COVID-19 and pregnancy: A European study on pre- and post-infection medication use.

PURPOSE: The COVID-19 pandemic has impacted medication needs and prescribing practices, including those affecting pregnant women. Our goal was to investigate patterns of medication use among pregnant women with COVID-19, focusing on variations by trimester of infection and location. METHODS: We conducted an observational study using six electronic healthcare databases from six European regions (Aragon/Spain; France; Norway; Tuscany, Italy; Valencia/Spain; and Wales/UK). The prevalence of primary care prescribing or dispensing was compared in the 30-day periods before and after a positive COVID-19 test or diagnosis. RESULTS: The study included 294,126 pregnant women, of whom 8943 (3.0%) tested positive for, or were diagnosed with, COVID-19 during their pregnancy. A significantly higher use of antithrombotic medications was observed particularly after COVID-19 infection in the second and third trimesters. The highest increase was observed in the Valencia region where use of antithrombotic medications in the third trimester increased from 3.8% before COVID-19 to 61.9% after the infection. Increases in other countries were lower; for example, in Norway, the prevalence of antithrombotic medication use changed from around 1-2% before to around 6% after COVID-19 in the third trimester. Smaller and less consistent increases were observed in the use of other drug classes, such as antimicrobials and systemic corticosteroids. CONCLUSION: Our findings highlight the substantial impact of COVID-19 on primary care medication use among pregnant women, with a marked increase in the use of antithrombotic medications post-COVID-19. These results underscore the need for further research to understand the broader implications of these patterns on maternal and neonatal/fetal health outcomes.

Feature-Specific Salience Maps in Human Cortex.

Priority map theory is a leading framework for understanding how various aspects of stimulus displays and task demands guide visual attention. Per this theory, the visual system computes a priority map, which is a representation of visual space indexing the relative importance, or priority, of locations in the environment. Priority is computed based on both salience, defined based on image-computable properties; and relevance, defined by an individual's current goals, and is used to direct attention to the highest-priority locations for further processing. Computational theories suggest that priority maps identify salient locations based on individual feature dimensions (e.g., color, motion), which are integrated into an aggregate priority map. While widely accepted, a core assumption of this framework, the existence of independent feature dimension maps in visual cortex, remains untested. Here, we tested the hypothesis that retinotopic regions selective for specific feature dimensions (color or motion) in human cortex act as neural feature dimension maps, indexing salient locations based on their preferred feature. We used fMRI activation patterns to reconstruct spatial maps while male and female human participants viewed stimuli with salient regions defined by relative color or motion direction. Activation in reconstructed spatial maps was localized to the salient stimulus position in the display. Moreover, the strength of the stimulus representation was strongest in the ROI selective for the salience-defining feature. Together, these results suggest that feature-selective extrastriate visual regions highlight salient locations based on local feature contrast within their preferred feature dimensions, supporting their role as neural feature dimension maps.SIGNIFICANCE STATEMENT Identifying salient information is important for navigating the world. For example, it is critical to detect a quickly approaching car when crossing the street. Leading models of computer vision and visual search rely on compartmentalized salience computations based on individual features; however, there has been no direct empirical demonstration identifying neural regions as responsible for performing these dissociable operations. Here, we provide evidence of a critical double dissociation that neural activation patterns from color-selective regions prioritize the location of color-defined salience while minimally representing motion-defined salience, whereas motion-selective regions show the complementary result. These findings reveal that specialized cortical regions act as neural "feature dimension maps" that are used to index salient locations based on specific features to guide attention.

Causes of death in children with congenital anomalies up to age 10 in eight European countries.

BACKGROUND: Congenital anomalies (CAs) increase the risk of death during infancy and childhood. This study aimed to evaluate the accuracy of using death certificates to estimate the burden of CAs on mortality for children under 10 years old. METHODS: Children born alive with a major CA between 1 January 1995 and 31 December 2014, from 13 population-based European CA registries were linked to mortality records up to their 10th birthday or 31 December 2015, whichever was earlier. RESULTS: In total 4199 neonatal, 2100 postneonatal and 1087 deaths in children aged 1-9 years were reported. The underlying cause of death was a CA in 71% (95% CI 64% to 78%) of neonatal and 68% (95% CI 61% to 74%) of postneonatal infant deaths. For neonatal deaths the proportions varied by registry from 45% to 89% and by anomaly from 53% for Down syndrome to 94% for tetralogy of Fallot. In children aged 1-9, 49% (95% CI 42% to 57%) were attributed to a CA. Comparing mortality in children with anomalies to population mortality predicts that over 90% of all deaths at all ages are attributable to the anomalies. The specific CA was often not reported on the death certificate, even for lethal anomalies such as trisomy 13 (only 80% included the code for trisomy 13). CONCLUSIONS: Data on the underlying cause of death from death certificates alone are not sufficient to evaluate the burden of CAs on infant and childhood mortality across countries and over time. Linked data from CA registries and death certificates are necessary for obtaining accurate estimates.

