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Safety of influenza immunization during pregnancy for the fetus and the neonate

2012; Elsevier BV; Volume: 207; Issue: 3 Linguagem: Inglês

10.1016/j.ajog.2012.07.002

1097-6868

Robert A. Bednarczyk, Dzifa Adjaye‐Gbewonyo, Saad B. Omer,

Vaccine Coverage and Hesitancy

Since the 1960s, pregnant women in the United States have been recommended to receive influenza vaccine. A maternal concern about the possibility of adverse fetal and neonatal outcomes after the vaccination of pregnant women has been cited as a reason for low maternal influenza vaccination coverage. Recent research has identified benefits to the fetus and neonate after maternal influenza vaccination that have prompted efforts to increase coverage in pregnant women. There is a long history of research findings that highlight the safety of vaccinating pregnant women. This review summarizes nearly 40 years of research on influenza vaccination of pregnant women and the lack of association with adverse fetal or neonatal outcomes. Future research should focus on vaccinations that are given in the first trimester of pregnancy and on product-specific analyses to account for differences in manufacturing processes. Since the 1960s, pregnant women in the United States have been recommended to receive influenza vaccine. A maternal concern about the possibility of adverse fetal and neonatal outcomes after the vaccination of pregnant women has been cited as a reason for low maternal influenza vaccination coverage. Recent research has identified benefits to the fetus and neonate after maternal influenza vaccination that have prompted efforts to increase coverage in pregnant women. There is a long history of research findings that highlight the safety of vaccinating pregnant women. This review summarizes nearly 40 years of research on influenza vaccination of pregnant women and the lack of association with adverse fetal or neonatal outcomes. Future research should focus on vaccinations that are given in the first trimester of pregnancy and on product-specific analyses to account for differences in manufacturing processes. In the United States, influenza immunization for pregnant women has been recommended for decades,1Burney L.E. Influenza immunization: statement.Public Health Rep. 1960; 75: 944Crossref PubMed Google Scholar with detailed recommendations for vaccinating pregnant women in all trimesters standardized in the mid-2000s.2Harper S.A. Fukuda K. Uyeki T.M. Cox N.J. Bridges C.B. Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP).MMWR Recomm Rep. 2004; 53: 1-40PubMed Google Scholar During most of the first decade of the 21st century, influenza vaccine uptake among pregnant women was relatively low, often 6 months of age, including pregnant women,9Centers for Disease Control and PreventionPrevention and control of influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2011.MMWR Morb Mortal Wkly Rep. 2011; 60: 1128-1132PubMed Google Scholar there may be a biologic plausibility for teratogenic effects. However, the nature and severity of possible teratogenic effects, if any, would vary by the gestational age at which the vaccine is received and the presence of a biologic mechanism by which specific effects could occur.Pregnancy-related labeling of vaccinesThe US Food and Drug Administration mandates the labeling of all drugs, including vaccines, based on 5 pregnancy categories to describe their safety and effectiveness. These categories are based on existing evidence from both animal and human pregnancy studies and range from category A, which indicates substantial evidence of no risk to the fetus, through category D, which indicates evidence of risk in human studies, although the benefits of the drug may outweigh potential risks (Table 2). Categories B and C are used to indicate a lack of sufficient data to make a clear designation; the combination of human and animal studies indicates that there is either little risk or that the risk is substantially outweighed by the benefit of the drug. The fifth category, X, indicates demonstrated risk to the fetus, with risks from the drug outweighing any potential benefits. Inactivated influenza vaccines currently are classified in categories B and C (Table 2). This classification primarily is due to the fact that prelicensure data on influenza vaccine safety and effectiveness during pregnancy is virtually nonexistent because of strict research ethics guidelines that govern the participation of pregnant women, who are considered a vulnerable population. Moreover, existing data from observational studies often do not reach the standard for studies that are considered in the determination of the Food and Drug Administration pregnancy categories.10Marshall V. Gruber M. Influenza immunization during pregnancy: US regulatory perspective.Am J Obstet Gynecol. 