Identification of Pregnancy Adverse Drug Reactions in Pharmacovigilance Reporting Systems: A Novel Algorithm Developed in EudraVigilance.

INTRODUCTION: There is a need to strengthen the evidence base regarding medication use during pregnancy and to facilitate the early detection of safety signals. EudraVigilance (EV) serves as the primary system for managing and analysing information concerning suspected adverse drug reactions (ADRs) within the European Economic Area. Despite its various functionalities, the current format for electronic submissions of safety reports lacks a specific data element indicating medicine exposure during pregnancy. OBJECTIVE: This paper aims to address the limitations of existing approaches by developing a rule-based algorithm in EV that more reliably identifies cases that are truly representative of an ADR during pregnancy. METHODS: The study utilised the standardised MedDRA query (SMQ) 'Pregnancy and neonatal topics' (PNT) as a benchmark for comparison. Recognising that the SMQ PNT also retrieves healthy pregnancy outcomes, contraceptive failure, failed abortifacients as well as ADRs not associated with pregnancy, a novel algorithm was tailored to improve the accuracy of identifying suspected ADRs occurring during pregnancy. RESULTS: Upon testing, the algorithm demonstrated superior performance, correctly predicting 90% of cases reporting an ADR during pregnancy, compared to 54% achieved by the SMQ PNT. The implementation of the algorithm in EV led to the retrieval of 202,426 cases. CONCLUSION: The development and successful testing of the novel algorithm represents a step forward in pregnancy-specific signal detection in EV. Because signals associated with pregnancy may be diluted in a large database such as EV, this study lays the groundwork for future research to evaluate the effectiveness of disproportionality methods on a more refined subset of pregnancy-related ADR reports.

Involvement of the European Medicines Agency in multi-stakeholder regulatory science research projects: experiences of staff members and project coordinators.

Background: The European Medicines Agency (EMA) interacts with many different stakeholders involved in the development of drugs, including academic researchers. In recent years, EMA has collaborated more closely with academia, inter alia by taking part in external research projects such as those set up under the Horizon 2020 program in general and the Innovative Medicines Initiative in particular. The aim of this study was to evaluate the perceived added value of EMA's involvement in these projects, both from the perspective of the Agency's participating Scientific Officers and of the coordinators of the consortia that undertook them. Methods: Semi-structured interviews were conducted with the coordinators of 21 ongoing or recently finalized projects in which EMA has participated, as well as with the Agency experts contributing to them. Results: In total, 40 individuals were interviewed, of whom 23 were project coordinators and 17 were EMA staff members. While most of the projects were reported to suffer from delays due to the SARS-CoV-2 pandemic, the consortia adapted to the circumstances and their members still expected to deliver on their objectives. EMA's input into the projects ranged from providing guidance by reviewing documents and attending meetings to creating project materials and disseminating them. The frequency of communication between EMA and the consortia varied widely. The projects generated a diverse set of outputs, which encompassed new or improved medicinal products, methodological standards, research infrastructures, and educational tools. All of the coordinators expressed that EMA's contributions to their projects had increased the scientific relevance of their consortium's work, and the EMA experts found that the knowledge and the deliverables produced by the projects were valuable, taking into consideration the time they had invested into them. In addition, interviewees highlighted some actions which could be taken to increase the regulatory significance of the project outcomes. Conclusion: EMA's engagement in external research projects benefits the consortia conducting them and supports the Agency's mission to foster scientific excellence and advance regulatory science.

Assuring Access to Safe Medicines in Pregnancy and Breastfeeding.

Scientists and regulators in Europe and the United States continue to seek methods and strategies to improve knowledge on rational use of medicines for pregnant and breastfeeding populations, an important subset of women's health. Regulatory agencies have made strides toward improvement, but much more is needed. Recognizing the importance of international collaboration, we have begun to consider how to address these important public health issues more globally. The health of the child begins with the health of the mother.

Strengthening regulatory science in academia: STARS, an EU initiative to bridge the translational gap.

Truly disruptive medicine innovation and new treatment paradigms tend to start in non-commercial research institutions. However, the lack of mutual understanding between medicine developers and regulators when it comes to medicine development significantly delays or even prevents the access of patients to these innovations. Here, we outline what regulatory-related barriers hamper the translational development of novel products or new treatment paradigms initiated in academia, and propose key steps towards improved regulatory dialogue among academia, funding bodies and regulatory authorities. Moreover, we briefly describe how the STARS (Strengthening Training of Academia in Regulatory Science) project aims to reach out to medicine innovators in academia to bridge the regulatory knowledge gap and enhance this dialogue to facilitate the implementation of academic research findings in clinical practice.