SAIL study of stroke, systemic embolism and bleeding outcomes with warfarin anticoagulation in non-valvular atrial fibrillation (S4-BOW-AF).

Aims: In patients with non-valvular atrial fibrillation (NVAF) prescribed warfarin, the association between guideline defined international normalised ratio (INR) control and adverse outcomes in unknown. We aimed to (i) determine stroke and systemic embolism (SSE) and bleeding events in NVAF patients prescribed warfarin; and (ii) estimate the increased risk of these adverse events associated with poor INR control in this population. Methods and results: Individual-level population-scale linked patient data were used to investigate the association between INR control and both SSE and bleeding events using (i) the National Institute for Health and Care Excellence (NICE) criteria of poor INR control [time in therapeutic range (TTR) <65%, two INRs <1.5 or two INRs >5 in a 6-month period or any INR >8]. A total of 35 891 patients were included for SSE and 35 035 for bleeding outcome analyses. Mean CHA2DS2-VASc score was 3.5 (SD = 1.7), and the mean follow up was 4.3 years for both analyses. Mean TTR was 71.9%, with 34% of time spent in poor INR control according to NICE criteria.SSE and bleeding event rates (per 100 patient years) were 1.01 (95%CI 0.95-1.08) and 3.4 (95%CI 3.3-3.5), respectively, during adequate INR control, rising to 1.82 (95%CI 1.70-1.94) and 4.8 (95% CI 4.6-5.0) during poor INR control.Poor INR control was independently associated with increased risk of both SSE [HR = 1.69 (95%CI = 1.54-1.86), P < 0.001] and bleeding [HR = 1.40 (95%CI 1.33-1.48), P < 0.001] in Cox-multivariable models. Conclusion: Guideline-defined poor INR control is associated with significantly higher SSE and bleeding event rates, independent of recognised risk factors for stroke or bleeding.

Learned feature regularities enable suppression of spatially overlapping stimuli.

Contemporary theories of attentional control state that information can be prioritized based on selection history. Even though theories agree that selection history can impact representations of spatial location, which in turn helps guide attention, there remains disagreement on whether nonspatial features (e.g., color) are modulated in a similar way. While previous work has demonstrated color suppression using visual search tasks, it is possible that the location corresponding to the distractor was suppressed, consistent with a spatial mechanism of suppression. Here, we sought to rule out this possibility by testing whether similar suppression of a learned distractor color can occur for spatially overlapping visual stimuli. On a given trial, two spatially superimposed stimuli (line arrays) were tilted either left or right of vertical and presented in one of four distinct colors. Subjects performed a speeded report of the orientation of the "target" array with the most lines. Critically, the distractor array was regularly one color, and this high-probability color was never the color of the target array, which encouraged learned suppression. In two experiments, responses to the target array were fastest when the distractor array was in the high-probability color, suggesting participants suppressed the distractor color. Additionally, when regularities were removed, the high-probability distractor color continued to benefit speeded target identification for individual subjects (E1) but slowed target identification (E2) when presented in the target array. Together, these results indicate that learned suppression of feature-based regularities modulates target detection performance independent of spatial location and persists over time.

Ten-Year Survival of Children With Congenital Anomalies: A European Cohort Study.

