The effect of mode of delivery on health-related quality-of-life in mothers: a systematic review and meta-analysis.

BACKGROUND: Previous research is inconclusive on the effects of mode of delivery on maternal health-related quality-of-life (HRQoL). We conducted a systematic review and meta-analysis to assess the current evidence for associations between mode of delivery and postpartum health-related quality-of-life. METHODS: Electronic databases MEDLINE ALL (OVID), Web of Science, The Cochrane Library, CINAHL and EMBASE (OVID) were searched for English written articles investigating the relationship between mode of delivery and quality-of-life published form inception to 15th October 2020. Two reviewers independently screened titles and abstracts, assessed full texts, and extracted data. Meta-analysis was conducted where possible. RESULTS: Twenty-one studies, including 19,879 women, met the inclusion criteria. A meta-analysis of 18 studies found HRQoL scores were significantly higher for women after vaginal delivery in comparison to caesarean (emergency and elective combined) (Effect Size (ES) 0.17, 95% CI 0.01-0.25, n = 7665) with highest scores after assisted vaginal delivery (ES 0.21, 95% CI 0.13-0.30, n = 2547). Physical functioning (ES 11.18, 95% CI = 2.29-20.06, n = 1746), physical role (ES 13.10, 95% CI = 1.16-25.05, n = 1471), vitality (ES 6.31, 95% CI = 1.14-10.29, n = 1746) and social functioning (ES 5.69, 95% CI = 1.26-10.11, n = 1746) were significantly higher after vaginal delivery compared to caesarean. CONCLUSIONS: Health-related quality-of-life scores were higher for women after vaginal delivery in comparison to caesarean section. Consequently, women should be encouraged to deliver vaginally where possible. The findings of this research should be available to the relevant population to help support informed choice.

Association between vitamin D supplementation or serum vitamin D level and susceptibility to SARS-CoV-2 infection or COVID-19 including clinical course, morbidity and mortality outcomes? A systematic review.

OBJECTIVE: To systemically review and critically appraise published studies of the association between vitamin D supplementation or serum vitamin D level and susceptibility to SARS-CoV-2 infection or COVID-19, including clinical course, morbidity and mortality outcomes. DESIGN: Systematic review. DATA SOURCES: MEDLINE (OVID), Embase (OVID), Cochrane Central Register of Controlled Trials, MedRxiv and BioRxiv preprint databases. COVID-19 databases of the WHO, Cochrane, CEBM Oxford and Bern University up to 10 June 2020. STUDY SELECTION: Studies that assessed vitamin D supplementation and/or low serum vitamin D in patients acutely ill with, or at risk of, severe betacoronavirus infection (SARS-CoV, MERS-CoV, SARS-CoV-2). DATA EXTRACTION: Two authors independently extracted data using a predefined data extraction form and assessed risk of bias using the Downs and Black Quality Assessment Checklist. RESULTS: Searches elicited 449 papers, 59 studies were eligible full-text assessment and 4 met the eligibility criteria of this review. The four studies were narratively synthesised and included (1) a cross-sectional study (n=107) suggesting an inverse association between serum vitamin D and SARS-CoV-2; (2) a retrospective cohort study (348 598 participants, 449 cases) in which univariable analysis showed that vitamin D protects against COVID-19; (3) an ecological country level study demonstrating a negative correlation between vitamin D and COVID-19 case numbers and mortality; and (4) a case-control survey (n=1486) showing cases with confirmed/probable COVID-19 reported lower vitamin D supplementation. All studies were at high/unclear risk of bias. CONCLUSION: There is no robust evidence of a negative association between vitamin D and COVID-19. No relevant randomised controlled trials were identified and there is no robust peer-reviewed published evidence of association between vitamin D levels and severity of symptoms or mortality due to COVID-19. Guideline producers should acknowledge that benefits of vitamin D supplementation in COVID-19 are as yet unproven despite increasing interest.

Information given by websites selling home self-sampling COVID-19 tests: an analysis of accuracy and completeness.

