B Keller-Stanislawski

Paul-Ehrlich-Institut, Langen, Hesse, Germany

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Publications (65)128.51 Total impact

  • Markus B Funk · Marion Frech · Robert Spranger · Brigitte Keller-Stanislawski
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    ABSTRACT: Cell-based medicinal products (CBMPs), a category of advanced-therapy medicinal products (ATMPs), are authorised for the European market by the European Commission by means of the centralized marketing authorisation. By conforming to the German Medicinal Products Act (Sec. 4b AMG), national authorisation can be granted by the Paul-Ehrlich-Institut in Germany exclusively for ATMPs not based on a routine manufacturing procedure. In both procedures, quality, efficacy, and safety are evaluated and the risk-benefit balance is assessed. For the centralised procedure, mainly controlled clinical trial data must be submitted, whereas the requirements for national procedures could be modified corresponding to the stage of development of the ATMP. After marketing authorization, the marketing authorization/license holder is obligated to report all serious adverse reactions to the competent authority and to provide periodic safety update reports. If necessary, post-authorization safety studies could be imposed. On the basis of these regulatory measures, the safety of advanced therapies can be monitored and improved.
    Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz 09/2015; DOI:10.1007/s00103-015-2240-4 · 1.42 Impact Factor
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    ABSTRACT: PML;progressive multifocal leukoencephalopathy;regulatory decision making
    Clinical Pharmacology &#38 Therapeutics 08/2015; DOI:10.1002/cpt.199 · 7.90 Impact Factor
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    ABSTRACT: Increased reporting of intravenous immunoglobulin (IVIG)-related hemolytic reactions (HRs) triggered an investigation by the German and Swiss health authorities to identify potential risk factors. From the EudraVigilance database HRs reported between 2008 and 2013 were retrieved for seven IVIG preparations. HRs were classified as mild to moderate (hemoglobin [Hb] decline < 2 g/dL)] or severe (Hb decline > 2 g/dL) and separately analyzed for IVIG doses of less than 2 g/kg body weight and 2 g/kg body weight or more. It was assessed whether HR reporting rates correlate with the isoagglutinin content of the different preparations. Of 569 HR cases retrieved, 103 cases were excluded due to insufficient data, leaving 466 for analysis. Ninety-three cases were classified as mild to moderate and 373 as severe. Approximately 80% of the severe HRs concerned patients with blood group A and only three patients with blood group O. Testing of isoagglutinin titers revealed substantial differences between the seven preparations. IVIG products with high anti-A/anti-B titers (≥32) had elevated HR reporting rates, particularly when cumulative doses at least 2 g/kg were administered. The isoagglutinin content of IVIGs correlates with the risk for HRs. Exclusion of high-titer donations and manufacturing steps that deplete isoagglutinins should be considered for risk mitigation. In patients with blood groups A or AB receiving doses of at least 2 g/kg, the use of IVIG batches with low isoagglutinin titers should be considered to prevent HRs. © 2015 AABB.
    Transfusion 07/2015; 55 Suppl 2(S2):S13-22. DOI:10.1111/trf.13113 · 3.23 Impact Factor
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    M. Funk · M. Frech · A. Lohmann · B. Keller-Stanislawski
    05/2015; 5(02):102-107. DOI:10.1055/s-0034-1397766
  • Markus B. Funk · Margarethe Heiden · Peter Volkers · Annette Lohmann · Brigitte Keller-Stanislawski
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    ABSTRACT: Background: To assess the impact of safety measures, we compared reporting rates of transfusion-related reactions before and after the implementation of six measures in 1999, 2004, 2006, 2008 and 2009. Methods: Reporting rates of transfusion-transmitted bacterial infection (TTBI), viral infection (TTVI) and immune-mediated transfusion-related acute lung injury (TRALI) were calculated on the basis of confirmed annual reports and distributed blood components. Results: The introduction of HCV NAT testing caused a significant reduction of HCV reporting rate from 1:0.6 to 1:83.16 million administered blood components (p Conclusion: On the basis of haemovigilance data, a significant benefit could be demonstrated for four of six implemented safety measures.