OBJECTIVES: To investigate the survival up to age 10 for children born alive with a major congenital anomaly (CA). METHODS: This population-based linked cohort study (EUROlinkCAT) linked data on live births from 2005 to 2014 from 13 European CA registries with mortality data. Pooled Kaplan-Meier survival estimates up to age 10 were calculated for these children (77 054 children with isolated structural anomalies and 4011 children with Down syndrome). RESULTS: The highest mortality of children with isolated structural CAs was within infancy, with survival of 97.3% (95% confidence interval [CI]: 96.6%-98.1%) and 96.9% (95% CI: 96.0%-97.7%) at age 1 and 10, respectively. The 10-year survival exceeded 90% for the majority of specific CAs (27 of 32), with considerable variations between CAs of different severity. Survival of children with a specific isolated anomaly was higher than in all children with the same anomaly when those with associated anomalies were included. For children with Down syndrome, the 10-year survival was significantly higher for those without associated cardiac or digestive system anomalies (97.6%; 95% CI: 96.5%-98.7%) compared with children with Down syndrome associated with a cardiac anomaly (92.3%; 95% CI: 89.4%-95.3%), digestive system anomaly (92.8%; 95% CI: 87.7%-98.2%), or both (88.6%; 95% CI: 83.2%-94.3%). CONCLUSIONS: Ten-year survival of children born with congenital anomalies in Western Europe from 2005 to 2014 was relatively high. Reliable information on long-term survival of children born with specific CAs is of major importance for parents of these children and for the health care professionals involved in their care.

Guidance of attention from visual working memory is feature-based, not object-based: Implications for models of feature binding.

A classic question in visual working memory (VWM) research is whether features from the same object are bound directly in an integrated representation or are maintained separately and bound only indirectly though shared location. Here, we examined this question using a novel method that probed the effects of VWM on the guidance of attention (rather than requiring explicit access to VWM content, as has typically been used). Participants remembered two color-shape conjunction objects. During a retention-interval search task, they searched for a target letter among distractor letters superimposed over color-shape conjunction items. There were two critical conditions. In the same-object-match condition, one search item matched both the color and shape of a single remembered object. In the different-object-match condition, one search item matched the color from one remembered object and the shape from the other. Robust effects of VWM-based guidance were observed, both when probing the incidental guidance of attention (Experiments 1 and 2) and the strategic guidance of attention (Experiment 3). Critically, in none of the experiments was the magnitude of guidance greater for same-object-match than for different-object-match. The results indicate that the representational units of guidance from VWM are individual features rather than integrated objects. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

From Inception to ConcePTION: Genesis of a Network to Support Better Monitoring and Communication of Medication Safety During Pregnancy and Breastfeeding.

In 2019, the Innovative Medicines Initiative (IMI) funded the ConcePTION project-Building an ecosystem for better monitoring and communicating safety of medicines use in pregnancy and breastfeeding: validated and regulatory endorsed workflows for fast, optimised evidence generation-with the vision that there is a societal obligation to rapidly reduce uncertainty about the safety of medication use in pregnancy and breastfeeding. The present paper introduces the set of concepts used to describe the European data sources involved in the ConcePTION project and illustrates the ConcePTION Common Data Model (CDM), which serves as the keystone of the federated ConcePTION network. Based on data availability and content analysis of 21 European data sources, the ConcePTION CDM has been structured with six tables designed to capture data from routine healthcare, three tables for data from public health surveillance activities, three curated tables for derived data on population (e.g., observation time and mother-child linkage), plus four metadata tables. By its first anniversary, the ConcePTION CDM has enabled 13 data sources to run common scripts to contribute to major European projects, demonstrating its capacity to facilitate effective and transparent deployment of distributed analytics, and its potential to address questions about utilization, effectiveness, and safety of medicines in special populations, including during pregnancy and breastfeeding, and, more broadly, in the general population.

An observational study of international normalized ratio control according to NICE criteria in patients with non-valvular atrial fibrillation: the SAIL Warfarin Out of Range Descriptors Study (SWORDS).

AIMS: In patients with non-valvular atrial fibrillation prescribed warfarin, the UK National Institute of Health and Care Excellence (NICE) defines poor anticoagulation as a time in therapeutic range (TTR) of <65%, any two international normalized ratios (INRs) within a 6-month period of ≤1.5 ('low'), two INRs ≥5 within 6 months, or any INR ≥8 ('high'). Our objectives were to (i) quantify the number of patients with poor INR control and (ii) describe the demographic and clinical characteristics associated with poor INR control. METHOD AND RESULTS: Linked anonymized health record data for Wales, UK (2006-2017) was used to evaluate patients prescribed warfarin who had at least 6 months of INR data. 32 380 patients were included. In total, 13 913 (43.0%) patients had at least one of the NICE markers of poor INR control. Importantly, in the 24 123 (74.6%) of the cohort with an acceptable TTR (≥65%), 5676 (23.5%) had either low or high INR readings at some point in their history. In a multivariable regression female gender, age (≥75 years), excess alcohol, diabetes heart failure, ischaemic heart disease, and respiratory disease were independently associated with all markers of poor INR control. CONCLUSION: Acceptable INR control according to NICE standards is poor. Of those with an acceptable TTR (>65%), one-quarter still had unacceptably low or high INR levels according to NICE criteria. Thus, only using TTR to assess effectiveness with warfarin has the potential to miss a large number of patients with non-therapeutic INRs who are likely to be at increased risk.