OBJECTIVES: To assess the accuracy and completeness of information provided by websites selling home self-sampling and testing kits for COVID-19. DESIGN: Cross-sectional observational study. SETTING: All websites (n=27) selling direct to user home self-sampling and testing kits for COVID-19 (41 tests) in the UK (39 tests) and USA (two tests) identified by a website search on 23 May 2020. MAIN OUTCOME MEASURES: Thirteen predefined basic information items to communicate to a user, including who should be tested, when and how testing should be done, test accuracy, and interpretation of results. RESULTS: Many websites did not provide the name or manufacturer of the test (32/41; 78%), when to use the test (10/41; 24%), test accuracy (12/41; 29%), and how to interpret results (21/41; 51%). Sensitivity and specificity were the most commonly reported test accuracy measures (either reported for 27/41 [66%] tests): we could only link these figures to manufacturers' documents or publications for four (10%) tests. Predictive values, most relevant to users, were rarely reported (five [12%] tests reported positive predictive values). For molecular virus tests, 9/23 (39%) websites explained that test positives should self-isolate, and 8/23 (35%) explained that test negatives may still have the disease. For antibody tests, 12/18 (67%) websites explained that testing positive does not necessarily infer immunity from future infection. Seven (39%) websites selling antibody tests claimed the test had a CE mark, when they were for a different intended use (venous blood rather than finger-prick samples). CONCLUSIONS: At the point of online purchase of home self-sampling COVID-19 tests, users in the UK are provided with incomplete, and, in some cases, misleading information on test accuracy, intended use, and test interpretation. Best practice guidance for communication about tests to the public should be developed and enforced for online sales of COVID-19 tests.

COVID-19 in cardiac arrest and infection risk to rescuers: A systematic review.

BACKGROUND: There may be a risk of COVID-19 transmission to rescuers delivering treatment for cardiac arrest. The aim of this review was to identify the potential risk of transmission associated with key interventions (chest compressions, defibrillation, cardiopulmonary resuscitation) to inform international treatment recommendations. METHODS: We undertook a systematic review comprising three questions: (1) aerosol generation associated with key interventions; (2) risk of airborne infection transmission associated with key interventions; and (3) the effect of different personal protective equipment strategies. We searched MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and the World Health Organization COVID-19 database on 24th March 2020. Eligibility criteria were developed individually for each question. We assessed risk of bias for individual studies, and used the GRADE process to assess evidence certainty by outcome. RESULTS: We included eleven studies: two cohort studies, one case control study, five case reports, and three manikin randomised controlled trials. We did not find any direct evidence that chest compressions or defibrillation either are or are not associated with aerosol generation or transmission of infection. Data from manikin studies indicates that donning of personal protective equipment delays treatment delivery. Studies provided only indirect evidence, with no study describing patients with COVID-19. Evidence certainty was low or very low for all outcomes. CONCLUSION: It is uncertain whether chest compressions or defibrillation cause aerosol generation or transmission of COVID-19 to rescuers. There is very limited evidence and a rapid need for further studies. Review registration: PROSPERO CRD42020175594.

Real-World Evidence to Assess Medication Safety or Effectiveness in Children: Systematic Review.

BACKGROUND: The promise of real-world evidence (RWE) is especially relevant to pediatrics, where medicines prescribed for children are often used without evidence derived from randomized clinical trials. OBJECTIVES: The aim of this systematic review was to describe the state of RWE in pediatrics by identifying observational studies published during 2016 that used RWE to assess medication safety or effectiveness in children. METHODS: An electronic search of PubMed was combined with an extended search of references within systematic reviews and expert suggestions. Studies were included if they reported on an infant or child under 18 years with exposure to medications; assessed safety or effectiveness; specified a comparison or control group, and were published in English in 2016. Data extraction was conducted by one team member using a standardized form and reviewed by a second team member. Study quality was assessed using the GRACE checklist for rating the quality of observational studies. RESULTS: After removing duplicates, 915 citations were screened and 29 studies met the eligibility criteria. Most of the eligible studies relied on primary data collection or chart review at a single institution and did not use the growing number of administrative or electronic health record databases available. One-quarter of the studies did not use well-established statistical methods to control for confounders. No single disease group or medication predominated, and age groups ranged from infants to adolescents. CONCLUSIONS: A small body of observational studies published in 2016 were categorized by the study team as using real-world data to assess medication safety or effectiveness in children. Studies varied in age groups, diseases or conditions, and methods, and may not have fully met the FDA definition of RWE. Our review indicates that the use of RWE is not fully developed in pediatrics, and suggests an opportunity to further develop capabilities and more fully leverage administrative and electronic health record databases to study medication safety and effectiveness in children. Our systematic review appears generalizable to pediatrics broadly, and documents that the high level of activity in RWE in general has had less of an impact on pediatrics.