The Clinical Practice Research Datalink for drug safety in pregnancy research: an overview.

Medicine use during pregnancy is common; however the safety of medicine use during pregnancy is largely unknown when a medicine comes to market. Electronic healthcare databases, including the Clinical Practice Research Datalink (CPRD), are increasingly being used for post-marketing surveillance in this field. The CPRD contains anonymised, longitudinal medical records routinely collected in primary care. Using CPRD data it is possible to identify medical records indicative of pregnancy, including pregnancy losses. Data on prescriptions issued can be used to determine maternal exposure and for about 80% of pregnancies it is possible to link the mother's medical record to the medical record of the child. Data in the medical records of the mother and child can then be used to identify adverse pregnancy outcomes, including congenital malformations. This paper describes some of the complexities involved in using CPRD data for pregnancy related research and discusses some of its strengths and limitations.

Healthcare databases in Europe for studying medicine use and safety during pregnancy.

PURPOSE: The aim of this study was to describe a number of electronic healthcare databases in Europe in terms of the population covered, the source of the data captured and the availability of data on key variables required for evaluating medicine use and medicine safety during pregnancy. METHODS: A sample of electronic healthcare databases that captured pregnancies and prescription data was selected on the basis of contacts within the EUROCAT network. For each participating database, a database inventory was completed. RESULTS: Eight databases were included, and the total population covered was 25 million. All databases recorded live births, seven captured stillbirths and five had full data available on spontaneous pregnancy losses and induced terminations. In six databases, data were usually available to determine the date of the woman's last menstrual period, whereas in the remainder, algorithms were needed to establish a best estimate for at least some pregnancies. In seven databases, it was possible to use data recorded in the databases to identify pregnancies where the offspring had a congenital anomaly. Information on confounding variables was more commonly available in databases capturing data recorded by primary-care practitioners. All databases captured maternal co-prescribing and a measure of socioeconomic status. CONCLUSION: This study suggests that within Europe, electronic healthcare databases may be valuable sources of data for evaluating medicine use and safety during pregnancy. The suitability of a particular database, however, will depend on the research question, the type of medicine to be evaluated, the prevalence of its use and any adverse outcomes of interest. © 2014 The Authors. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons, Ltd.

Guillain-Barré syndrome and adjuvanted pandemic influenza A (H1N1) 2009 vaccines: a multinational self-controlled case series in Europe.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Colorectal cancer risk reduction following macrogol exposure: a cohort and nested case control study in the UK.

BACKGROUND AND AIMS: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

International collaboration to assess the risk of Guillain Barré Syndrome following Influenza A (H1N1) 2009 monovalent vaccines.

BACKGROUND: The global spread of the 2009 novel pandemic influenza A (H1N1) virus led to the accelerated production and distribution of monovalent 2009 Influenza A (H1N1) vaccines (pH1N1). This pandemic provided the opportunity to evaluate the risk of Guillain-Barré syndrome (GBS), which has been an influenza vaccine safety concern since the swine flu pandemic of 1976, using a common protocol among high and middle-income countries. The primary objective of this project was to demonstrate the feasibility and utility of global collaboration in the assessment of vaccine safety, including countries both with and without an established infrastructure for vaccine active safety surveillance. A second objective, included a priori, was to assess the risk of GBS following pH1N1 vaccination. METHODS: The primary analysis used the self-controlled case series (SCCS) design to estimate the relative incidence (RI) of GBS in the 42 days following vaccination with pH1N1 vaccine in a pooled analysis across databases and in analysis using a meta-analytic approach. RESULTS: We found a relative incidence of GBS of 2.42 (95% CI 1.58-3.72) in the 42 days following exposure to pH1N1 vaccine in analysis of pooled data and 2.09 (95% CI 1.28-3.42) using the meta-analytic approach. CONCLUSIONS: This study demonstrates that international collaboration to evaluate serious outcomes using a common protocol is feasible. The significance and consistency of our findings support a conclusion of an association between 2009 H1N1 vaccination and GBS. Given the rarity of the event the relative incidence found does not provide evidence in contradiction to international recommendations for the continued use of influenza vaccines.

Asthma management in pregnancy.

BACKGROUND: Asthma is common during pregnancy, however research is limited regarding the extent and timing of changes in asthma management associated with pregnancy. OBJECTIVE: 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. METHODS: 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. RESULTS: 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 ß2-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). CONCLUSION: 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.