2012; 207: S57-S62Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar Thus, the current classification of influenza vaccines is indicative of a lack of available data to demonstrate vaccine safety in pregnancy rather than a lack of adequate safety data per se, which is balanced against the existing knowledge base of the benefit of influenza vaccine to pregnant women. Proposed revisions to the current labeling system are currently under consideration.10Marshall V. Gruber M. Influenza immunization during pregnancy: US regulatory perspective.Am J Obstet Gynecol. 2012; 207: S57-S62Abstract Full Text Full Text PDF PubMed Scopus (12) Google ScholarTABLE 2Licensed influenza vaccine products according to Food and Drug Administration pregnancy categoriesCategoryDescription10Marshall V. Gruber M. Influenza immunization during pregnancy: US regulatory perspective.Am J Obstet Gynecol. 2012; 207: S57-S62Abstract Full Text Full Text PDF PubMed Scopus (12) Google ScholarVaccine (manufacturer)aVaccine pregnancy category data obtained from the most recent influenza vaccine package inserts available on the Food and Drug Administration website (available at: http://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/ucm093830.htm; accessed: Feb. 13, 2012);Vaccine typeAAdequate and well-controlled studies have failed to demonstrate a risk to the fetus in the first trimester of pregnancy (and there is no evidence of risk in later trimesters) with animal reproduction studies, if available, and did not demonstrate a risk to the fetus.BAnimal reproduction studies have not demonstrated a risk to the fetus, and there are no adequate and well-controlled studies in pregnant women.ORAnimal reproduction studies have shown an adverse effect (other than a decrease in fertility), but adequate and well-controlled studies in pregnant women have not demonstrated a risk to the fetus during the first trimester of pregnancy (and there is no evidence of a risk in later trimesters).Agriflu (Novartis Vaccines and Diagnostics, Inc, Emeryville, CA)TIVbInjectable, seasonal (types A & B) influenza vaccine;FluLaval (ID Biomedical Corporation of Quebec, Laval, Quebec, Canada)TIVFluarix (GlaxoSmithKline Biologicals, Brentford, Middlesex, UK)TIVCAnimal reproduction studies have shown an adverse effect on the fetus, and there are no adequate and well-controlled studies in humans; however, potential benefits may warrant the use of the drug in pregnant women, despite potential risks. ORThere are no animal reproduction studies and no adequate and well-controlled studies in humans.Afluria (CSL Limited, Parkville, Victoria, Australia)TIVFluvirin (Novartis Vaccines and Diagnostics Ltd)TIVFluzone (Sanofi Pasteur, Inc, Swiftwater, PA)TIVFluMist (MedImmune, LLC, Gaithersburg, MD)LAIVcIntranasal, produced as a trivalent, seasonal vaccine (FluMist) or monovalent vaccine for pandemic H1N1; not recommended for use in pregnancy;Influenza Virus Vaccine, H5N1 (Sanofi Pasteur, Inc)MIVdInjectable, offered for pandemic influenza.Influenza A (H1N1) 2009 Monovalent Vaccine (CSL Limited, ID Biomedical Corporation of Quebec, Novartis Vaccines and Diagnostics Ltd, Sanofi Pasteur Inc)MIVInfluenza A (H1N1) 2009 Monovalent Vaccine (MedImmune, LLC)LAIVDThere is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans; however, potential benefits may warrant the use of the drug in pregnant women, despite potential risks.XStudies in animals or humans have demonstrated fetal abnormalities, and/or there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience; the risks that are involved in the use of the drug in pregnant women clearly outweigh potential benefits.LAIV, live attenuated influenza vaccine; MIV, monovalent inactivated vaccine; TIV, trivalent inactivated