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To evaluate the risk of foetal loss associated with pandemic influenza vaccination in pregnancy. Retrospective cohort study. UK General Practice Research Database Pregnancies ending in delivery or spontaneous foetal death after 21 October 2009 and starting before 01 January 2010. Hazard ratios of foetal death for vaccinated compared to unvaccinated pregnancies were estimated for gestational weeks 9 to 12, 13 to 24 and 25 to 43 using discrete-time survival analysis. Separate models were specified to evaluate whether the potential effect of vaccination on foetal loss might be transient (for ~4 weeks post vaccination only) or more permanent (for the duration of the pregnancy). 39,863 pregnancies meeting our inclusion criteria contributed a total of 969,322 gestational weeks during the study period. 9,445 of the women were vaccinated before or during pregnancy. When the potential effect of vaccination was assumed to be transient, the hazard of foetal death during gestational weeks 9 through 12 (HR(unadj) 0.56; CI(95) 0.43 to 0.73) and 13 through 24 (HR(unadj) 0.45; CI(95) 0.28 to 0.73) was lower in the 4 weeks after vaccination than in other weeks. Where the more permanent exposure definition was specified, vaccinated pregnancies also had a lower hazard of foetal loss than unvaccinated pregnancies in gestational weeks 9 through 12 (HR(unadj) 0.74; CI(95) 0.62 to 0.88) and 13 through 24 (HR(unadj) 0.59; CI(95) 0.45 to 0.77). There was no difference in the hazard of foetal loss during weeks 25 to 43 in either model. Sensitivity analyses suggest the strong protective associations observed may be due in part to unmeasured confounding. Influenza vaccination during pregnancy does not appear to increase the risk of foetal death. This study therefore supports the continued recommendation of influenza vaccination of pregnant women.

Asthma is common during pregnancy, however research is limited regarding the extent and timing of changes in asthma management associated with pregnancy. To determine the prevalence of asthma during pregnancy and identify changes in treatment and asthma exacerbation rates associated with pregnancy, while controlling for seasonal influences. Pregnant women with asthma were identified from the UK General Practice Research Database between 2000 and 2008. For each woman asthma medication prescribed during the study period was identified; for each product combination the British Thoracic Society medication-defined asthma treatment step was identified. Asthma exacerbations were identified during pregnancy and in the corresponding 12 months prior. Analyses of changes in asthma treatment and exacerbation rates during pregnancy relative to the corresponding period 12 months prior, to control for seasonality, were stratified by trimester and asthma treatment intensity level. The prevalence of treated asthma in pregnancies resulting in a delivery was 8.3%. From 14,141 pregnancies, in 12,828 women with asthma, 68.4% received prescriptions for a short-acting β2-agonist and 41.2% for inhaled corticosteroids; 76.5% were managed with asthma treatment Step 1 or 2. Poor persistence to inhaled corticosteroids, defined as a gap of up to 60 days between prescriptions, was common. In 45.0% of pregnancies, an increase in average treatment step was observed whereas in 25.6% the treatment step decreased. Treatment intensity remained the same in 29.5% of pregnancies. Exacerbations occurred in 4.8% of pregnancies compared to 5.9% in the same season the year before (p<0.001). Exacerbation rates during pregnancy were slightly lower than in the year before. However, treatment patterns and exacerbation rates in this study suggest asthma control during pregnancy is variable, and women may require close monitoring especially in those with evidence of poor control before pregnancy.

Background: A systematic review of literature published between 1980 and 2007, on the incidence of myasthenia gravis, was undertaken. Methods: All relevant papers found through searches of Medline, Embase and Science Direct were critically appraised and an assessment was made of the reliability of the reported incidence data. Results: Thirty-one studies were included in the review, the majority of which investigated populations in Europe. The incidence rates reported were between 3.0 and 30.0/1,000,000/year. However, it is thought that the rates at the upper end of this range, reported by the prospective studies, provided the most accurate estimates. Overall, incidence rates have increased over time owing to a greater awareness of the disease and improved methods of diagnosis. Conclusions: The most accurate estimate of incidence of myasthenia gravis was around 30/ 1,000,000/year. The incidence in children and adolescents aged 0–19 years was found to be between 1.0 and 5.0/ 1,000,000/year. The rates presented in this review are likely to be an underestimate of the true incidence rates, as mild cases will have been missed and cases in the elderly will have been misdiagnosed.

