Stephen A. Roberts

STUDY QUESTION: Has the average birthweight (BW) for singletons born in the UK through ART changed between 1991 and 2018 relative to the general population? SUMMARY ANSWER: The average gestation-adjusted BW for ART singletons increased steadily between 1991 and 2012 before becoming almost static until 2018; these changes were not observed in the general UK population. WHAT IS KNOWN ALREADY: Many older studies have shown that ART babies are low BW (LBW) compared to naturally conceived babies. Some subsequent evidence suggests that the average BW for fresh and frozen transfer ART babies has increased over recent years. STUDY DESIGN, SIZE, DURATION: This cohort study utilized the UK Human Fertilisation and Embryology Authority (HFEA) dataset of 140 859 singleton ART babies born between 1991 and 2018 in the UK following both fresh and frozen embryo transfer (FET). Comparative aggregated data of 11 790 372 singleton babies born in the UK general population during the same period were obtained from NHS Digital. PARTICIPANTS/MATERIALS, SETTING, METHODS: The HFEA dataset was used to explore ART BW (raw or gestation-adjusted) and gestational age trends between 1991 and 2018. Appropriate regression models assessed the outcomes and adjusted for child sex, available treatment factors (fresh/frozen ET, embryo transfer stage (cleavage or blastocyst transfer), number of embryos transferred, ovarian stimulation, ICSI, treatment centre/clinic, and pre-implantation genetic screening of embryos) and patient factors (maternal age, previous IVF attempts, previous live births, previous pregnancies, ethnicity, country of treatment within the UK (England, Northern Ireland, Scotland, and Wales), funding source, total number of oocytes retrieved, and infertility causes (endometriosis, idiopathic, ovulatory, tubal diagnosis, and male factor)). BW, LBW, and macrosomia models were additionally adjusted for gestational age. Segmented trend analysis using linear splines was used to capture non-linear time effects for BW and gestation outcomes. For the general population data, mean BW and gestation outcomes were assessed as raw, unadjusted yearly averages. MAIN RESULTS AND THE ROLE OF CHANCE: Unadjusted raw BW trends show that ART babies were initially smaller than the general population, but over time, are becoming closer to it. Fully adjusted mean ART BW increased by ∼75 g between 1991 and 2012, and after that, it was almost static. A drop in ART raw BW starting in 2013 was concurrent with a drop in average gestation by an overall average of 2.5 days between 2012 and 2018. The mean raw BW in the general population remained almost static over the study period and consistently higher than the ART BW average, with a notable drop beginning in 2013, concurrent with a decline in average gestation. Between 1991 and 2000, and 2012 and 2018, average gestation trends were comparable in the ART and general population, with varying patterns between 2001 and 2012. LIMITATIONS, REASONS FOR CAUTION: We could only explore factors available in the dataset, possibly missing some unobserved/unrecorded covariates such as socio-economic and lifestyle factors. The ART dataset used required patient consent, leading to the exclusion of ∼40% of all cycles conducted during the study period. WIDER IMPLICATIONS OF THE FINDINGS: ART singletons getting bigger over time is reassuring, as fewer ART babies now have adverse birth outcomes such as LBW. This is desirable within the developmental origins of health and disease (DOHaD) framework, which links adverse child outcomes to later-life disease predisposition. These changes in ART singletons (not observed in the general population) might be the result of changes or improvements in ART technologies, clinic practices, and ART patient population characteristics. Therefore, there is a need to continue monitoring BW-related outcomes such as large for gestational age and macrosomia, which are more prevalent in frozen ET ART babies and, though directly associated with the observed increase in average ART BW, can be detrimental to child health. FUNDING: This study was funded by the EU H2020 Marie Sklodowska-Curie Innovative Training Networks (ITN) grant Dohartnet (H2020-MSCA-ITN-2018-812660). DISCLOSURES: The authors have no competing interests to declare. TRIAL REGISTRATION NUMBER: n/a.

In the contemporary digital age, where technology permeates many aspects of daily life, researchers are constantly seeking innovative methods to gather data effectively and efficiently. Traditional...

