic analysis identified issues of doctors relying on pharmacists to correct their errors and being reluctant to alter the prescribing of fellow doctors. There was a lack of recognition of nurses' roles and frequent policy non-adherence. Stress, workload and lack of staff at key times were perceived to be major contributors to errors., Conclusions: This study has quantified areas of concern relating to patient safety culture in Qatar and suggested important behavioural determinants. Rather than focusing on changing behaviour at the individual practitioner level, action may be required at the organisational strategic level to review policies, structures (including resource allocation and distribution) and processes which aim to promote patient safety culture., Competing Interests: The authors have declared that no competing interests exist.

Aims: Applying version 2 of the STOPP/START criteria to discharge prescriptions of older adults discharged from a general medical unit, the aim of this study is to assess potentially inappropriate medications (PIMs) and potential prescribing omissions (PPOs) and their association with hospital readmission and mortality., Methods: Discharge medications, co-morbidities and patient demographics were recorded over an 8-month period for consecutive emergency admissions of patients aged ≥65 years. PIMs and PPOs were identified using version 2 of the STOPP/START criteria. Multivariate analysis for association of PIMs and PPOs with re-admissions and mortality during the follow-up period were assessed using binary logistic regression., Results: Data for 259 patients with a mean age of 77 (65-99, 51% female) were analysed. At discharge, the mean number of co-morbidities and medications per patient were 5.4 (SD: 2.1 range: 0-14) and 9.3 (SD: 4.0 range: 1-31) respectively. During the follow-up period (mean 41.5 months, SD: 2.0 range: 38-46 months), 50.2% of patients had died and the median number of readmissions was two (IQR: 1-4 range: 0-33). Prescription of more than five medications was significantly associated with PIMs and PPOs (OR: 2.75, 95% CI: 1.34-5.62 and OR 3.20, 95% CI: 1.57-6.54 respectively). Presence of a PIM was associated with three or more readmissions (OR: 2.43 95% CI: 1.19-4.98) and PPOs with mortality (OR: 1.88, 95% CI: 1.09-3.27)., Conclusions: Using version 2 of the STOPP/START criteria, the presence of PIMs and/or PPOs in older adults discharged from hospital is significantly associated with repeated hospital admissions and mortality respectively., (© 2018 The British Pharmacological Society.)

Background: Intravenous ketorolac is commonly administered to children for the control of postoperative pain. An effect site EC 50 for analgesia of 0.37 mg . L -1 is described in adults., Aims: The aim of this study was to review age- and weight-related effects on ketorolac pharmacokinetic parameters in children and current dosing schedules., Methods: Pooled intravenous ketorolac (0.5 mg . kg -1 ) concentration-time data in children aged 2 months to 16 years were analyzed using nonlinear mixed-effects models. Allometry was used to scale to a 70 kg person., Results: There were 64 children aged 2 months to 16 years (641 plasma concentrations) available for analysis. A two-compartment mammillary model was used to describe pharmacokinetics. Clearance was 2.53 (CV 45.9%) L . h -1. 70 kg -1 and intercompartment clearance was 4.43 (CV 95.6%) L . h -1. 70 kg -1 . Both central (V1) and peripheral (V2) volumes of distribution decreased with age over the first few years of postnatal life to reach V1 6.89 (CV 30.3%) L . 70 kg -1 and V2 5.53 (CV 47.6%) L . 70 kg -1 ., Conclusion: Clearance, expressed as L . h -1. kg -1 , decreased with age from infancy. A dosing regimen of 0.5 mg . kg -1 every 6 hours maintains a trough concentration larger than 0.37 mg . L -1 in children 9 months to 16 years of age. This dosing regimen is consistent with current recommendations., (© 2017 John Wiley & Sons Ltd.)

Background: Pregnant women are routinely prescribed medicines while self-medicating with herbal natural products to treat predominantly pregnancy related conditions. The aim of this study was to assess the potential for herb-drug interactions (HDIs) in pregnant women and to explore possible herb-drug interactions and their potential clinical significance., Methods: A cross-sectional survey of women during early pregnancy or immediately postpartum in North-East Scotland. Outcome measures included; Prescription medicines use excluding vitamins and potential HDIs assessed using Natural Medicines Comprehensive Database., Results: The survey was completed by 889 respondents (73% response rate). 45.3% (403) reported the use of at least one prescription medicine, excluding vitamins. Of those taking prescription medicines, 44.9% (181) also reported concurrent use of at least one HNP (Range 1-12). A total of 91 different prescription medicines were reported by respondents using HNPs. Of those taking prescription medicines, 44.9% (181) also reported concurrent use of at least one HNP (Range 1-12). Thirty-four herb-drug interactions were identified in 23 (12.7%) women with the potential to increase the risk of postpartum haemorrhage, alter maternal haemodynamics, and enhance maternal/fetal CNS depression. Almost all were rated as moderate (93.9%), one as a potentially major (ginger and nifedipine) and only one minor (ondansetron and chamomile)., Conclusion: Almost half of pregnant women in this study were prescribed medicines excluding vitamins and minerals and almost half of these used HNPs. Potential moderate to severe HDIs were identified in an eighth of the study cohort. Healthcare professionals should be aware that the concurrent use of HNPs and prescription medicines during pregnancy is common and carries potential risks.