Medicines prescribed for asthma, discontinuation and perinatal outcomes, including breastfeeding: A population cohort analysis.

OBJECTIVES: To explore associations between exposures to medicines prescribed for asthma and their discontinuation in pregnancy and preterm birth [<37 or <32 weeks], SGA [<10th and <3rd centiles], and breastfeeding at 6-8 weeks. METHODS: Design. A population-based cohort study. Setting. The Secure Anonymised Information Linkage [SAIL] databank in Wales, linking maternal primary care data with infant outcomes. Population. 107,573, 105,331, and 38,725 infants born 2000-2010 with information on premature birth, SGA and breastfeeding respectively, after exclusions. Exposures. maternal prescriptions for asthma medicines or their discontinuation in pregnancy. Methods. Odds ratios for adverse pregnancy outcomes were calculated for the exposed versus the unexposed population, adjusted for smoking, parity, age and socio-economic status. RESULTS: Prescriptions for asthma, whether continued or discontinued during pregnancy, were associated with birth at<32 weeks' gestation, SGA <10th centile, and no breastfeeding (aOR 1.33 [1.10-1.61], 1.10 [1.03-1.18], 0.93 [0.87-1.01]). Discontinuation of asthma medicines in pregnancy was associated with birth at<37 weeks' and <32 weeks' gestation (aOR 1.22 [1.06-1.41], 1.53 [1.11-2.10]). All medicines examined, except ICS and SABA prescribed alone, were associated with SGA <10th centile. CONCLUSIONS: Prescription of asthma medicines before or during pregnancy was associated with higher prevalence of adverse perinatal outcomes, particularly if prescriptions were discontinued during pregnancy. Women discontinuing medicines during pregnancy could be identified from prescription records. The impact of targeting close monitoring and breastfeeding support warrants exploration.

Measuring follow-up time in routinely-collected health datasets: Challenges and solutions.

A key requirement for longitudinal studies using routinely-collected health data is to be able to measure what individuals are present in the datasets used, and over what time period. Individuals can enter and leave the covered population of administrative datasets for a variety of reasons, including both life events and characteristics of the datasets themselves. An automated, customizable method of determining individuals' presence was developed for the primary care dataset in Swansea University's SAIL Databank. The primary care dataset covers only a portion of Wales, with 76% of practices participating. The start and end date of the data varies by practice. Additionally, individuals can change practices or leave Wales. To address these issues, a two step process was developed. First, the period for which each practice had data available was calculated by measuring changes in the rate of events recorded over time. Second, the registration records for each individual were simplified. Anomalies such as short gaps and overlaps were resolved by applying a set of rules. The result of these two analyses was a cleaned set of records indicating start and end dates of available primary care data for each individual. Analysis of GP records showed that 91.0% of events occurred within periods calculated as having available data by the algorithm. 98.4% of those events were observed at the same practice of registration as that computed by the algorithm. A standardized method for solving this common problem has enabled faster development of studies using this data set. Using a rigorous, tested, standardized method of verifying presence in the study population will also positively influence the quality of research.

The architecture of working memory: Features from multiple remembered objects produce parallel, coactive guidance of attention in visual search.

Theories of working memory (WM) differ in their claims about the number of items that can be maintained in a state that directly interacts with other, ongoing cognitive operations (termed the focus of attention). A similar debate has arisen in the literature on visual working memory (VWM), focused on the number of items that can simultaneously interact with attentional priority. In 3 experiments, we used a redundancy-gain paradigm to provide a comprehensive test of the latter question. Participants searched for 2 cued features (e.g., a color and a shape) within a search array. The cued feature values changed on a trial-by-trial basis, requiring VWM. The target (when present) could match 1 of the cued features (single-target trials) or both cued features (redundant-target trials). We tested whether response time distributions contained a substantial proportion of trials with redundant-target responses that were faster than predicted by 2 independent guidance processes operating in parallel (i.e., violations of the race-model inequality). Violations are consistent with a coactive architecture in which both cued values guide attention in parallel and sum on the priority map. Robust violations were observed in all cases predicted by the hypothesis that multiple items in VWM can guide attention simultaneously, and these results were inconsistent with the hypothesis that guidance is limited to a single item simultaneously. When considered in the larger context of the literature on VWM and attention, the present results are consistent with a model of WM architecture in which the focus of attention can maintain multiple, independent representations. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Pregnancy in teenagers diagnosed with type 1 diabetes mellitus in childhood: a national population-based e-cohort study.