The risk of Guillain-Barré syndrome (GBS) following the United States' 1976 swine flu vaccination campaign in the USA led to enhanced active surveillance during the pandemic influenza (A(H1N1)pdm09) immunization campaign. This study aimed to estimate the risk of GBS following influenza A(H1N1)pdm09 vaccination. A self-controlled case series (SCCS) analysis was performed in Denmark, Finland, France, Netherlands, Norway, Sweden, and the United Kingdom. Information was collected according to a common protocol and standardised procedures. Cases classified at levels 1-4a of the Brighton Collaboration case definition were included. The risk window was 42 days starting the day after vaccination. Conditional Poisson regression and pooled random effects models estimated adjusted relative incidences (RI). Pseudo likelihood and vaccinated-only methods addressed the potential contraindication for vaccination following GBS. Three hundred and three (303) GBS and Miller Fisher syndrome cases were included. Ninety-nine (99) were exposed to A(H1N1)pdm09 vaccination, which was most frequently adjuvanted (Pandemrix and Focetria). The unadjusted pooled RI for A(H1N1)pdm09 vaccination and GBS was 3.5 (95% Confidence Interval (CI): 2.2-5.5), based on all countries. This lowered to 2.0 (95% CI: 1.2-3.1) after adjustment for calendartime and to 1.9 (95% CI: 1.1-3.2) when we accounted for contra-indications. In a subset (Netherlands, Norway, and United Kingdom) we further adjusted for other confounders and there the RI decreased from 1.7 (adjusted for calendar month) to 1.4 (95% CI: 0.7-2.8), which is the main finding. This study illustrates the potential of conducting European collaborative vaccine safety studies. The main, fully adjusted analysis, showed that the RI of GBS was not significantly elevated after influenza A(H1N1)pdm09 vaccination (RI = 1.4 (95% CI: 0.7-2.8). Based on the upper limits of the pooled estimate we can rule out with 95% certainty that the number of excess GBS cases after influenza A(H1N1)pdm09 vaccination would be more than 3 per million vaccinated.

Objective To identify predictors of poorer physical function in established psoriatic arthritis (PsA). Methods PsA patients with disease duration of ≥10 years were identified from the Bath longitudinal cohort. Physical function was assessed using the Stanford Health Assessment Questionnaire (HAQ). Sex, age at diagnosis, duration of symptoms prior to diagnosis, smoking, treatment and year of diagnosis were included in a multivariable regression analysis to identify associations with HAQ. Results 267 patients were identified for inclusion. The median age was 56 years (IQR 45–63), median disease duration was 13 years (IQR 10–18) and median HAQ score was 0.63 (IQR 0.13–1.25). The model predicted significant increases in HAQ related to smoking (0.23, 95% CI 0.04 to 0.42), age >50 years at diagnosis (0.27, 95% CI 0.03 to 0.51), symptom duration of ≥1 year before diagnosis (0.22, 95% CI 0.02 to 0.42), female sex (0.39, 95% CI 0.20 to 0.57) and history of treatment with an anti-TNF agent (0.63, 95% CI 0.32 to 0.93) at follow-up. Conclusions Smoking, delay to diagnosis, older age at diagnosis, female sex and a history of anti-TNF treatment are associated with worse physical function in established PsA.

Animal studies have demonstrated macrogol laxatives may reduce colorectal cancer (CRC) risk. This study aimed to investigate the association between macrogol prescribing and CRC risk. A case-control study nested within a cohort of laxative users was conducted using data from the UK General Practice Research Database. Six controls per case were identified and to account for the lead time of CRC, additional control sets were selected on the index date backdated by 1 to 5 years. Exposure to macrogols and covariate status before each of the backdated index dates was established. Conditional logistic regression was used to calculate the risk of CRC following macrogol prescribing adjusted for potential confounders. 4734 incident CRC cases were identified; 2722, 2195, 1789, 1481 and 1214 had received a laxative prescription before the index dates backdated by 1 to 5 years. A suggestion of a non-significant reduction in CRC risk associated with 'macrogol after other laxative' prescribing was observed when the index date was backdated by 1 and 2 years, ORadj = 0.87 (CI950.74-1.03) and ORadj = 0.80 (CI950.65-1.00) compared to non-macrogol laxative exposure. The odds ratios reduced further and were significant when backdated by 3, 4 and 5 years, ORadj = 0.68 (CI950.50-0.92), ORadj = 0.60 (CI950.40-0.90) and ORadj = 0.30 (CI950.14-0.64) respectively. This reduction in risk was not observed, however, for 'macrogol only' and 'macrogol before other laxative' exposure categories. In this study we observed a reduced CRC risk associated with macrogol prescribing after accounting for the lead time for CRC. Further studies are required to determine whether the association is causal and whether it can partly be explained by selective prescribing.