Comparing drug effectiveness in children: A systematic review.

PURPOSE: The purpose of the study is to assess the current state of the art in pediatric comparative effectiveness research, potential gaps, and areas for improvement. METHODS: Relevant articles from inception to February 2015 were retrieved from Embase and Medline. We sequentially screened titles, abstracts, and full texts, with independent validation. Data regarding general information and study methods including statistical analysis were extracted. Study quality was assessed using Newcastle-Ottawa Scale (NOS). Investigated drugs were ranked and compared with data on the prevalence of pediatric drug use. RESULTS: Three thousand nine hundred twenty-six abstracts were screened for eligibility and inclusion, and 164 articles were included in the review. Most studies were from North America (46.7%). Only 78 studies (47.6%) reported the design: 90.8% were cohort studies. Neonates were least frequently investigated. The drugs that were most often studied included systemic antibacterials (11.4%), psycholeptics (7.9%), and antiepileptics (7.6%). Adjustment for confounding was made using propensity scores in 8.5% of the studies. Studies that did not report the design were of lower quality. Many effectiveness studies were done on antineoplastic agents, which are not frequently used and few studies on analgesics and drugs for obstructive airway diseases which are frequently prescribed. CONCLUSIONS: There is ample opportunity to improve comparative effectiveness research for drugs used in pediatrics. Routinely prescribed drugs were seldom investigated. Modern methods for confounding adjustment, such as propensity scores, were rarely used.

Masking by vaccines in pediatric drug safety signal detection in the EudraVigilance database.

PURPOSE: Postmarketing drug safety surveillance relies upon measures of disproportionate reporting in spontaneous reporting systems. It has been hypothesized that products or events reported frequently may "mask" signals. METHODS: We analyzed the masking effect of vaccines in pediatrics in the EudraVigilance database by conducting disproportionality analysis in the full database (containing vaccine exposures) and in a restricted set (excluding vaccine exposures). We measured performance of the reporting odds ratio (ROR) in both data sets using a pediatric-specific drug reference set and in the absence of a reference set. We assessed masking effects across age groups and conducted a classification tree (CART) analysis. RESULTS: Removal of vaccines decreased the ROR values both in negative and positive controls. Exceptions were drug-event combinations including outcomes frequent in vaccine reports. When restricted to positive control associations, removal of vaccine-related events resulted in increased ROR values for events commonly reported following vaccination. For events rarely associated with vaccination, ROR values decreased for all age groups, especially infants. Analysis in the absence of a reference set showed decrease in ROR following vaccine removal and CART revealed that change in ROR with vaccine removal depended upon age and proportion of reports including a vaccine. CONCLUSIONS: Removal of vaccines for signal detection in a pediatric population has an impact on ROR, dependent upon the reporting frequency of the event of interest in combination with vaccines. We recommend stratification by age and removal of vaccine exposures if the investigated adverse drug reactions include those typically reported in association with vaccines for the age strata.

Impact of different assumptions on estimates of childhood diseases obtained from health care data: A retrospective cohort study.