Background: Although medication is generally avoided wherever possible during pregnancy, pharmacotherapy is required for the treatment of pregnancy associated hypertension, which remains a leading cause of maternal and fetal morbidity and mortality. The long-term effects to the child of in-utero exposure to antihypertensive agents remains largely unknown., Objective: The aim of this study was to systematically review published studies on adverse outcomes to the child associated with in-utero exposure to antihypertensive medications., Methods: OVID, Scopus, EBSCO Collections, the Cochrane Library, and Web of Science databases were searched for relevant publications published between January 1950 and October 2016 and a total of 688 potentially eligible studies were identified., Results: Following review, 47 primary studies were eligible for inclusion. The Critical Appraisal Skills Programme checklist was used to assess study quality. Five studies were of excellent quality; the remainder were either mediocre or poor. Increased risk of low birth weight, low size for gestational age, preterm birth, and congenital defects following in-utero exposure to all antihypertensive agents were identified. Two studies reported an increased risk of attention deficit hyperactivity disorder following exposure to labetalol, and an increased risk of sleep disorders following exposure to methyldopa and clonidine., Conclusion: The current systematic review demonstrates a paucity of relevant published high-quality studies. A small number of studies suggest possible increased risk of adverse child health outcomes; however, most published studies have methodological weaknesses and/or lacked statistical power thus preventing any firm conclusions being drawn.

Importance: Attention-deficit/hyperactivity disorder (ADHD) affects 39 million people worldwide; in isolation, it doubles annual health care costs and, when associated with comorbid mental health problems, it quadruples the costs., Objective: To compare the education and health outcomes of schoolchildren treated for ADHD with their peers., Design, Setting, and Participants: In this population-based cohort study, individual-level record linkage was performed of 8 Scotland-wide administrative databases covering dispensed prescriptions, admissions to acute and psychiatric hospitals, maternity records, annual pupil census, examinations, school absences and exclusions, and unemployment. The study cohort comprised 766 244 children attending Scottish primary, secondary, and special schools at any point between September 21, 2009, and September 18, 2013. Data analysis was performed from June 1, 2015, to December 6, 2016., Exposures: Medication approved solely for ADHD treatment., Main Outcomes and Measures: Special educational needs, academic attainment, unauthorized absence, exclusion, age at leaving school, unemployment after leaving, and hospitalization. Outcomes were adjusted for potential sociodemographic, maternity, and comorbidity confounders., Results: Of the 766 244 schoolchildren, 7413 (1.0%) were treated for ADHD; 6287 (84.8%) were male. These children had higher rates of unauthorized absence (adjusted incidence rate ratio [IRR], 1.16; 95% CI, 1.14-1.19) and exclusion (adjusted IRR, 5.79; 95% CI, 5.45-6.16), more commonly had a record of special educational need (adjusted odds ratio [OR], 8.62; 95% CI, 8.26-9.00), achieved lower academic attainment (adjusted OR, 3.35; 95% CI, 3.00-3.75), were more likely to leave school before age 16 years (1546 [64.3%] vs 61 235 [28.4%]), and were more likely to be unemployed (adjusted OR, 1.39; 95% CI, 1.25-1.53). Children with ADHD were more likely to require hospitalization overall (adjusted hazard ratio [HR], 1.25; 95% CI, 1.19-1.31) and for injury (adjusted HR, 1.52; 95% CI, 1.40-1.65)., Conclusions and Relevance: Even while receiving medication, children with ADHD fare worse than their peers across a wide range of outcomes relating not only to education but also to health.

