Safety of Immunization during Pregnancy A review of the evidence Global Advisory Committee on Vaccine Safety © World Health Organization 2014 All rights reserved. Publications of the World Health Organization are available on the WHO website (www.who.int) or can be purchased from WHO Press, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: +41 22 791 3264; fax: +41 22 791 4857; e-mail: [email protected]). Requests for permission to reproduce or translate WHO publications –whether for sale or for non-commercial distribution– should be addressed to WHO Press through the WHO website (www.who.int/about/licensing/copyright_form/en/index.html). 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Layout coordinator: WHO/GRA Design and layout: Jean-Claude Fattier Safety of Immunization during Pregnancy A review of the evidence Global Advisory Committee on Vaccine Safety CONTENTS Acknowledgements ....................................................................................................6 1 Introduction ..........................................................................................................7 2 Methodology ........................................................................................................8 3 Vaccines reviewed ................................................................................................9 3.1 Inactivated vaccines ...........................................................................................9 3.1.1 Non-adjuvanted inactivated trivalent seasonal and monovalent pandemic influenza vaccines ....................................................................9 3.1.2 Adjuvanted influenza vaccines ................................................................11 3.1.3 Meningococcal vaccines .........................................................................12 3.1.4 Tetanus toxoid vaccines ..........................................................................13 3.2 Live attenuated vaccines ..................................................................................15 3.2.1 Rubella mono and combined live attenuated vaccines .............................15 3.2.2 Oral poliovirus vaccines ...........................................................................17 3.2.3 Yellow fever vaccines ..............................................................................18 4 Obstacles to accurate assessment of risk ..........................................................21 4.1 Summary and overall recommendations ..........................................................21 References .................................................................................................................24 Global Advisory Committee on Vaccine Safety ACKNOWLEDGEMENTS We would like to acknowledge the contribution to this review received from the subgroup on safety of vaccines during pregnancy and lactation of the Global Advisory Committee on Vaccine Safety (GACVS). The subgroup was composed of six GACVS members: Brigitte Keller-Stanislawski, Hanna Nohynek, Robert Pless, Gargandeep Kang, Melinda Wharton, Punam Mangtani, and supported by Kathy Neuzil (PATH) and Janet Englund (University of Washington, Seattle Children’s Hospital) as independent experts. Philipp Lambach and Patrick Zuber provided WHO secretarial support. 6 Safety of Immunization during Pregnancy – A review of the evidence 1. INTRODUCTION Vaccine-preventable infectious diseases are responsible for significant maternal, neonatal, and young infant morbidity and mortality. Changes in the immune response in pregnant women – which are thought to occur in order to allow the woman to tolerate the semi-allogeneic foetus – may interfere with the development of the specific immune response to pathogens. These immunological changes may alter the susceptibility of the woman and the foetus to certain infectious diseases (1) and increase the risk of more serious outcomes. The immature adaptive immune systems of neonates and premature infants make them particularly vulnerable to morbidity and mortality due to infection. Immunization of pregnant women can protect them directly against vaccine-preventable infections, and in so doing potentially protect the foetus. It can also directly protect the foetus and infant via specific antibodies transferred from the mother during the pregnancy. At its meeting in November 2011, the Strategic Advisory Group of Experts (SAGE) of WHO asked the Global Advisory Committee on Vaccine Safety (GACVS) to provide support to a review of evidence on the safety of vaccinations in pregnant and lactating women. This request related to uncertainties about the safety of vaccination – whether intended or inadvertent – of pregnant women during mass vaccination campaigns. Such evidence would be particularly important in situations where manufacturers do not recommend the vaccination of pregnant women on solely precautionary grounds. However, evidence related to this issue is limited, as pre-licensing clinical trials of vaccines do not usually include pregnant and lactating women. Reports available also provide limited post-licensing data, as once again, pregnant women are usually not included in clinical trials. This in turn has limited the ability to make evidence-based decisions and provide optimal guidance on the use of vaccines in this population. 7 Global Advisory Committee on Vaccine Safety 2. METHODOLOGY This report presents an overview of the relevant literature on the safety of vaccination of pregnant women. In addition to reviewing the published literature, GACVS contacted regulatory authorities and pharmaceutical companies to obtain results of ongoing surveillance programmes for pertussis-containing and meningococcal vaccines in pregnant women. The cut-off point for the literature review was May 2013. The availability and amount of data were assessed, as well as their overall quality in terms of consistency, strengths, and weaknesses. The conclusions are based on expert discussion and consensus rather than on a systematic review and grading system. This report focuses on vaccines that are currently available, with priority for review given to vaccines on the basis of two key criteria: n their potential to reduce morbidity in the pregnant woman and/or her fetus; and n their use (or anticipated use) in vaccination campaigns targeting pregnant women as well as vaccination campaigns where pregnant women may be inadvertently vaccinated. Once the specific vaccines for review had been selected, a standard framework was developed which addressed the following issues: n the demonstrated or potential benefit of vaccination during pregnancy; this included evidence of disease morbidity in pregnant women and foetuses, and of the efficacy or effectiveness of the vaccine in pregnant women; n evidence of safety of vaccination or lack of evidence of adverse pregnancy outcomes; data from clinical trials, observational studies, published case reports, case series and passive surveillance systems were assessed, as were theoretical considerations and experimental data relating to potential harm to the fetus and the mother (e.g. type of vaccine, ability of the vaccine strain to cross the placenta, risk of infection related to gestational age). The pregnancy outcomes considered included maternal morbidity and mortality, miscarriage/stillbirth, prematurity, small size for gestational age, and congenital anomalies. The results are reported in the form of a summary of available relevant literature and an outline of methodological issues to be considered when planning clinical trials and post- marketing safety studies of vaccines in pregnant women. Recommendations for further investigations are made. The aim of this review is to guide the standardization of both the process of policy formulation and the format for recommendations for pregnant women. 8 Safety of Immunization during Pregnancy – A review of the evidence 3. VACCINES REviEWED 3.1 INACTivaTED vaCCINES Immunization with inactivated vaccines or toxoids during pregnancy is not expected to be associated with any increased risk to the foetus. Inactivated vaccines with novel adjuvants, however, may need to be considered and evaluated on a case-by-case basis as there is more limited experience related to those products. Safety data from vaccinated pregnant women were reviewed for seasonal trivalent