Background: Hazardous prescribing is an important and expensive preventable cause of patient harm, which can be identified using electronic healthcare records. In our Programme Grant we investigated the large-scale roll-out of a type of clinical decision support called OptimiseRx ^® (First Databank, Hearst Health, Exeter, United Kingdom) (which had not been independently evaluated previously) and two large-scale roll-outs of pharmacist-led IT-based intervention (an intervention that had been shown to reduce hazardous prescribing in a cluster randomised trial). Objectives: To estimate harm and economic impact of specific hazardous prescribing events. To investigate whether a clinical decision support intervention (OptimiseRx) was associated with reduction in hazardous prescribing. To investigate whether a pharmacist-led IT-based intervention was associated with reduction in hazardous prescribing. To undertake economic and process evaluations of both interventions. Design and methods: The harm and economic impact of hazardous prescribing events were investigated using data from published sources to generate estimates of patient outcomes and cost associated with 11 prescribing safety indicators. An incomplete (not randomised) stepped-wedge design study with control groups was used to investigate the effectiveness of OptimiseRx (409 general practices). Incremental cost-effectiveness ratios were generated for OptimiseRx compared with standard care (cost per hazardous prescribing event prevented), subgroup analysis: cost per quality-adjusted life-year. Incomplete stepped-wedge design studies [East Midlands study (343 and 115 general practices); whole of England study (725 and 179 general practices)] investigated the effectiveness of pharmacist-led IT-based intervention. Incremental cost-effectiveness ratios were generated for pharmacist-led IT-based intervention compared with standard care (cost per hazardous prescribing event prevented, cost per quality-adjusted life-year). Data from interviews, focus groups, a survey and stakeholder events were analysed qualitatively to identify factors influencing the sustained implementation and operation of OptimiseRx or pharmacist-led IT-based intervention. Setting and participants: The interventions took place in general practices in England. The process evaluation involved clinicians, patients and other stakeholders in England. Interventions: Clinical decision support intervention (OptimiseRx). Pharmacist-led IT-based intervention. Main outcome measures: Changes in hazardous prescribing rates. Cost per quality-adjusted life-year. Data sources: Clinical Practice Research Datalink. ResearchOne. General practice clinical records. Process evaluation with clinicians, patients and other stakeholders. Results: All the hazardous prescribing events studied were associated with loss of quality-adjusted life-years. The costliest for the National Health Service were prescriptions of antipsychotics to patients with dementia (£1168 per patient) and anticoagulants in combination with nonsteroidal anti-inflammatory drugs (£1020 per patient). Of 409 practices included in the clinical decision support study, 227 (56%) were intervention practices. Deployment of OptimiseRx was associated with a 10% reduction in exposure to hazardous prescribing after 2 years (odds ratio 0.90, 95% confidence interval 0.88 to 0.92). OptimiseRx costs £14–48 per hazardous prescribing event prevented, depending on time point and patient volume. Based on two indicators only, OptimiseRx costs £236 per quality-adjusted life-year gained at 6 months and becomes dominant (quality-adjusted life-year increasing; cost saving) at 24 months. Of 343 general practices included in the East Midlands pharmacist-led IT-based intervention evaluation, we completed further data extraction for 115 (33.5%) of these. Pharmacist-led IT-based intervention was associated with a decrease in hazardous prescribing of 18% (adjusted odds ratio 0.82, 95% confidence interval 0.78 to 0.86) at 6 months, and 22% (adjusted odds ratio 0.78, 95% confidence interval 0.73 to 0.84) at 24 months post intervention. Pharmacist-led IT-based intervention generates approximately 0.15 quality-adjusted life-years per practice extra compared with no intervention. Expected savings do not fully offset delivery costs, so pharmacist-led IT-based intervention costs just over £1000 per practice. Pharmacist-led IT-based intervention was estimated to be £7449. With 12- and 24-month intervention effects, health gains rise to over 0.2 quality-adjusted life-years and net expenditure falls to < £800 per practice; around £3500 per quality-adjusted life-year gained. Of 725 practices that implemented pharmacist-led IT-based intervention nationally, we had usable data for only 179 because of the COVID-19 pandemic. For these practices, pharmacist-led IT-based intervention was associated with a reduction in hazardous prescribing of 11% (adjusted odds ratio 0.89, 95% confidence interval 0.86 to 0.92) at 6 months post intervention. The process evaluation studies demonstrated the importance of collaboration and system-level support for the clinical decision support and pharmacist-led IT-based interventions. Limitations: The main limitation was that we could not robustly evaluate the impact of OptimiseRx on serious harm outcomes and the analysis was limited for pharmacist-led IT-based intervention because of the COVID-19 pandemic. Future work: Further research is needed to determine whether interventions that reduce hazardous prescribing, also reduce serious harm to patients. Conclusions: Large-scale implementation of OptimiseRx was associated with reduced hazardous prescribing, at less than £50 per hazardous prescribing event avoided. Large-scale implementation of pharmacist-led IT-based intervention was also associated with reduced hazardous prescribing with a cost per quality-adjusted life-year of £7449. It should be noted, however, that these were quasi-experimental studies using observational data and so the findings may have been affected by unknown confounding. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Programme Grants for Applied Research programme (NIHR award ref: RP-PG-1214-20012) and is published in full in Programme Grants for Applied Research ; Vol. 14, No. 15. See the NIHR Funding and Awards website for further award information.