Aims: To assess the prevalence of potentially inappropriate medications (PIMs) use in a population of community-based multicompartment compliance aid (MCA) users in north-east Scotland., Methods: Data for MCAs dispensed by 48 of the 50 community pharmacies in Aberdeen City between 1 st June to 31 st October 2014, together with concurrently prescribed medications, patient demographics and Carstairs index of social deprivation were recorded. Drug-specific quality indicators for PIMs from the Swedish National Board of Health and Welfare were applied and bivariate logistic regression analysis used to assess for associations with demographic variables., Results: The median age was 82 years (range 12-105 years, 59% female). A total of 1977 PIMs were identified affecting 57.8% of patients. A quarter of patients were prescribed ≥10 medications and 43% had a prescription containing at least one clinically significant drug-drug interaction (DDI). Ten drug groups accounted for 76% of all DDIs. A significant increase in the risk for at least one PIM was associated with female sex (for all indicators of PIM use), age <80 years (three or more psychotropic medicines [OR 5.88, 2.96-11.70, P < 0.001]) and lower socioeconomic status (prescription of ≥10 medications [OR: 1.43, 95% CI: 1.16-1.78], prescription of a long-acting benzodiazepine [OR: 1.84, CI: 1.14-2.98])., Conclusions: MCA use is associated with a significant incidence of PIMs particularly affecting those younger than 80 years and those living in deprived areas. Our findings indicate the need for a more aggressive multidisciplinary approach to the review of the medications prescribed to MCA users., (© 2016 The British Pharmacological Society.)

Background: Over the last decade academic interest in the prevalence and nature of herbal medicines use by pregnant women has increased significantly. Such data are usually collected by means of an administered questionnaire survey, however a key methodological limitation using this approach is the need to clearly define the scope of 'herbals' to be investigated. The majority of published studies in this area neither define 'herbals' nor provide a detailed checklist naming specific 'herbals' and CAM modalities, which limits inter-study comparison, generalisability and the potential for meta-analyses. The aim of this study was to compare the self-reported use of herbs, herbal medicines and herbal products using two different approaches implemented in succession., Methods: Cross-sectional questionnaire surveys of women attending for their mid-trimester scan or attending the postnatal unit following live birth at the Royal Aberdeen Maternity Hospital, North-East Scotland. The questionnaire utilised two approaches to collect data on 'herbals' use, a single closed yes/no answer to the question "have you used herbs, herbal medicines and herbal products in the last three months"; and a request to tick which of a list of 40 'herbals' they had used in the same time period., Results: A total of 889 responses were obtained of which 4.3% (38) answered 'yes' to herbal use via the closed question. However, using the checklist 39% (350) of respondents reported the use of one or more specific 'herbals' (p<0.0001). The 312 respondents who reported 'no' to 'herbals' use via the closed question but "yes" via the checklist consumed a total of 20 different 'herbals' (median 1, interquartile range 1-2, range 1-6)., Conclusions: This study demonstrates that the use of a single closed question asking about the use of 'herbals', as frequently reported in published studies, may not yield valid data resulting in a gross underestimation of actual use.

Objective: To describe the effect of age and body size on enantiomer selective pharmacokinetic (PK) of intravenous ketorolac in children using a microanalytical assay., Methods: Blood samples were obtained at 0, 15 and 30 min and at 1, 2, 4, 6, 8 and 12 h after a weight-dependent dose of ketorolac. Enantiomer concentration was measured using a liquid chromatography tandem mass spectrometry method. Non-linear mixed-effect modelling was used to assess PK parameters., Key Findings: Data from 11 children (1.7-15.6 years, weight 10.7-67.4 kg) were best described by a two-compartment model for R(+), S(-) and racemic ketorolac. Only weight (WT) significantly improved the goodness of fit. The final population models were CL = 1.5 × (WT/46)(0.75) , V1  = 8.2 × (WT/46), Q = 3.4 × (WT/46)(0.75) , V2  = 7.9 × (WT/46), CL = 2.98 × (WT/46), V1  = 13.2 × (WT/46), Q = 2.8 × (WT/46)(0.75) , V2  = 51.5 × (WT/46), and CL = 1.1 × (WT/46)(0.75) , V1  = 4.9 × (WT/46), Q = 1.7 × (WT/46)(0.75) and V2  = 6.3 × (WT/46)for R(+), S(-) and racemic ketorolac., Conclusions: Only body weight influenced the PK parameters for R(+) and S(-) ketorolac. Using allometric size scaling significantly affected the clearances (CL, Q) and volumes of distribution (V1 , V2 )., (© 2015 Royal Pharmaceutical Society.)