Pandemic influenza vaccination during pregnancy: an investigation of vaccine uptake during the 2009/10 pandemic vaccination campaign in Great Britain.

BACKGROUND: Pregnant women in Great Britain were recommended to receive influenza A(H1N1)pdm09 vaccines during the 2009/10 influenza pandemic, however uptake of the vaccines by pregnant women was reported to have been very low. AIM: We sought to estimate uptake of influenza A(H1N1)pdm09 vaccines and to investigate predictors of vaccine uptake in pregnant women in Great Britain during the 2009/10 pandemic. RESULTS: Uptake of influenza A(H1N1)pdm09 vaccines by pregnant women was 21.6%. Pregnant women with an underlying health condition increasing the risk of influenza-related complications had a higher vaccination rate than pregnant women without such conditions. The hazard ratio comparing these two groups decreased logarithmically throughout pregnancy from 9.3 in the first week to 1.3 by the end of pregnancy. Increasing maternal age (HR 1.01, CI 95 1.01-1.01), having a previous delivery recorded (HR 1.21, CI95 1.16-1.27) and living in Scotland (HR 2.58, CI95 2.34-2.85) or Wales (HR 1.37, CI95 1.20-1.57) as opposed to England were all also associated with an increase in vaccination uptake rates throughout pregnancy. DISCUSSION: Uptake of influenza A(H1N1)pdm09 vaccines by pregnant women was low. None of the potential predictors evaluated in this study were strong enough to account for this, however information on health beliefs and GP recommendation were not available. If the low rates reported here are to be improved new strategies to increase uptake of influenza vaccine in pregnant women need to be identified, evaluated and implemented. METHODS: Uptake rates were calculated using data from the UK General Practice Research Database (GPRD). Predictors of vaccination were identified using a Cox proportional hazards model.

Smoking and delay to diagnosis are associated with poorer functional outcome in psoriatic arthritis.

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.

Transplantation for acute liver failure in patients exposed to NSAIDs or paracetamol (acetaminophen): the multinational case-population SALT study.

BACKGROUND: Most NSAIDs are thought to be able to cause hepatic injury and acute liver failure (ALF), but the event rates of those leading to transplantation (ALFT) remain uncertain. OBJECTIVES: The aim of the study was to estimate population event rates for NSAID-associated ALFT METHODS: This was a case-population study of ALFT in 57 eligible liver transplant centres in seven countries (France, Greece, Ireland, Italy, The Netherlands, Portugal and the UK). Cases were all adults registered from 2005 to 2007 for a liver transplant following ALFT without identified clinical aetiology, exposed to an NSAID or paracetamol (acetaminophen) within 30 days before the onset of clinical symptoms. NSAID and paracetamol population exposures were assessed using national sales data from Intercontinental Marketing Services (IMS). Risk was estimated as the rate of ALFT per million treatment-years (MTY). RESULTS: In the 52 participating centres, 9479 patients were registered for transplantation, with 600 for ALFT, 301 of whom, without clinical aetiology, had been exposed to a drug within 30 days. Of these 301 patients, 40 had been exposed to an NSAID and 192 to paracetamol (81 of whom were without overdose). Event rates per MTY were 1.59 (95 % CI 1.1-2.2) for all NSAIDs pooled, 2.3 (95 % CI 1.2-3.9) for ibuprofen, 1.9 (95 % CI 0.8-3.7) for nimesulide, 1.6 (95 % CI 0.6-3.4) for diclofenac and 1.6 (95 % CI 0.3-4.5) for ketoprofen. For paracetamol, the event rate was 3.3 per MTY (95 % CI 2.6-4.1) without overdoses and 7.8 (95 % CI 6.8-9.0) including overdoses. CONCLUSIONS: ALF leading to registration for transplantation after exposure to an NSAID was rare, with no major difference between NSAID. Non-overdose paracetamol-exposed liver failure was twice more common than NSAID-exposed liver failure.

Methodology for a multinational case-population study on liver toxicity risks with NSAIDs: the Study of Acute Liver Transplant (SALT).