    Transfusion Medicine and Hemotherapy 05/2015; 42(4):240-246. DOI:10.1159/000381996 · 1.82 Impact Factor
  • Doris Oberle · Ursula Drechsel-Bäuerle · Irene Schmidtmann · Geert Mayer · Brigitte Keller-Stanislawski
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    ABSTRACT: Following the 2009 pandemic, reports of an association between an AS03 adjuvanted H1N1 pandemic influenza vaccine and narcolepsy were published. Besides determining background incidence rates for narcolepsy in Germany this study aimed at investigating whether there was a change in incidence rates of narcolepsy between the pre-pandemic, pandemic, and the post-pandemic period on the population level. Retrospective epidemiological study on the incidence of narcolepsy with additional capture-recapture analysis. German sleep centers. Eligible were patients with an initial diagnosis of narcolepsy (ICD10 Code G47.4) within the period from 1 January 2007 to 31 December 2011. None; observational study. A total of 342 sleep centers were invited to participate in the study. Adequate and suitable data were provided by 233 sleep centers (68.1%). A total of 1198 patients with an initial diagnosis of narcolepsy within the observed period were included, of whom 106 (8.8%) were children and adolescents under the age of 18 years and 1092 (91.2%) were adults. In children and adolescents, the age-standardized adjusted incidence rate significantly increased from 0.14/100,000 person-years in the pre-pandemic period to 0.50/100,000 person-years in the post-pandemic period (incidence density ratio, IDR 3.57; 95% CI 1.94-7.00). In adults, no significant change was detectable. This increase started in spring 2009. For the years 2007-2011, valid estimates for the incidence of narcolepsy in Germany were provided. In individuals under 18, the incidence rates continuously increased from spring 2009. Copyright © 2015 Associated Professional Sleep Societies, LLC. All rights reserved.
    Sleep 03/2015; 38(10). DOI:10.5665/sleep.5060 · 4.59 Impact Factor
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    ABSTRACT: Vaccine-preventable infectious diseases are responsible for significant maternal, neonatal, and young infant morbidity and mortality. While there is emerging scientific evidence, as well as theoretical considerations, indicating that certain vaccines are safe for pregnant women and fetuses, policy formulation is challenging because of perceived potential risks to the fetus. This report presents an overview of available evidence on pregnant women vaccination safety monitoring in pregnant women, from both published literature and ongoing surveillance programs. Safety data were reviewed for vaccines against diseases which increase morbidity in pregnant women, their fetus or infant as well as vaccines which are used in mass vaccination campaigns against diseases. They include inactivated seasonal and pandemic influenza, mono- and combined meningococcal polysaccharide and conjugated vaccines, tetanus toxoid and acellular pertussis combination vaccines, as well as monovalent or combined rubella, oral poliomyelitis virus and yellow fever vaccines. No evidence of adverse pregnancy outcomes has been identified from immunization of pregnant women with these vaccines.
    Vaccine 10/2014; 32(52). DOI:10.1016/j.vaccine.2014.09.052 · 3.62 Impact Factor
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    D Oberle · A C Jenke · R von Kries · D Mentzer · B Keller-Stanislawski
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    ABSTRACT: Recently published pharmacoepidemiological studies associate the currently authorized Rotavirus (RV) vaccines with intussusception (IS). We aimed at investigating whether, in Germany, there are excess IS cases in RV vaccinees compared with the background incidence before market authorization in 2006. Suspected cases of IS following receipt of RV vaccines reported to the Paul-Ehrlich-Institut (PEI) from 2006 to 2010 were reviewed and validated against the criteria of the Brighton Collaboration's definition for IS. An observed-versus-expected analysis was conducted using standardized morbidity ratio (SMR) methods based on age-specific incidence rates for IS ranging from 19.2 to 98.5 per 100,000 person-years. A total of 27 cases of suspected IS in RV vaccinees were reported to the PEI. No excess of IS cases could be detected 1-7 days after receipt of either RV vaccine after any dose in the first year of life; however, in infants aged 3-5 months, a significantly increased SMR for IS was found in a risk window of 1-7 days after the first dose of either RV vaccine [SMRs: Rotarix® 4.6 (95 % CI 1.5-10.7); RotaTeq® 5.8 (95 % CI 1.2-17.1)]. A significantly increased risk of IS in a risk window of 1-7 days after RV vaccination was not found when the first dose was administered earlier. Therefore, it is recommended to start the vaccination course at 6-12 weeks of age.
    Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz 02/2014; 57(2):234-241. DOI:10.1007/s00103-013-1893-0 · 1.42 Impact Factor
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    G Falkenhorst · T Harder · C Remschmidt · M Terhardt · F Zepp · T Ledig · S Wicker · B Keller-Stanislawski · T Mertens
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    ABSTRACT: The German Standing Committee on Vaccination (STIKO) recommends seasonal influenza vaccination for children and adolescents with chronic medical conditions that put them at risk for severe influenza illness. In addition to trivalent inactivated influenza vaccines (TIV), a trivalent live-attenuated influenza vaccine (LAIV) was licensed for children and adolescents aged 2-17 years in the European Union in 2011. Employing the methodology of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) working group, we examined the evidence for efficacy and safety of LAIV relative to TIV to guide STIKO's decision on whether LAIV should be preferentially recommended for at-risk children. In our meta-analysis of data from two randomized trials directly comparing LAIV and TIV in children aged ≤ 6 years, the protective efficacy of LAIV against laboratory-confirmed influenza was 53 % [95 % confidence interval (CI): 45-61 %] higher than that of TIV. A similar study in individuals aged 6-17 years showed a 32 % (95 % CI: 3-52 %) higher efficacy of LAIV. The quality of the evidence for a superior protective efficacy of LAIV against all relevant clinical outcomes was rated 'moderate' for children aged 2-6 years and 'low' for the age group 7-17 years. Regarding safety outcomes, the available data suggest no significant differences between LAIV and TIV. Based on these results, STIKO recommends that LAIV should be used preferentially for influenza vaccination of at-risk children aged 2-6 years. In children and adolescents aged 7-17 years, either LAIV or TIV may be used without specific preference. Possible contraindications and the vaccinee's and his/her guardians' preferences should be taken into account.
    Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz 11/2013; 56(11):1557-1564. DOI:10.1007/s00103-013-1844-9 · 1.42 Impact Factor
  • D Mentzer · H Meyer · B Keller-Stanislawski
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    ABSTRACT: Although effective monovalent and combined measles vaccines have been available for several decades in Germany, measles outbreaks continue to occur leading to severe cases of measles and even death. Possible reasons for the low acceptance of the measles vaccination are concerns about adverse events and serious complications following vaccination. In this report, we have summarized and assessed all adverse events reported in Germany from 2001 to 2012 after vaccination with monovalent- and combined measles-containing vaccines. A total of 1,696 suspected adverse reaction reports describing 5,297 adverse events were sent to the Paul Ehrlich Institute (PEI) between 1 January 2001 and 31 December 2012. The calculated mean reporting rate was 5.7 reports per 100,000 vaccine doses released by the PEI. Analysis of the reports indicates that measles-containing vaccines are well tolerated with a constantly low rate of adverse events reported. Compared to the high rate of serious complications following wild-type measles infection, the benefit of measles-containing vaccines clearly outweighs the anticipated risks of adverse events.
    Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz 09/2013; 56(9):1253-9. · 1.42 Impact Factor
  • D. Mentzer · H. Meyer · B. Keller-Stanislawski
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    ABSTRACT: Obwohl seit Jahrzehnten wirksame Einzel- oder Kombinationsimpfstoffe gegen Masern in Deutschland zur Verfügung stehen, kommt es immer wieder zu größeren Masernausbrüchen, in deren Folge Menschen schwer erkranken oder sterben. Einer der Gründe für die unzureichende Akzeptanz der Masernimpfung in der Bevölkerung ist möglicherweise die Angst vor unerwünschten Wirkungen und schweren Impfkomplikationen. Daher wurden alle Verdachtsfallberichte über unerwünschte Wirkungen nach Impfung mit masernhaltigen Impfstoffen, die aus Deutschland in den Jahren 2001 bis 2012 gemeldet wurden, zusammengefasst und bewertet. Dem PEI sind im Zeitraum vom 01.01.2001 bis zum 31.12.2012 insgesamt 1696 Verdachtsfälle von Nebenwirkungen mit 5297 Reaktionen nach Masernmono- und Kombinationsimpfstoffen berichtet worden. 76,7 % der Meldungen wurden als schwerwiegend klassifiziert. Die mittlere Melderate betrug ca. 5,7 Fallmeldungen auf 100.000 vom PEI für Deutschland freigegebenen Impfdosen. Die Auswertung der Meldungen weist auf die gute Verträglichkeit masernhaltiger Einzel- und Kombinationsimpfstoffe hin und zeigt eine konstant niedrige Rate von gemeldeten Komplikationen in Bezug auf die Anzahl der durchgeführten Impfungen. Vergleicht man die schweren und relativ häufigen Komplikationen der Maserninfektion mit den gemeldeten Verdachtsfallberichten, so ergibt sich eine uneingeschränkt positive Nutzen-Risiko-Bewertung der Masernimpfstoffe.
    Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz 09/2013; 56(9). DOI:10.1007/s00103-013-1792-4 · 1.42 Impact Factor
  • A Hilger · C Arras-Reiter · B Keller-Stanislawski · B Ljungberg · C Male · D Mentzer · R Seitz · G Silvester
    Haemophilia 05/2013; 19(3):349-50. DOI:10.1111/hae.12151 · 2.60 Impact Factor
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    ABSTRACT: We report the case of a child presenting with non-febrile seizures 6 and 13 days after the first vaccination with a measles-, mumps-, rubella- and varicella- (MMRV-) combination vaccine. Measles virus RNA was detected in the patient's serum, throat, and urine. Genotyping revealed the vaccine virus strain Schwarz.
    Clinical and vaccine Immunology: CVI 05/2013; 20(7). DOI:10.1128/CVI.00084-13 · 2.47 Impact Factor
  • Dr. Dr. D. Oberle MSc · C. Pönisch · G. Mayer · B. Keller-Stanislawski
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    ABSTRACT: In Schweden und Finnland sind bis Mitte 2010 mehrere Fälle einer Narkolepsie bei Kindern und Jugendlichen im Alter von 12 bis 16 Jahren im zeitlichen Zusammenhang mit der Impfung mit Pandemrix® neu aufgetreten, sodass eine Assoziation vermutet wurde. Um diese Hypothese zu untersuchen, wurden mehrere Studien initiiert. Im Rahmen von einigen europäischen epidemiologischen Studien wurde mittlerweile eine Assoziation zwischen der Impfung mit Pandemrix® und dem Auftreten von Narkolepsie bei Kindern und Jugendlichen gezeigt, für Frankreich wurde auch ein erhöhtes Risiko für Narkolepsie bei geimpften Erwachsenen berichtet. Das Paul-Ehrlich-Institut führt in Zusammenarbeit mit der Deutschen Gesellschaft für Schlafforschung und Schlafmedizin (DGSM) seit Mai 2011 eine deutschlandweite epidemiologische Studie zu den Risikofaktoren von Narkolepsie durch. Im Dezember 2012 wurde von der zuständigen Ethikkommission ein Amendment genehmigt. Das Studiendesign entspricht einer retrospektiven gematchten multizentrischen Fall-Kontroll-Studie. Die Rekrutierung von Narkolepsieverdachtsfällen findet in deutschen schlafmedizinischen Zentren statt. Diese identifizieren Patienten aus ihrem Klinikinformationssystem, die im Zeitraum 01.04.2009 bis 31.12.2012 wegen exzessiver Tagesschläfrigkeit in ein schlafmedizinisches Zentrum zum multiplen Schlaflatenztest (MSLT) überwiesen wurden. Validiert werden die Verdachtsfälle von Narkolepsie anhand der von der Brighton Collaboration (BC) vorgeschlagenen vorläufigen Falldefinition durch zwei unabhängige Experten. Sobald ein Fall validiert ist, werden vom Studiensekretariat alters- und geschlechtsgematcht populationsbasierte Kontrollen aus der gleichen Postleitregion rekrutiert. Eine zweite Kontrollgruppe stellen sog. testnegative Kontrollen dar, d. h. Patienten mit exzessiver Tagesschläfrigkeit, bei denen eine Narkolepsie sicher ausgeschlossen wurde. Über Telefoninterviews werden von Fällen und Kontrollen Daten zu Grunderkrankungen, Infektionen und Impfungen erhoben. Die statistische Analyse erfolgt mithilfe einer multivariaten konditionalen logistischen Regression. Der vorliegende Artikel berichtet über den aktuellen Kenntnisstand zur Assoziation zwischen der Impfung mit Pandemrix® und dem Auftreten von Narkolepsie und beschreibt detailliert das aktualisierte Studiendesign.