vaccine.Bednarczyk. Influenza vaccine safety for fetus and neonate. Am J Obstet Gynecol 2012.a Vaccine pregnancy category data obtained from the most recent influenza vaccine package inserts available on the Food and Drug Administration website (available at: http://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/ucm093830.htm; accessed: Feb. 13, 2012);b Injectable, seasonal (types A & B) influenza vaccine;c Intranasal, produced as a trivalent, seasonal vaccine (FluMist) or monovalent vaccine for pandemic H1N1; not recommended for use in pregnancy;d Injectable, offered for pandemic influenza. Open table in a new tab Early studies of influenza immunization in pregnancy (before 2000)One of the earliest studies to examine fetal effects of maternal influenza vaccination was published in 1973. As part of a larger study to examine factors that were associated with abnormalities that developed in the prenatal and neonatal periods, Heinonen et al11Heinonen O.P. Shapiro S. Monson R.R. Hartz S.C. Rosenberg L. Slone D. Immunization during pregnancy against poliomyelitis and influenza in relation to childhood malignancy.Int J Epidemiol. 1973; 2: 229-235Crossref PubMed Scopus (183) Google Scholar examined malignancies that arose after exposure to polio or influenza vaccines in utero. Among children of nearly 2300 women who received influenza vaccine during pregnancy, there was only 1 malignancy that was identified within the first year of life, which was comparable with expected background rates.During the 1976 "swine flu" vaccination campaign, there were 2 examinations of the use of the influenza A/NJ/76 vaccine in pregnant women.12Deinard A.S. Ogburn Jr, P. A/NJ/8/76 influenza vaccination program: effects on maternal health and pregnancy outcome.Am J Obstet Gynecol. 1981; 140: 240-245PubMed Scopus (82) Google Scholar, 13Sumaya C.V. Gibbs R.S. Immunization of pregnant women with influenza A/New Jersey/76 virus vaccine: reactogenicity and immunogenicity in mother and infant.J Infect Dis. 1979; 140: 141-146Crossref PubMed Scopus (144) Google Scholar In a small study of 56 pregnant women who received the vaccine in the second or third trimester, all immunized mothers had live births; 3 newborn infants exhibited congenital defects, which is a level that was similar to that observed in a matched control group of unvaccinated women.13Sumaya C.V. Gibbs R.S. Immunization of pregnant women with influenza A/New Jersey/76 virus vaccine: reactogenicity and immunogenicity in mother and infant.J Infect Dis. 1979; 140: 141-146Crossref PubMed Scopus (144) Google Scholar Another larger study, comprising 189 women who were vaccinated just before or during pregnancy and 517 pregnant women who were not vaccinated, found no fetal complications in the vaccinated group and no differences between children born to vaccinated and unvaccinated mothers with regard to teratogenicity, infant birth outcomes, or physical or neurologic assessments through 8 weeks old.12Deinard A.S. Ogburn Jr, P. A/NJ/8/76 influenza vaccination program: effects on maternal health and pregnancy outcome.Am J Obstet Gynecol. 1981; 140: 240-245PubMed Scopus (82) Google ScholarLater studies (2000 and later) before H1N1 influenza pandemicAfter the 1976 influenza immunization campaign, there was little research that examined the effect and safety of influenza vaccine in pregnant women until the early 2000s. In a large retrospective cohort study that was conducted through a review of automated medical claims records over 5 influenza seasons (1997-2002), Black et al14Black S.B. Shinefield H.R. France E.K. Fireman B.H. Platt S.T. Shay D. Effectiveness of influenza vaccine during pregnancy in preventing hospitalizations and outpatient visits for respiratory illness in pregnant women and their infants.Am J Perinatol. 2004; 21: 333-339Crossref PubMed Scopus (162) Google Scholar found no maternal deaths or difference in the rate of preterm births between pregnant women who received the influenza vaccine during pregnancy (n = 3719) and pregnant women who did not receive influenza vaccine (n = 45,866). Although the crude rates of cesarean delivery were elevated among vaccinated mothers, this difference did not persist after adjustment for maternal age.14Black S.B. Shinefield H.R. France E.K. Fireman B.H. Platt S.T. Shay D. Effectiveness of influenza vaccine during pregnancy in preventing hospitalizations and outpatient visits for respiratory illness in pregnant women and their infants.Am J Perinatol. 