Objective: To estimate the prevalence, indications, and associated factors for complementary and alternative medicine use during the last trimester of pregnancy., Methods: A questionnaire survey was conducted of women with a live birth (N=700) admitted to the postnatal unit at the Royal Aberdeen Maternity Hospital, northeast Scotland. Outcome measures included: complementary and alternative medicine used; vitamins and minerals used; reasons for complementary and alternative medicine use; independent associated factors for use; views; and experiences. Descriptive and inferential statistical analysis was performed., Results: The response rate was 79.6% of eligible women. Two thirds of respondents (61.4%) reported using complementary and alternative medicine, excluding vitamins and minerals, during the third trimester. Respondents reported using a total of 30 different complementary and alternative medicine modalities, of which oral herbal products were the most common (38% of respondents, 40 different products). The independent associated factors for complementary and alternative medicine use identified were: complementary and alternative medicine use before pregnancy (odds ratio [OR] 4.36, 95% confidence interval [CI] 2.39-7.95, P<.001); a university education (OR 2.41, 95% CI 1.46-4.0, P=.001), and complementary and alternative medicine use by family or friends (OR 2.36, 95% CI 1.61-3.47, P<.001). There was no association with health care professional recommendations. Users were significantly more likely than nonusers to agree that complementary and alternative medicines were safer than prescribed medicines (P=.006), less likely to be associated with side effects (P≤.001), and could interfere with conventional medicines (P≤.001)., Conclusion: Despite the majority of respondents, and notably users, being uncertain about their safety and effectiveness, complementary and alternative medicine modalities and complementary and alternative medicine products are widely used during the third trimester of pregnancy in this study population. Although prior use was the most significant independent associated factor, the role of family and friends, rather than health professionals, in the decision to use complementary and alternative medicine may be of concern., Level of Evidence: III.

Objective: To determine the prevalence and explore predictors of Complementary and Alternative Medicine (CAM) use during early pregnancy., Study Design: A questionnaire survey of pregnant women (500) attending for mid trimester scan at the maternity services in Grampian, North-East Scotland. Outcome measures included; CAM used; vitamins and minerals used; independent predictors of use; views and experiences. Descriptive and inferential statistical analysis., Results: The response rate was 66%. Two thirds of respondents (63%) reported using CAM, excluding vitamins and minerals, during early pregnancy. Respondents reported using a total of 28 different CAM modalities, of which oral herbal products were the most common (37% of respondents, 25 different products). The independent predictors of CAM use identified were: use by family and friends (OR 4.1, 95% CI 2.3-7.3, p<0.001); ethnicity (non-white British) (OR 3.4, 95% CI 1.8-6.8, p<0.001); and use prior to pregnancy (OR 2.4, 95% CI 1.2-4.8, p=0.014). In comparison to prescribed medicines, most users were uncertain if CAM were safer (63%), more effective (66%), free from possible adverse effects (46%) or drug-CAM interactions (50%)., Conclusions: Despite the majority of respondents being uncertain about their safety and effectiveness, CAM modalities and CAM products are widely used during the early stages of pregnancy in this study population. The role of family and friends rather than health professionals in the decision to use CAM may be of concern and requires further investigation., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background: Because of relatively small treatment numbers together with low adverse drug reaction (ADR) reporting rates the timely identification of ADRs affecting children and young people is problematic. The primary objective of this study was to assess the utility of unplanned medication discontinuation as a signal for possible ADRs in children and young people., Methods: Using orlistat as an exemplar, all orlistat prescriptions issued to patients up to 18 years of age together with patient characteristics, prescription duration, co-prescribed medicines and recorded clinical (Read) codes were identified from the Primary Care Informatics Unit database between 1st Jan 2006-30th Nov 2009. Binary logistic regression was used to assess association between characteristics and discontinuation., Results: During the study period, 79 patients were prescribed orlistat (81% female, median age 17 years). Unplanned medication discontinuation rates for orlistat were 52% and 77% at 1 and 3-months. Almost 20% of patients were co-prescribed an anti-depressant. One month unplanned medication discontinuation was significantly lower in the least deprived group (SIMD 1-2 compared to SIMD 9-10 OR 0.09 (95% CI0.01 - 0.83)) and those co-prescribed at least one other medication. At 3 months, discontinuation was higher in young people (≥17 yr versus, OR 3.07 (95% CI1.03 - 9.14)). Read codes were recorded for digestive, respiratory and urinary symptoms around the time of discontinuation for 24% of patients. Urinary retention was reported for 7.6% of patients., Conclusions: Identification of unplanned medication discontinuation using large primary care datasets may be a useful tool for pharmacovigilance signal generation and detection of potential ADRs in children and young people.