    Somnologie - Schlafforschung und Schlafmedizin 03/2013; 17(1). DOI:10.1007/s11818-013-0604-2
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    M B Funk · N Gross · S Gross · A Hunfeld · A Lohmann · S Guenay · K M Hanschmann · B Keller-Stanislawski
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    ABSTRACT: Objective: Due to an increasing number of reported thromboembolic events (TEE) after the administration of one intravenous immunoglobulin (IVIG) and one subcutaneous immunoglobulin (SCIG), pharmacovigilance and laboratory data were collected to analyse the root cause and assess the reporting frequency of TEEs for various IG products. Methods: Paul-Ehrlich-Institut retrospectively analysed 228 reports of TEEs associated with six different IG products and estimated annual TEE-reporting rates based on worldwide sale figures over a period of 6 years (2006-2011). In addition, non-activated partial thromboplastin time (NAPTT) testing was performed to capture pro-coagulant potential of six IG products (four IVIG and two SCIG). Results: For three IVIGs, the drug-related TEE-reporting rates remained stable from 2006 to 2011 (0-0·83 cases per 1000 kg IVIG distributed). In contrast, the TEE rate of one IVIG increased significantly from 0·33 cases in 2006 to nearly nine cases in 2010 (P < 0·001). The NAPTT testing of IG products with a low TEE rate revealed a NAPTT time >200 s and a NAPTT ratio >0·8, whereas TEE-associated batches of IG products with an increased TEE rate had a NAPTT ratio <0·8. After modifications of manufacturing processes, a normalization of NAPTT results and a decrease in TEE rates could be demonstrated.
    Vox Sanguinis 02/2013; 105(1). DOI:10.1111/vox.12025 · 2.80 Impact Factor
  • Doris F Oberle · Mayer G · Keller-Stanislawski B.
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    ABSTRACT: In Germany, routine RV-vaccination is not adopted into the national immunization schedule as of 2012. Because RV-vaccines were already on the market since 2006, in 2010 a moderate (58%) and low (22%) vaccine uptake was observed in the 5 eastern federal states (EFS) and the 11 western federal states (WFS), respectively. To assess the impact of RV-vaccination, we compared the incidence rates (IR) of RV-related hospitalizations before (2004‒2006) and in seasons after (2008/09-2010/11) RV-vaccine introduction in Germany by utilizing data from the national mandatory disease reporting system. In the EFS, the IR was significantly reduced in age-groups < 18 mo in 2008/09 and in age-groups < 24 mo in 2009/10-2010/11. In the WFS an IR-reduction was observed only in age-groups < 12 mo in 2008/09 and in age-groups < 18 mo in 2009/10-2010/11. Overall IR-reduction in age-groups < 24 mo comparing 2008-11 with 2004-06 was 36% and 25% in EFS and WFS, respectively. In addition, we computed IR-ratios (IRR) in the seasons after mid-2006 with negative binomial regression. The effect of vaccination was independent from the geographic region. Vaccination was associated with a significant reduction in RV-related hospitalizations in the age-groups 6-23 mo. Most prominently, vaccination of 50% of infants led to an estimated decrease in age group 6-11 mo by 42%. No significant reduction was observed in age-groups ≥ 24 mo. In conclusion, in the German setting with low to moderate vaccine uptake, RV-related hospitalization incidence decreased substantially depending on the achieved vaccination coverage, but only in the first two years of life.