PURPOSE: Accurate estimates of disease incidence in children are required to support pediatric drug development. Analysis of electronic health care records (EHR) may yield such estimates but pediatric-specific methods are lacking. We aimed to understand the impact of assumptions regarding duration of disease episode and length of run-in period on incidence estimates from EHRs. METHODS: Children aged 0 to 17 years (5-17 years for asthma) registered in the Integrated Primary Care Information database between 2002 and 2014 were studied. We tested the impact of the following: maximum duration of disease episode (0, 14, 30, 60, and 90 days) on recurrent diseases (acute otitis media [common] and acute pyelonephritis [rare]); and database run-in period on chronic diseases-asthma (common) and type 1 diabetes (DM) (rare). We calculated incidence rate ratios with 95% confidence intervals and stratified using 1-year age categories. RESULTS: Altogether, 503 495 children were registered. The incidence of acute otitis media was highest in <2-year-old children; using 30 days disease duration as reference, the rate increased with 8% if the duration was 14 days and decreased with 8% when extended to 60 days. Disease duration did not impact acute pyelonephritis (rare). No run-in (to exclude prevalent cases) versus 24-month run-in period overestimated the incidence rate for asthma and DM by a factor of 2. CONCLUSIONS: Analysis of EHR allows for estimation of disease incidence in children, but assumptions regarding episode length and run-in period impact the incidence estimates. Such assumptions may be routinely explored.

Pharmacoepidemiology in pediatrics: Needs, challenges and future directions for research.

Despite international initiatives to promote clinical research in pediatrics, there are still many gaps of knowledge in the use of drugs to treat this specific population. When important information cannot be derived only from clinical trials, use of available observational research tools is required. In this paper, we provide an overview of the particular interest of pharmacoepidemiological research into the evaluation of drug effects in children and adolescents. We also sought to underline the unique challenges and specific needs regarding this research. Implementation of innovative methodologies and expansion of database networks to perform necessary studies could further improve performances of observational research.

Choice of time period to identify confounders for propensity score matching, affected the estimate: a retrospective cohort study of drug effectiveness in asthmatic children.

OBJECTIVES: To control for confounding by indication in comparative (drug) effectiveness studies, propensity score (PS) methods may be used. Since childhood diseases or outcomes often present as acute events, we compared the effect of using different look-back periods in electronic health-care data, to construct PSs. This was applied in our research on the effect of a combination of inhaled corticosteroids/long-acting beta-2 agonists (ICS + LABA), either as fixed combination or used as loose combination (2 separate inhaler devices) in the prevention of severe asthma exacerbations. METHODS: We created a cohort of children (5-17 years) diagnosed with asthma from the Dutch Integrated Primary Care information database. Within this cohort, we identified new users of ICS + LABA, either as fixed combination or loose combination (2 separate inhaler devices). The outcome of interest was severe asthma exacerbations. PSs for type of treatment were created using comorbidity and drug use history in different time windows: 1 week, 1 month, 3 months, 1 year, and full history prior to the start of treatment. PSs were used for matching subjects in both exposure groups. Time to first asthma exacerbation was analyzed with Cox proportional hazard regression. The results were compared with published clinical trials. RESULTS: Of 39,682 asthmatic children, 3,500 (8.8%) were new users of either ICS + LABA fixed (3,324 [95.0%]) or loose (176 [5.0%]). The crude hazard ratio (HR) for a severe asthma exacerbation, comparing ICS + LABA fixed to loose was 0.37 (95% confidence interval [CI]: 0.20-0.66). PS-matched HRs (1 week, 1 month, 3 month, 1 year, and full history) were 0.48 (95% CI: 0.22-1.04); 0.60 (95% CI: 0.26-1.38), 0.69 (95% CI: 0.31-1.57), 0.56 (CI: 0.25-1.24), and 0.58 (CI: 0.24-1.36), respectively. CONCLUSIONS: PS matching can be used to control for confounding in pediatric comparative (drug) effectiveness studies, the impact of different look-back periods to implement the PS is important. Controlling for confounders occurring in the 3 months preceding drug exposure may yield results comparable to clinical trial results.

Drug Safety Monitoring in Children: Performance of Signal Detection Algorithms and Impact of Age Stratification.