Background: Primary glomerulonephritis (pGN) is a significant contributor to end-stage kidney disease (ESKD) and presents a significant healthcare burden. However, the epidemiology of ESKD-pGN in the UK remains poorly characterised. Methods: We analysed UK Renal Registry data for adults initiating kidney replacement therapy (KRT) between 1999 and 2019, with follow-up to December 2021. The incident cohort included patients starting KRT from 2008 onwards, when national population coverage was achieved, reflecting incidence of KRT initiation due to primary glomerulonephritis rather than overall disease incidence. Incidence rates were normalised to population and analysed using multivariable Poisson regression. Overall patient and graft survival were assessed using Cox regression models with time-dependent covariates, adjusted for demographic variables. Patients managed conservatively were not captured, limiting conclusions to advanced disease requiring KRT. Adult polycystic kidney disease (ADPKD) served as a reference disease. Results: The cohort included 10,308 pGN and 8,302 ADPKD patients. Median age at KRT start in pGN was 54 years, with 71.6% male. Overall incidence of KRT from pGN was 11.8 pmp, with rates of 17.4 pmp for males and 6.6 pmp for females, mainly driven by IgAN, rising until 2015 then declining. ADPKD incidence was 9.8 (males) and 8.2 (females) pmp. Incidence varied by age, sex, and deprivation, with higher rates in older adults with MN (IRR 1.75, 95% CI 1.45–2.11) and MPGN (IRR 1.70, 95% CI 1.22–2.38) compared with ADPKD. Pre-emptive transplantation was less common in pGN (13.5%) than ADPKD (22.8%). Overall survival was similar, but outcomes differed by modality: in pGN, 10-year survival was 81.8% after transplantation, 55.5% on PD, and 37.9% on haemodialysis. Among pGN subtypes, IgAN had favourable graft survival and comparable 5-year survival on PD and transplantation (92.1% vs 92.6%). Graft survival was highest in ADPKD. Conclusions: This national study reveals evolving epidemiology from ESKD-pGN in the UK. These findings may inform resource allocation, and targeted interventions to enhance care and outcomes in pGN.

Introduction: The Saving Babies’ Lives Care Bundle (SBLCB) was introduced in England in 2015 and was updated in 2019 (SBLCBv2). This study aimed to describe the degree to which SBLCBv2 was implemented in practice and describe contemporary experiences of receiving and delivering antenatal and intrapartum care informed by the recommendations of SBLCBv2. Methods: This cross-sectional questionnaire study was conducted in 28 National Health Service maternity units across England between October and December 2023. The study had two arms, one for maternity service users and one for healthcare professionals. Maternity service users aged ≥16 years who had given birth in the last 12 months were invited to participate in an online survey which contained closed questions about elements of the SBLCBv2, and two free-text questions about their experiences of receiving antenatal and intrapartum care. Maternity healthcare professionals from participating sites were invited to complete a separate questionnaire about delivering care. Responses were summarised by descriptive statistics. Results: 1140 women and 633 healthcare professionals participated. The majority of staff reported implementing all five elements of SBLCBv2, though this varied from 57% (prevention of preterm birth) to 99% (smoking cessation). Service users frequently reported receiving interventions that were part of SBLCBv2: 26% were offered Aspirin and 97% monitored fetal movement. Staff generally reported positive experiences of implementing the SBLCBv2, feeling that it supported clinical decision making. 89% and 86% of service users reported a positive experience in pregnancy and labour, respectively. This was underpinned by positive staff attitudes, behaviours and communication, and being listened to and involved in decisions about care. Conclusions: SBLCBv2 has been integrated into clinical practice, though some elements require additional focus to increase implementation (e.g., preterm birth). Maternity staff may benefit from additional training to discuss the reasons for and results of interventions to reduce the risk of pregnancy complications.