    Human Vaccines & Immunotherapeutics 09/2012; 8(10). DOI:10.4161/hv.21593 · 2.37 Impact Factor
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    ABSTRACT: Novel immunosuppressive/modulating therapies with monoclonal antibodies (MABs) have been associated with progressive multifocal leukoencephalopathy (PML), a potentially fatal disease of the brain caused by the JC virus. Taking the complex diagnostic testing and heterogeneous clinical presentation of PML into account, an agreed case definition for PML is a prerequisite for a thorough assessment of PML. A working group was established to develop a standardised case definition for PML which permits data comparability across clinical trials, postauthorisation safety studies and passive postmarketing surveillance. The case definition is designed to define levels of diagnostic certainty of reported PML cases following treatment with MABs. It was subsequently used to categorise retrospectively suspected PML cases from Germany reported to the Paul-Ehrlich-Institute as the responsible national competent authority. The algorithm of the case definition is based on clinical symptoms, PCR for JC virus DNA in cerebrospinal fluid, brain MRI, and brain biopsy/autopsy. The case definition was applied to 119 suspected cases of PML following treatment with MABs and is considered to be helpful for case ascertainment of suspected PML cases for various MABs covering a broad spectrum of indications. Even if the available information is not yet complete, the case definition provides a level of diagnostic certainty. The proposed case definition permits data comparability among different medicinal products and among active as well as passive surveillance settings. It may form a basis for meaningful risk analysis and communication for regulators and healthcare professionals.
    Journal of neurology, neurosurgery, and psychiatry 07/2012; 83(9):927-33. DOI:10.1136/jnnp-2012-302478 · 6.81 Impact Factor
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    ABSTRACT: A(H1N1)v2009 influenza vaccination of pregnant women was a challenge for health care providers, as little safety data were available. We prospectively followed the pregnancies of women who were vaccinated at any time during pregnancy or ≤ 4 weeks prior to conception and compared these outcomes to a control cohort matched by the estimated date of birth. Primary endpoints: rate of spontaneous abortion and major malformations. Secondary endpoints: preeclampsia, gestational age at birth, and birth weight. Pregnancy outcome of 323 women immunized with adjuvanted or non-adjuvanted A(H1N1)v2009 influenza vaccines from 2009-09-28 to 2010-03-31 were compared to 1329 control subjects. The risk for spontaneous abortions (HR 0.89; 95% CI 0.36-2.19) and the rate of major malformations (all trimesters: OR 0.87; 95% CI 0.38-1.77; preconception and first trimester exposure: OR 0.79; 95% CI 0.13-2.64) did not vary between the two cohorts. Furthermore, there was no increase in preeclampsia, prematurity, and intrauterine growth retardation in the vaccinated cohort. The results of our study do not indicate a risk for the pregnant woman and the developing embryo/fetus after H1N1 vaccination. We provide and apply methods novel in observational studies on pregnancy outcome, especially if a single dose exposure is investigated.
    Vaccine 05/2012; 30(30):4445-52. DOI:10.1016/j.vaccine.2012.04.081 · 3.62 Impact Factor
  • H-P Hartung · B Keller-Stanislawski · R.A. Hughes · H.C. Lehmann
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    ABSTRACT: Guillain-Barré Syndrome (GBS) is an acquired, monophasic inflammatory polyradiculoneuritis of autoimmune origin, which occurs after infection and occasionally also after vaccination. Seasonal and pandemic influenza vaccines have in particular been implicated as triggers for GBS. However, a number of recent studies indicate that infection with influenza virus may also cause GBS. This review summarizes the epidemiological and experimental data of the association of GBS with exposure to influenza antigens by immunization (including vaccines against A/H1N1/2009) and infection. Vaccination against influenza is associated with a very low risk for the occurrence of GBS. In contrast infection with influenza may play a more important role as a triggering factor for GBS than previously assumed.
    Der Nervenarzt 04/2012; 83(6):714-30. DOI:10.1007/s00115-012-3479-8 · 0.79 Impact Factor