INTRODUCTION: Spontaneous reports of suspected adverse drug reactions (ADRs) can be analyzed to yield additional drug safety evidence for the pediatric population. Signal detection algorithms (SDAs) are required for these analyses; however, the performance of SDAs in the pediatric population specifically is unknown. We tested the performance of two SDAs on pediatric data from the US FDA Adverse Event Reporting System (FAERS) and investigated the impact of age stratification and age adjustment on the performance of SDAs. METHODS: We tested the performance of two established SDAs: the proportional reporting ratio (PRR) and the empirical Bayes geometric mean (EBGM) on a pediatric dataset from FAERS (2004-2012). We compared the performance of the SDAs with a published pediatric-specific reference set by calculating diagnostic test-related statistics, including the area under the curve (AUC) of receiver operating characteristics. Impact of age stratification and age-adjustment on the performance of the SDAs was assessed. Age adjustment was performed by pooling (Mantel-Hanszel) stratum-specific estimates. RESULTS: A total of 115,674 pediatric reports (patients aged 0-18 years) comprising 893,587 drug-event combinations (DECs) were analysed. Crude values of the AUC were similar for both SDAs: 0.731 (PRR) and 0.745 (EBGM). Stratification unmasked four DECs, e.g., 'ibuprofen and thrombocytopenia'. Age adjustment did not improve performance. CONCLUSION: The performance of the two tested SDAs was similar in the pediatric population. Age adjustment does not improve performance and is therefore not recommended to be performed routinely. Stratification can reveal new associations, and therefore is recommended when either drug use is age-specific or when an age-specific risk is suspected.

Pharmacoepidemiological safety studies in children: a systematic review.

PURPOSE: In order to identify challenges in pediatric pharmacoepidemiological safety studies, we assessed the characteristics of such (published) studies. METHODS: Relevant articles from inception to 2013 were retrieved from Embase and Medline. We sequentially screened titles, abstracts and full texts with independent validation. We systematically collected data regarding general information, study methods and results. RESULTS: Out of 4825 unique articles, 268 full texts (5.6%) were retained; 147 (54.9%) pertained to drugs rather than vaccines. Considering the 268 studies, 202 (75.4%) concerned children and adolescents (2 to 11 years) and 14 (5.3%) included preterm newborns. Most studies originated from North America (154 [57.5%]) or Europe (92 [34.3%]). Only 47 studies (17.5%) were privately funded. The majority (174 [64.9%]) were cohort studies. Out of 268 studies, 196 (73.1%) collected data retrospectively; paper medical charts were the most common data source for the exposures (85 [31.7%]) and outcomes (122 [45.5%]). Only 3 (2.0%) drug-only studies investigated rarely used drugs. Considering all 268 studies, only 27 (10.1%) reported sample size or power calculation. Most (75 [51.0%]) drug-only studies corrected confounding by multivariate modeling unlike stratification in 66 (55.9%) vaccine-only studies. Considering 75 child-only studies without any statistically significant result, 41 (54.7%) did not discuss lack of power. CONCLUSIONS: Although the field of pediatric pharmacoepidemiology is steadily developing evaluation seldom includes neonates, is mainly focused on few drug classes and safety outcomes and concerns mainly drug use in developed countries. Small study size is a specific challenge in pediatrics. Reporting should be improved. © 2016 The Authors. Pharmacoepidemiology and Drug Safety Published by John Wiley & Sons Ltd.

Current needs in pediatric pharmacoepidemiology.