AIMS/HYPOTHESIS: The aim of this study was to describe the characteristics and outcomes of pregnancies in a national cohort of teenage (<20 years) and young adult women (≥20 years) with and without childhood-onset (<15 years) type 1 diabetes. We hypothesised that, owing to poor glycaemic control during the teenage years, pregnancy outcomes would be poorer in teenage mothers with type 1 diabetes than young adult mothers with type 1 diabetes and mothers without diabetes. METHODS: The Brecon Register of childhood-onset type 1 diabetes diagnosed in Wales since 1995 was linked to population-based datasets in the Secure Anonymised Information Linkage (SAIL) Databank, creating an electronic cohort (e-cohort) of legal births (live or stillbirths beyond 24 weeks' gestation) to women aged less than 35 years between 1995 and 2013 in Wales. Teenage pregnancy rates were calculated based on the number of females in the same birth cohort in Wales. Pregnancy outcomes, including pre-eclampsia, preterm birth, low birthweight, macrosomia, congenital malformations, stillbirths and hospital admissions during the first year of life, were obtained from electronic records for the whole Welsh population. We used logistic and negative binomial regression to compare outcomes among teenage and young adult mothers with and without type 1 diabetes. RESULTS: A total of 197,796 births were eligible for inclusion, including 330 to girls and women with childhood-onset type 1 diabetes, of whom 68 were teenagers (age 14-19 years, mean 17.9 years) and 262 were young adults (age 20-32 years, mean 24.0 years). The mean duration of diabetes was 14.3 years (9.7 years for teenagers; 15.5 years for young adults). Pregnancy rates were lower in teenagers with type 1 diabetes than in teenagers without diabetes (mean annual teenage pregnancy rate between 1999 and 2013: 8.6 vs 18.0 per 1000 teenage girls, respectively; p < 0.001). In the background population, teenage pregnancy was associated with deprivation (p < 0.001), but this was not the case for individuals with type 1 diabetes (p = 0.85). Glycaemic control was poor in teenage and young adult mothers with type 1 diabetes (mean HbA1c based on closest value to conception: 81.3 and 80.2 mmol/mol [9.6% and 9.5%], respectively, p = 0.78). Glycaemic control improved during pregnancy in both groups but to a greater degree in young adults, who had significantly better glycaemic control than teenagers by the third trimester (mean HbA1c: 54.0 vs 67.4 mmol/mol [7.1% vs 8.3%], p = 0.01). All adverse outcomes were more common among mothers with type 1 diabetes than mothers without diabetes. Among those with type 1 diabetes, hospital admissions during the first year of life were more common among babies of teenage vs young adult mothers (adjusted OR 5.91 [95% CI 2.63, 13.25]). Other outcomes were no worse among teenage mothers with type 1 diabetes than among young adult mothers with diabetes. CONCLUSIONS/INTERPRETATION: Teenage girls with childhood-onset type 1 diabetes in Wales are less likely to have children than teenage girls without diabetes. Teenage pregnancy in girls with type 1 diabetes, unlike in the background population, is not associated with social deprivation. In our cohort, glycaemic control was poor in both teenage and young adult mothers with type 1 diabetes. Pregnancy outcomes were comparable between teenage and young adult mothers with type 1 diabetes, but hospital admissions during the first year of life were five times more common among babies of teenage mothers with type 1 diabetes than those of young adult mothers with diabetes.

Developing a standardised approach to the aggregation of inpatient episodes into person-based spells in all specialties and psychiatric specialties.