STUDY QUESTION: Is patient consent to research associated with the distribution of population characteristics and study outcomes in ART cohort studies? SUMMARY ANSWER: The distribution of population characteristics in the patient consent subset differs from that in the non-consent subset and is not fully representative of the general ART population; thus, study results of population subsets requiring patient consent may be subject to bias. WHAT IS KNOWN ALREADY: Non-consent in epidemiological studies may bias study results if the consent subset differs systematically from the non-consent subset and is thus not representative of the full study population. ART cohort datasets may be biased if they require patients to consent to use their data. As an example, from September 2009 onwards, ART patients in the UK have been asked for specific ‘consent to disclosure of identifying information’ (CD) for research studies. STUDY DESIGN, SIZE, DURATION: This cohort study utilized an anonymized version of the Human Fertilisation and Embryology Authority (HFEA) dataset containing all CD and non-CD autologous ART treatment cycles (n = 819 512) conducted from 2004 to 2018 in the UK. A live birth (LB) subset of 155 986 singletons born during the same period was used to analyse child outcomes. Additionally, an aggregated version of the HFEA dataset was used to explore CD trends by clinic type (National Health Service [NHS], private, or both NHS and privately funded). PARTICIPANTS/MATERIALS, SETTING, METHODS: The dataset containing all gamete cycles was used to explore factors associated with giving CD and to compare LB outcome trends (number of LBs per yearly treatment cycles started) between CD and non-CD cycles. The LB subset was used to compare the birthweight outcomes (low birthweight (LBW = birthweight < 2500 g or otherwise) and macrosomia (birthweight ≥4000 g or otherwise)) between CD and non-CD cycles. Logistic regression models explored the association between CD and population characteristics and the impact of CD on birthweight outcomes over the calendar years. Each regression model was adjusted for potential confounders: for all models (maternal age, ethnicity, previous IVF cycles, previous pregnancies, previous LBs, causes of infertility (tubal, endometriosis, male factor, ovulatory, unknown), and embryo transfer type and stage); for LB and birthweight models (ICSI, elective single embryo transfer, and ovarian stimulation); and additionally for birthweight models (child sex and gestation). MAIN RESULTS AND THE ROLE OF CHANCE: During the study period, CD rates increased from 16% at its inception in 2009 to 64% in 2018. Fewer cycles from older patients (40–44 years old) and ethnic minorities (Black and Asian) gave CD. Cycles with previous ART treatments and LBs had lower rates of giving CD. CD was also associated with LB rates (higher in the CD group) and LBW (slightly more prevalent in the non-CD group). CD rates were consistently higher in NHS-only funded clinics than in clinics with partly or fully private funding. It may be possible to adjust for much of the post-2009 bias by weighting by the probability of inclusion derived from supplementary data. LIMITATIONS, REASONS FOR CAUTION: Important factors not provided or unavailable in the dataset included socio-economic and lifestyle factors. Additionally, the anonymized dataset provided to us had banded/categorized maternal age, gestation, and birthweight variables, possibly limiting our estimates’ precision. WIDER IMPLICATIONS OF THE FINDINGS: This study shows that using only consented data in ART observational cohort studies may result in a sample that differs from the non-consented sample and general ART population. Specifically, our results show differences in the distribution of population characteristics, LB, and LBW outcomes between CD and non-CD groups in the UK HFEA ART register dataset. Careful attention is therefore required when analysing and interpreting these and similar cohort data; failure to consider the impact of consent will likely produce misleading results. In the HFEA register, this applies to research studies using CD data (including bespoke data requests and linkage studies) after the introduction of CD in October 2009. A potential solution weighting by the probability of consent is briefly introduced. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by the EU H2020 Marie Sklodowska-Curie Innovative Training Networks (ITN) grant Dohartnet (H2020-MSCA-ITN-2018-812660). The authors have no competing interests to declare. TRIAL REGISTRATION NUMBER: N/A.