PURPOSE: The European Committee for Human Medicinal Products (CHMP) requested a multinational study with the aim to investigate the risk of acute liver failure (ALF) leading to registration for transplantation in patients exposed to non-steroidal anti-inflammatory drugs (NSAIDs). The method of this multinational, multicentre, retrospective case-population study, named SALT (Study of Acute Liver Transplant), is documented here. METHODS: This was a multicentre, multinational retrospective case-population study performed in France, Italy, Portugal, Greece, Ireland, the Netherlands and the UK. The study period was 3 years (1 January 2005-31 December 2007). Cases were patients ≥ 18 years of age with ALF at the time of registration on the transplant list for liver transplantation who had been exposed to an NSAID within 30 days preceding the initial symptoms of liver disease (index date). Exposure was defined as exposure to any NSAID. Per country rates of NSAID-exposed transplantation-registered ALF were computed as the ratio of the number of cases identified in the country to total population exposure. Overall and per-drug sales for NSAIDs and for paracetamol were obtained from Intercontinental Marketing Services (IMS) Health for all participating countries. Population exposure was measured as the defined daily dose and as estimated annual number of patients exposed (primary endpoint) with 95 % confidence intervals. RESULTS: The study protocol was approved by the CHMP. Of the 57 eligible liver transplant centres, 54 agreed to participate in the study. All national authorizations were received with relevant administrative burden, mainly due to bureaucracy. CONCLUSION: The present study created a multinational research network to estimate population-based absolute rates of drug-exposed ALF leading to registration on the transplantation list. This study design was chosen to obtain a fast response to a public health issue, namely, that of an increased risk of a rare, very serious adverse reaction. This model could be used to study other drug-related issues in ALF.

The incidence of narcolepsy in Europe: before, during, and after the influenza A(H1N1)pdm09 pandemic and vaccination campaigns.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Colorectal cancer incidence on the General Practice Research Database.

PURPOSE: The General Practice Research Database (GPRD) contains longitudinal patient medical records collected within UK primary care. This study aimed to identify incident cases of colorectal cancer on the GPRD and to compare incidence rates for 2007 with those reported by the UK cancer registries. METHODS: Algorithms were created to identify incident cases of colorectal cancer on the GPRD and cases were required to have additional medical codes to support the diagnosis. Age-specific and sex-specific incidence rates for 2007 were calculated using the GPRD data and compared with those reported by the cancer registries. RESULTS: Trends in colorectal cancer by age and sex were similar for the two data sources; however, the incidence of colorectal cancer on the GPRD was lower than that of the registries, particularly when supporting evidence was required: 57.0 compared with 70.2 per 100 000 per year for men and 42.0 compared with 56.6 per 100 000 per year for women. Inclusion of cases without supporting evidence still resulted in lower rates but increased the GPRD rates to 63.7 and 48.4 for men and women, respectively. The largest discrepancy was observed in the older age groups. CONCLUSION: Colorectal cancer rates on the GPRD were lower than those reported by UK cancer registries, especially when requiring supporting evidence in addition to a diagnosis code. It appears that the requirement of supporting evidence on the GPRD for colorectal cancer identification may result in some true cases being excluded, particularly in the very elderly. Copyright © 2012 John Wiley & Sons, Ltd.

Administrative complexities for a European observational study despite directives harmonising requirements.

PURPOSE: For pharmacoepidemiological studies in Europe, accessing data should require only authorisation by the relevant data protections committees, as expected from the 1995 Data Protection Directive (95/46/EC). Our experience from a multinational observational study across seven European countries shows that this is certainly not the case. METHODS: The study was a multicentre, multinational, case-population study in European liver transplant centres in seven countries, retrospectively evaluating a 3-year period. Before data collection started, the procedures to obtain the necessary authorisations for the participating countries were defined. REMARKS: In France, a single opinion from a single data protection committee was enough to start the study. In Italy, Portugal, Greece and the UK, there was a national authority, but the hospitals requested the approval by their local committees/bodies irrespective of whether the authorisation of the national committee came after or before that of local ones. In Ireland, only one hospital participated, and the opinion of its ethics committee was sufficient. In the Netherlands, the opinion of the institutional review board of the local coordinating centre was necessary to obtain the opinions from the institutional review boards of the other hospitals. The information requested by the different committees and the time to obtain the approvals varied, even within the same country. CONCLUSION: This degree of complexity and disharmony, and resulting cost, was observed in a simple retrospective study. Regulators will need to be aware that these time-consuming, expensive and useless complexities must be factored in when estimating the time and cost of a study.

Evaluating the hazard of foetal death following H1N1 influenza vaccination; a population based cohort study in the UK GPRD.

BACKGROUND: 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. METHODOLOGY/PRINCIPAL FINDINGS: 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. CONCLUSIONS/SIGNIFICANCE: 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.