BACKGROUND: Electronic health record (EHR) data are available for research in all UK nations and cross-nation comparative studies are becoming more common. All UK inpatient EHRs are based around episodes, but episode-based analysis may not sufficiently capture the patient journey. There is no UK-wide method for aggregating episodes into standardised person-based spells. This study identifies two data quality issues affecting the creation of person-based spells, and tests four methods to create these spells, for implementation across all UK nations. METHODS: Welsh inpatient EHRs from 2013 to 2017 were analysed. Phase one described two data quality issues; transfers of care and episode sequencing. Phase two compared four methods for creating person spells. Measures were mean length of stay (LOS, expressed in days) and number of episodes per person spell for each method. RESULTS: 3.5% of total admissions were transfers-in and 3.1% of total discharges were transfers-out. 68.7% of total transfers-in and 48.7% of psychiatric transfers-in had an identifiable preceding transfer-out, and 78.2% of total transfers-out and 59.0% of psychiatric transfers-out had an identifiable subsequent transfer-in. 0.2% of total episodes and 4.0% of psychiatric episodes overlapped with at least one other episode of any specialty. Method one (no evidence of transfer required; overlapping episodes grouped together) resulted in the longest mean LOS (4.0 days for all specialties; 48.5 days for psychiatric specialties) and the fewest single episode person spells (82.4% of all specialties; 69.7% for psychiatric specialties). Method three (evidence of transfer required; overlapping episodes separated) resulted in the shortest mean LOS (3.7 days for all specialties; 45.8 days for psychiatric specialties) and the most single episode person spells; (86.9% for all specialties; 86.3% for psychiatric specialties). CONCLUSIONS: Transfers-in appear better recorded than transfers-out. Transfer coding is incomplete, particularly for psychiatric specialties. The proportion of episodes that overlap is small but psychiatric episodes are disproportionately affected. The most successful method for grouping episodes into person spells aggregated overlapping episodes and required no evidence of transfer from admission source/method or discharge destination codes. The least successful method treated overlapping episodes as distinct and required transfer coding. The impact of all four methods was greater for psychiatric specialties.

Antidepressant prescriptions, discontinuation, depression and perinatal outcomes, including breastfeeding: A population cohort analysis.

OBJECTIVES: To explore associations between exposure to antidepressants, their discontinuation, depression [medicated or unmediated] and preterm birth [<37 and <32 weeks], small for gestational age (SGA) [<10th and <3rd centiles], breastfeeding [any] at 6-8 weeks. METHODS: Design: A population-based cohort study. Setting: The Secure Anonymised Information Linkage [SAIL] databank in Wales, linking maternal primary care data with infant outcomes. Participants: 107,573, 105,331, and 38,725 infants born 2000-2010 with information on prematurity, SGA and breastfeeding respectively, after exclusions. Exposures: Maternal antidepressant prescriptions in trimesters 2 or 3, discontinuation after trimester 1, recorded diagnosis of depression [medicated or unmediated] in pregnancy. Methods: Odds ratios for adverse pregnancy outcomes were calculated, adjusted for smoking, parity, socio-economic status, and depression. RESULTS: Exclusive formula feeding at 6-8 weeks was associated with prescriptions in trimesters 2 or 3 for any antidepressants (adjusted odds ratio [aOR] 0.81, 95% confidence intervals 0.67-0.98), SSRIs [aOR 0.77, 0.62-0.95], particularly higher doses [aOR 0.45, 0.23-0.86], discontinuation of antidepressants or SSRIs after trimester 1 (aOR 0.70, 0.57-0.83 and 0.66, 0.51-0.87), diagnosis of depression aOR 0.76 [0.70-0.82), particularly if medicated (aOR 0.70, 0.58-0.85), rather than unmedicated (aOR 0.87, 0.82-0.92). Preterm birth at <37 and <32 weeks' gestation was associated with diagnosis of depression (aOR 1.27, 1.17-1.38, and 1.33, 1.09-1.62), particularly if medicated (aOR 1.56, 1.23-1.96, and 1.63, 0.94-2.84); birth at <37 weeks was associated with antidepressants, (aOR 1.24, 1.04-1.49]. SGA <3rd centile was associated with antidepressants (aOR 1.43, 1.07-1.90), and SSRIs (aOR 1.46, 1.06-2.00], particularly higher doses [aOR 2.10, 1.32-3.34]. All adverse outcomes were associated with socio-economic status and smoking. IMPLICATIONS: Exposure to antidepressants or depression increased risks of exclusive formula feeding at 6-8 weeks, and prescription of antidepressants was associated with SGA <3rd centile. Prescription of antidepressants offers a useful marker to target additional support and additional care before and during pregnancy and lactation.

Long term extension of a randomised controlled trial of probiotics using electronic health records.