This systematic literature review of the epidemiology of Guillain-Barré syndrome (GBS) identifies trends in incidence rates by age, study method and cause of disease. It is important to have a reliable estimate of incidence to determine and investigate any changes: no previous systematic reviews of GBS have been found. After critical assessment of the reliability of the reported data, incidence rates were extracted from all relevant papers published between 1980 and 2008, identified through searches of Medline, Embase and Science Direct. Sixty-three papers were included in this review; these studies were prospective, retrospective reviews of medical records or retrospective database studies. Ten studies reported on the incidence in children (0-15 years old), and found the annual incidence to be between 0.34 and 1.34/100,000. Most studies investigated populations in Europe and North America and reported similar annual incidence rates, i.e. between 0.84 and 1.91/100,000. A decrease in incidence over the time between the 1980s and 1990s was found. Up to 70% of cases of GBS were caused by antecedent infections. Our best estimate of the overall incidence of GBS was between 1.1/100,000/year and 1.8/100,000/year. The incidence of GBS increased with age after 50 years from 1.7/100,000/year to 3.3/100,000/year.

Research on sex differences in central nervous system disorders has developed substantially in recent years. Here, we discuss selected examples and the implications for drug development.Research on sex differences in central nervous system disorders has developed substantially in recent years. Here, we discuss selected examples and the implications for drug development.

► We identified 2608 narcolepsy cases in 6 EU countries between 2000 and 2010. ► After pandemic vaccination, incidence rates increased in Finland, Sweden and Denmark. ► In Denmark, the increase did not follow high pandemic vaccination coverage. ► In Italy, the Netherlands and the United Kingdom no increased rates were seen. In August 2010 reports of a possible association between exposure to AS03 adjuvanted pandemic A(H1N1)pdm09 vaccine and occurrence of narcolepsy in children and adolescents emerged in Sweden and Finland. In response to this signal, the background rates of narcolepsy in Europe were assessed to rapidly provide information for signal verification. We used a dynamic retrospective cohort study to assess the narcolepsy diagnosis rates during the period 2000–2010 using large linked automated health care databases in six countries: Denmark, Finland, Italy, the Netherlands, Sweden and the United Kingdom. Overall, 2608 narcolepsy cases were identified in almost 280 million person years (PY) of follow up. The pooled incidence rate was 0.93 (95% CI: 0. 90–0.97) per 100,000 PY. There were peaks between 15 and 30 year of age (women>men) and around 60 years of age. In the age group 5–19 years olds rates were increased after the start of pandemic vaccination compared to the period before the start of campaigns, with rate ratios (RR) of 1.9 (95% CI: 1.1–3.1) in Denmark, 6.4 (95% CI: 4.2–9.7) in Finland and 7.5 (95% CI: 5.2–10.7) in Sweden. Cases verification in the Netherlands had a significant effect on the pattern of incidence over time. The results of this incidence study provided useful information for signal verification on a population level. The safety signal of increased narcolepsy diagnoses following the start of the pandemic vaccination campaign as observed in Sweden and Finland could be observed with this approach. An increase in narcolepsy diagnoses was not observed in other countries, where vaccination coverage was low in the affected age group, or did not follow influenza A(H1N1)pdm09 vaccination. Patient level analyses in these countries are being conducted to verify the signal in more detail.

[...]when medicines are needed to treat disorders that occur in pregnancy or during the breastfeeding period, or when unintended exposure to medicines occurs in unplanned pregnancies, there is uncertainty regarding the choice of treatment and the potential impact on the child. While post-authorization studies are sometimes requested to collect safety data in pregnant and breastfeeding individuals, usually, routine pharmacovigilance (signal detection and post-authorization safety update reports) is relied upon for generating information in this population once the products are on the market.1,2 The overall consequence is possible under-prescription of medicines in these individuals and missing or ambiguous pregnancy-specific dosing recommendations in the SmPC (Summary of Product Characteristics).3,4 Hence, before, and long after real-world evidence is available, the use of medicinal products tends to be discouraged during pregnancy and breastfeeding. From a physiology and pharmacology point of view, pregnant and breastfeeding individuals represent complex and dynamic systems.9 MIDD approaches, including population pharmacokinetics/pharmacodynamics, physiologically-based pharmacokinetic modeling, and quantitative systems pharmacology, can integrate available knowledge on the drug pharmacology, in vitro or in vivo nonclinical data and clinical data to quantify these complex systems and enable predictions of drug exposure and clinical response during pregnancy and lactation. Among the different MIDD approaches, physiology-based pharmacokinetic (PBPK) modeling is expected by drug developers and regulators alike to have a prominent role in drug development in pregnant and breastfeeding individuals, given its ability to distinctly describe physiological and pharmacological processes.10,11 Already, different software providers are including pregnancy and lactation modules in their platforms.12–14 PBPK can serve for early-in-development PK prediction by integrating drug parameters, systems knowledge (i.e., changes in absorption, distribution, metabolism, excretion (ADME) in pregnancy, lactating mother, neonate-infant, transplacental or/and mammary gland drug transfer), in vitro data (permeability, metabolism, active transporters, etc.) and in vivo data from nonclinical and clinical experiments.