2004; 21: 333-339Crossref PubMed Scopus (162) Google Scholar Another examination of medical records was conducted in a Houston, TX, hospital over 5 influenza seasons (1998-2003).15Munoz F.M. Greisinger A.J. Wehmanen O.A. et al.Safety of influenza vaccination during pregnancy.Am J Obstet Gynecol. 2005; 192: 1098-1106Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar Of the 252 pregnant women who received influenza vaccine, a subset of 225 women were matched on health insurance type, age, and month of delivery to a group of 826 pregnant women who had not been immunized against influenza. Types of birth outcomes (uncomplicated vaginal, complicated/assisted vaginal, or cesarean delivery) were similar between groups; the only significant difference in adverse outcomes was an elevated level of congenital anomalies among infants born to unvaccinated mothers; all other neonatal outcomes were similar across groups.15Munoz F.M. Greisinger A.J. Wehmanen O.A. et al.Safety of influenza vaccination during pregnancy.Am J Obstet Gynecol. 2005; 192: 1098-1106Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar Another 5-year follow-up study in Texas consisted of a prospective, population-based surveillance program between 2003 and 2008 to examine any risk of malformations after influenza vaccination during pregnancy. Among 8690 women who were vaccinated during pregnancy (439 in the first trimester, 8251 in the second or third trimester), the total major fetal malformations that were identified were 2% in each group, which matched the 2% baseline level of malformations in children born to women who did not receive influenza vaccine.16Sheffield J. Greer L. Chao T. et al.No association of malformations with first trimester influenza vaccination.Am J Obstet Gynecol. 2009; 201: S232Abstract Full Text Full Text PDF Google ScholarIn 2011, Moro et al17Moro P.L. Broder K. Zheteyeva Y. et al.Adverse events in pregnant women following administration of trivalent inactivated influenza vaccine and live attenuated influenza vaccine in the Vaccine Adverse Event Reporting System, 1990-2009.Am J Obstet Gynecol. 2011; 204: 146.e1-146.e7Abstract Full Text Full Text PDF Scopus (120) Google Scholar published a review of nearly 20 years of adverse events after influenza vaccination of pregnant women that were reported to the Vaccine Adverse Events Reporting System (VAERS). A total of 175 fetal and neonatal adverse event reports were identified, most of which (n = 148) were related to exposure to injected trivalent influenza vaccine, with an additional 27 events after administration of live attenuated influenza vaccine, which is contraindicated for use in pregnant women because it contains attenuated live virus. A total of 20 spontaneous abortions (17 after trivalent inactivated vaccine and 3 after live attenuated influenza vaccine) and 6 stillbirths were in the VAERS reports. Reports of congenital anomalies included single reports of 8 different malformations, with no evidence of increased levels of congenital anomalies or patterns of occurrence of specific conditions. In the neonatal period, a total of 4 adverse events were reported (meningitis, developmental disability, jaundice, autism), again with no evidence of increased or unexpected patterns of adverse events in neonates.17Moro P.L. Broder K. Zheteyeva Y. et al.Adverse events in pregnant women following administration of trivalent inactivated influenza vaccine and live attenuated influenza vaccine in the Vaccine Adverse Event Reporting System, 1990-2009.Am J Obstet Gynecol. 2011; 204: 146.e1-146.e7Abstract Full Text Full Text PDF Scopus (120) Google Scholar It is important to note that VAERS is a passive reporting system with methodologic limitations that include the lack of a defined denominator of the vaccine doses that were administered, a lack of direct assessments of causality for specific reported adverse events, and the ability to report any outcome even without definitive diagnosis.18Chen R.T. Rastogi S.C. Mullen J.R. et al.The Vaccine Adverse Event Reporting System (VAERS).Vaccine. 