Most randomised controlled trials (RCTs) are relatively short term and, due to costs and available resources, have limited opportunity to be re-visited or extended. There is no guarantee that effects of treatments remain unchanged beyond the study. Here, we illustrate the feasibility, benefits and cost-effectiveness of enriching standard trial design with electronic follow up. We completed a 5-year electronic follow up of a RCT investigating the impact of probiotics on asthma and eczema in children born 2005-2007, with traditional fieldwork follow up to two years. Participants and trial outcomes were identified and analysed after five years using secure, routine, anonymised, person-based electronic health service databanks. At two years, we identified 93% of participants and compared fieldwork with electronic health records, highlighting areas of agreement and disagreement. Retention of children from lower socio-economic groups was improved, reducing volunteer bias. At 5 years we identified a reduced 82% of participants. These data allowed the trial's first robust analysis of asthma endpoints. We found no indication that probiotic supplementation to pregnant mothers and infants protected against asthma or eczema at 5 years. Continued longer-term follow up is technically straightforward.

Selective Serotonin Reuptake Inhibitor (SSRI) Antidepressants in Pregnancy and Congenital Anomalies: Analysis of Linked Databases in Wales, Norway and Funen, Denmark.

BACKGROUND: Hypothesised associations between in utero exposure to selective serotonin reuptake inhibitors (SSRIs) and congenital anomalies, particularly congenital heart defects (CHD), remain controversial. We investigated the putative teratogenicity of SSRI prescription in the 91 days either side of first day of last menstrual period (LMP). METHODS AND FINDINGS: Three population-based EUROCAT congenital anomaly registries- Norway (2004-2010), Wales (2000-2010) and Funen, Denmark (2000-2010)-were linked to the electronic healthcare databases holding prospectively collected prescription information for all pregnancies in the timeframes available. We included 519,117 deliveries, including foetuses terminated for congenital anomalies, with data covering pregnancy and the preceding quarter, including 462,641 with data covering pregnancy and one year either side. For SSRI exposures 91 days either side of LMP, separately and together, odds ratios with 95% confidence intervals (ORs, 95%CI) for all major anomalies were estimated. We also explored: pausing or discontinuing SSRIs preconception, confounding, high dose regimens, and, in Wales, diagnosis of depression. Results were combined in meta-analyses. SSRI prescription 91 days either side of LMP was associated with increased prevalence of severe congenital heart defects (CHD) (as defined by EUROCAT guide 1.3, 2005) (34/12,962 [0.26%] vs. 865/506,155 [0.17%] OR 1.50, 1.06-2.11), and the composite adverse outcome of 'anomaly or stillbirth' (473/12962, 3.65% vs. 15829/506,155, 3.13%, OR 1.13, 1.03-1.24). The increased prevalence of all major anomalies combined did not reach statistical significance (3.09% [400/12,962] vs. 2.67% [13,536/506,155] OR 1.09, 0.99-1.21). Adjusting for socio-economic status left ORs largely unchanged. The prevalence of anomalies and severe CHD was reduced when SSRI prescriptions were stopped or paused preconception, and increased when >1 prescription was recorded, but differences were not statistically significant. The dose-response relationship between severe CHD and SSRI dose (meta-regression OR 1.49, 1.12-1.97) was consistent with SSRI-exposure related risk. Analyses in Wales suggested no associations between anomalies and diagnosed depression. CONCLUSION: The additional absolute risk of teratogenesis associated with SSRIs, if causal, is small. However, the high prevalence of SSRI use augments its public health importance, justifying modifications to preconception care.

Prescribing of Antidiabetic Medicines before, during and after Pregnancy: A Study in Seven European Regions.

AIM: To explore antidiabetic medicine prescribing to women before, during and after pregnancy in different regions of Europe. METHODS: A common protocol was implemented across seven databases in Denmark, Norway, The Netherlands, Italy (Emilia Romagna/Tuscany), Wales and the rest of the UK. Women with a pregnancy starting and ending between 2004 and 2010, (Denmark, 2004-2009; Norway, 2005-2010; Emilia Romagna, 2008-2010), which ended in a live or stillbirth, were identified. Prescriptions for antidiabetic medicines issued (UK) or dispensed (non-UK) during pregnancy and/or the year before or year after pregnancy were identified. Prescribing patterns were compared across databases and over calendar time. RESULTS: 1,082,673 live/stillbirths were identified. Pregestational insulin prescribing during the year before pregnancy ranged from 0.27% (CI95 0.25-0.30) in Tuscany to 0.45% (CI95 0.43-0.47) in Norway, and increased between 2004 and 2009 in all countries. During pregnancy, insulin prescribing peaked during the third trimester and increased over time; third trimester prescribing was highest in Tuscany (2.2%) and lowest in Denmark (0.5%). Of those prescribed an insulin during pregnancy, between 50.5% in Denmark and 88.8% in the Netherlands received an insulin analogue alone or in combination with human insulin, this proportion increasing over time. Oral products were mainly metformin and prescribing was highest in the 3 months before pregnancy. Metformin use during pregnancy increased in some countries. CONCLUSION: Pregestational diabetes is increasing in many areas of Europe. There is considerable variation between and within countries in the choice of medication for treating pregestational diabetes in pregnancy, including choice of insulin analogues and oral antidiabetics, and very large variation in the treatment of gestational diabetes despite international guidelines.