Objective To compare the risk of hospitalisation for conditions originating in the perinatal period between children conceived via assisted reproductive technology and those that are naturally conceived, differentiating by treatment type. Study design, setting and participants Population-based record-linkage study of children born after assisted reproduction in the UK between 2002 and 2009 (n=44 618), their naturally conceived siblings (n=8462) and matched naturally conceived population (n=89 072) controls linked to their hospital inpatient records up to 31 March 2016. Primary and secondary outcome measures Robust estimates of the overall and cause-specific risk of hospital admission for adverse perinatal events and the comparison of outcomes by type of treatment. Results Over the study period, 17 132 (38.40%) children conceived via assisted reproduction and 30 306 (34.02%) and 1738 (20.54%) naturally conceived population and sibling controls, respectively, were admitted to the hospital for severe perinatal events. Compared with the population controls, singletons (Risk ratio (95% CI 1.30 (1.26, 1.34))) and twins (1.01 (0.99, 1.03)) conceived via assisted reproduction exhibited a higher risk of hospitalisation for any adverse perinatal event. However, no such increase was observed in the within-sibling analysis (0.97 (0.84, 1.12)). Similar patterns were seen for diagnoses related to length of gestation and fetal growth (vs population controls: 1.37 (1.29, 1.46); vs siblings: 1.17 (0.86, 1.60)); birth trauma (vs population controls: 1.23 (1.04, 1.44); vs siblings: 0.78 (0.47, 1.30)); respiratory and cardiovascular disorders (vs population controls: 1.28 (1.20, 1.38); vs siblings: 0.72 (0.53, 0.98)); infections (vs population controls: 1.30 (1.06, 1.59); vs siblings: 0,68 (0.24, 1.90)) and several other conditions. Associations were similar when comparing in vitro fertilisation to intracytoplasmic sperm injection and were higher when comparing fresh to frozen embryo transfers. Conclusion Children conceived via assisted reproduction showed modest increases in the risk of hospitalisations for severe perinatal events when compared with population controls, although these findings were attenuated in the sibling analyses. The imprecision of within-sibling analyses highlights the need for larger studies to explore potential causal effects.

Introduction The diagnosis of asthma is often based on characteristic patterns of symptoms in the absence of an alternative explanation, resulting in over and under diagnosis. Therefore, diagnostic guidelines usually recommend including confirmation of variable airflow obstruction. Some recommend using a sequence of objective tests; however the tests used, the specific cut-off values and the specified order are yet to be validated. We aimed to determine the optimal cut-off values and series of investigations to diagnose asthma. We also explore the potential for novel tests of small airways function and biomarkers, which could be incorporated into future diagnostic pathways. Methods and analysis The Rapid Access Diagnostics for Asthma study is an observational study of 300 symptomatic patients with ‘clinician-suspected asthma’ and healthy controls (aged ≥3 to Ethics and dissemination The study was approved by Greater Manchester East Research Ethics Committee (18/NW/0777). All participants or parents/guardians are required to provide written informed consent and children to provide written assent. The results will be published in peer-review journals and disseminated widely at conferences and with the help of Asthma and Lung UK (www.asthmaandlung.org.uk). Trial registration number ISRCTN11676160.

Significance Statement: Reliable prediction tools are needed to personalize treatment in ANCA-associated GN. More than 1500 patients were collated in an international longitudinal study to revise the ANCA kidney risk score. The score showed satisfactory performance, mimicking the original study (Harrell's C=0.779). In the development cohort of 959 patients, no additional parameters aiding the tool were detected, but replacing the GFR with creatinine identified an additional cutoff. The parameter interstitial fibrosis and tubular atrophy was modified to allow wider access, risk points were reweighted, and a fourth risk group was created, improving predictive ability (C=0.831). In the validation, the new model performed similarly well with excellent calibration and discrimination (n=480, C=0.821). The revised score optimizes prognostication for clinical practice and trials. Background: Reliable prediction tools are needed to personalize treatment in ANCA-associated GN. A retrospective international longitudinal cohort was collated to revise the ANCA renal risk score. Methods: The primary end point was ESKD with patients censored at last follow-up. Cox proportional hazards were used to reweight risk factors. Kaplan–Meier curves, Harrell's C statistic, receiver operating characteristics, and calibration plots were used to assess model performance. Results: Of 1591 patients, 1439 were included in the final analyses, 2:1 randomly allocated per center to development and validation cohorts (52% male, median age 64 years). In the development cohort (n=959), the ANCA renal risk score was validated and calibrated, and parameters were reinvestigated modifying interstitial fibrosis and tubular atrophy allowing semiquantitative reporting. An additional cutoff for kidney function (K) was identified, and serum creatinine replaced GFR (K0: 450 µmol/L=11 points). The risk points for the percentage of normal glomeruli (N) and interstitial fibrosis and tubular atrophy (T) were reweighted (N0: >25%=0, N1: 10%–25%=4, N2: n=480, C=0.821). Conclusions: The updated score optimizes clinicopathologic prognostication for clinical practice and trials.