PURPOSE: We report on a needs assessment conducted by the International Society of Pharmacoepidemiology (ISPE) Pediatric Special Interest Group (SIG) to identify critical needs in pediatric pharmacoepidemiology and directions for future activities. METHODS: A mixed methods survey using a structured interview was conducted in the SIG and ISPE membership to elicit information about current activities in pediatric pharmacoepidemiology and identify critical methodologic issues. The interviews were conducted in two phases over 2013 and 2014, beginning with interviews of SIG members and expanding to the wider ISPE membership. Members of the SIG conducted the interviews and summarized the responses. RESULTS: Twenty-nine ISPE members participated in the needs assessment The respondents reported working with a total of 59 distinct databases, with only eight databases used by more than one respondent. Seventeen respondents (57%) reported issues of limited sample sizes, noting that the problem intensifies when studying age sub-groups or specific genetic populations. Missing data elements were a problem in three main areas: lack of detailed medication information, inability to link to parental data, and lack of detailed information about age. Respondents reported the need for data elements not typically required in studies of adults, such as birthweight and current height and weight, as well as school performance and mental health status. CONCLUSIONS: Our needs assessment describes a preliminary picture of the emerging sub-specialty of pediatric pharmacoepidemiology encompassing a range of age sub-groups, disease areas, and medical specialties. The assessment also documents a body of methodologic challenges unique to pharmacoepidemiologic research in children. Copyright © 2016 John Wiley & Sons, Ltd.

Reference set for performance testing of pediatric vaccine safety signal detection methods and systems.

BACKGROUND: Safety signal detection in spontaneous reporting system databases and electronic healthcare records is key to detection of previously unknown adverse events following immunization. Various statistical methods for signal detection in these different datasources have been developed, however none are geared to the pediatric population and none specifically to vaccines. A reference set comprising pediatric vaccine-adverse event pairs is required for reliable performance testing of statistical methods within and across data sources. METHODS: The study was conducted within the context of the Global Research in Paediatrics (GRiP) project, as part of the seventh framework programme (FP7) of the European Commission. Criteria for the selection of vaccines considered in the reference set were routine and global use in the pediatric population. Adverse events were primarily selected based on importance. Outcome based systematic literature searches were performed for all identified vaccine-adverse event pairs and complemented by expert committee reports, evidence based decision support systems (e.g. Micromedex), and summaries of product characteristics. Classification into positive (PC) and negative control (NC) pairs was performed by two independent reviewers according to a pre-defined algorithm and discussed for consensus in case of disagreement. RESULTS: We selected 13 vaccines and 14 adverse events to be included in the reference set. From a total of 182 vaccine-adverse event pairs, we classified 18 as PC, 113 as NC and 51 as unclassifiable. Most classifications (91) were based on literature review, 45 were based on expert committee reports, and for 46 vaccine-adverse event pairs, an underlying pathomechanism was not plausible classifying the association as NC. CONCLUSION: A reference set of vaccine-adverse event pairs was developed. We propose its use for comparing signal detection methods and systems in the pediatric population.

Pediatric drug safety signal detection: a new drug-event reference set for performance testing of data-mining methods and systems.

BACKGROUND: Better evidence regarding drug safety in the pediatric population might be generated from existing data sources such as spontaneous reporting systems and electronic healthcare records. The Global Research in Paediatrics (GRiP)-Network of Excellence aims to develop pediatric-specific methods that can be applied to these data sources. A reference set of positive and negative drug-event associations is required. OBJECTIVE: The aim of this study was to develop a pediatric-specific reference set of positive and negative drug-event associations. METHODS: Considering user patterns and expert opinion, 16 drugs that are used in individuals aged 0-18 years were selected and evaluated against 16 events, regarded as important safety outcomes. A cross-table of unique drug-event pairs was created. Each pair was classified as potential positive or negative control based on information from the drug's Summary of Product Characteristics and Micromedex. If both information sources consistently listed the event as an adverse event, the combination was reviewed as potential positive control. If both did not, the combination was evaluated as potential negative control. Further evaluation was based on published literature. RESULTS: Selected drugs include ibuprofen, flucloxacillin, domperidone, methylphenidate, montelukast, quinine, and cyproterone/ethinylestradiol. Selected events include bullous eruption, aplastic anemia, ventricular arrhythmia, sudden death, acute kidney injury, psychosis, and seizure. Altogether, 256 unique combinations were reviewed, yielding 37 positive (17 with evidence from the pediatric population and 20 with evidence from adults only) and 90 negative control pairs, with the remainder being unclassifiable. CONCLUSION: We propose a drug-event reference set that can be used to compare different signal detection methods in the pediatric population.