Asthma medication prescribing before, during and after pregnancy: a study in seven European regions.

OBJECTIVES: To explore utilisation patterns of asthma medication before, during and after pregnancy as recorded in seven European population-based databases. DESIGN: A descriptive drug utilisation study. SETTING: 7 electronic healthcare databases in Denmark, Norway, the Netherlands, Italy (Emilia Romagna and Tuscany), Wales, and the Clinical Practice Research Datalink representing the rest of the UK. PARTICIPANTS: All women with a pregnancy ending in a delivery that started and ended between 2004 and 2010, who had been present in the database for the year before, throughout and the year following pregnancy. MAIN OUTCOME MEASURES: The percentage of deliveries where the woman received an asthma medicine prescription, based on prescriptions issued (UK) or dispensed (non-UK), during the year before, throughout or during the year following pregnancy. Asthma medicine prescribing patterns were described for 3-month time periods and the choice of asthma medicine and changes in prescribing over the study period were evaluated in each database. RESULTS: In total, 1,165,435 deliveries were identified. The prevalence of asthma medication prescribing during pregnancy was highest in the UK and Wales databases (9.4% (CI95 9.3% to 9.6%) and 9.4% (CI95 9.1% to 9.6%), respectively) and lowest in the Norwegian database (3.7% (CI95 3.7% to 3.8%)). In the year before pregnancy, the prevalence of asthma medication prescribing remained constant in all regions. Prescribing levels peaked during the second trimester of pregnancy and were at their lowest during the 3-month period following delivery. A decline was observed, in all regions except the UK, in the prescribing of long-acting ß-2-agonists during pregnancy. During the 7-year study period, there were only small changes in prescribing patterns. CONCLUSIONS: Differences were found in the prevalence of prescribing of asthma medications during and surrounding pregnancy in Europe. Inhaled ß-2 agonists and inhaled corticosteroids were, however, the most popular therapeutic regimens in all databases.

Antiepileptic drug prescribing before, during and after pregnancy: a study in seven European regions.

PURPOSE: The aim of this study was to explore antiepileptic drug (AED) prescribing before, during and after pregnancy as recorded in seven population-based electronic healthcare databases. METHODS: Databases in Denmark, Norway, the Netherlands, Italy (Emilia Romagna/Tuscany), Wales and the Clinical Practice Research Datalink, representing the rest of the UK, were accessed for the study. Women with a pregnancy starting and ending between 2004 and 2010, which ended in a delivery, were identified. AED prescriptions issued (UK) or dispensed (non-UK) at any time during pregnancy and the 6 months before and after pregnancy were identified in each of the databases. AED prescribing patterns were analysed, and the choice of AEDs and co-prescribing of folic acid were evaluated. RESULTS: In total, 978 957 women with 1 248 713 deliveries were identified. In all regions, AED prescribing declined during pregnancy and was lowest during the third trimester, before returning to pre-pregnancy levels by 6 months following delivery. For all deliveries, the prevalence of AED prescribing during pregnancy was 51 per 10 000 pregnancies (CI95 49-52%) and was lowest in the Netherlands (43/10 000; CI95 33-54%) and highest in Wales (60/10 000; CI95 54-66%). In Denmark, Norway and the two UK databases lamotrigine was the most commonly prescribed AED; whereas in the Italian and Dutch databases, carbamazepine, valproate and phenobarbital were most frequently prescribed. Few women prescribed with AEDs in the 3 months before pregnancy were co-prescribed with high-dose folic acid: ranging from 1.0% (CI95 0.3-1.8%) in Emilia Romagna to 33.5% (CI95 28.7-38.4%) in Wales. CONCLUSION: The country's differences in prescribing patterns may suggest different use, knowledge or interpretation of the scientific evidence base. The low co-prescribing of folic acid indicates that more needs to be done to better inform clinicians and women of childbearing age taking AEDs about the need to offer and receive complete preconception care.