1994; 12: 542-550Crossref PubMed Scopus (335) Google Scholar VAERS works best to detect signals for adverse events to be further investigated; the lack of a signal that is related to the seasonal influenza vaccination of pregnant women after nearly 2 decades of tracking is reassuring.17Moro P.L. Broder K. Zheteyeva Y. et al.Adverse events in pregnant women following administration of trivalent inactivated influenza vaccine and live attenuated influenza vaccine in the Vaccine Adverse Event Reporting System, 1990-2009.Am J Obstet Gynecol. 2011; 204: 146.e1-146.e7Abstract Full Text Full Text PDF Scopus (120) Google Scholar Although the trimester of vaccination was reported, there was not a systematic evaluation of adverse events by vaccination timing.17Moro P.L. Broder K. Zheteyeva Y. et al.Adverse events in pregnant women following administration of trivalent inactivated influenza vaccine and live attenuated influenza vaccine in the Vaccine Adverse Event Reporting System, 1990-2009.Am J Obstet Gynecol. 2011; 204: 146.e1-146.e7Abstract Full Text Full Text PDF Scopus (120) Google ScholarA randomized controlled trial of influenza immunization in pregnant women was conducted in 340 pregnant women in Bangladesh between August 2004 and December 2005.19Zaman K. Roy E. Arifeen S. et al.Effectiveness of maternal influenza immunization in mothers and infants.N Engl J Med. 2008; 259: 1555-1564Crossref Scopus (978) Google Scholar There were no differences between the intervention (influenza vaccine) and control (pneumococcal polysaccharide vaccine) groups for fetal or neonatal adverse events, and none of the reported adverse events were judged to be related to vaccine receipt or participation in the study.19Zaman K. Roy E. Arifeen S. et al.Effectiveness of maternal influenza immunization in mothers and infants.N Engl J Med. 2008; 259: 1555-1564Crossref Scopus (978) Google Scholar However, the vaccines that were administered in this trial were given in the third trimester, after the period when most malformations or other adverse fetal outcomes would occur.2009 H1N1 pandemic influenza vaccine studiesAfter the identification of the pandemic 2009 influenza A virus in April 2009, a monovalent vaccine was developed and was ready for distribution by October 2009, in anticipation of the following influenza season. Pregnant women were identified as being at increased risk of severe disease after infection with this influenza strain and were recommended strongly to be vaccinated.3Centers for Disease Control and PreventionUse of influenza A (H1N1) 2009 monovalent vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2009.MMWR Recomm Rep. 2009; 58: 1-8Google Scholar During the development and testing of these monovalent vaccines, there were a number of clinical trials20Zuccotti G. Pogliani L. Pariani E. Amendola A. Zanetti A. Transplacental antibody transfer following maternal immunization with a pandemic 2009 influenza A(H1N1) MF59-adjuvanted vaccine.JAMA. 2010; 304: 2360-2361Crossref PubMed Scopus (54) Google Scholar, 21Horiya M. Hisano M. Iwasaki Y. et al.Efficacy of double vaccination with the 2009 pandemic influenza A (H1N1) vaccine during pregnancy.Obstet Gynecol. 2011; 118: 887-894Crossref PubMed Scopus (19) Google Scholar, 22Jackson L.A. Patel S.M. Swamy G.K. et al.Immunogenicity of an inactivated monovalent 2009 H1N1 influenza vaccine in pregnant women.J Infect Dis. 2011; 204: 854-863Crossref PubMed Scopus (88) Google Scholar and observational studies23Mackenzie I.S. Macdonald T.M. Shakir S. et al.Influenza H1N1 (swine flu) vaccination: a safety surveillance feasibility study using self-reporting of serious adverse events and pregnancy outcomes.Br J Clin Pharmacol. 2012; 73: 801-811Crossref PubMed Scopus (36) Google Scholar, 24Moro P.L. Broder K. Zheteyeva Y. et al.Adverse events following administration to pregnant women of influenza A (H1N1) 2009 monovalent vaccine reported to the Vaccine Adverse Event Reporting System.Am J Obstet Gynecol. 2011; 205: 473.e1-473.e9Abstract Full Text Full Text PDF Scopus (88) Google Scholar, 25Omon E. Damase-Michel C. Hurault-Delarue C. et al.Non-adjuvanted 2009 influenza A (H1N1)v vaccine in pregnant women: the results of a French prospective descriptive study.Vaccine. 2011; 29: 9649-9654Crossref PubMed Scopus (31) Google Scholar, 26Tavares F. Nazareth I. Monegal J.S. Kolte I. Verstraeten T. Bauchau V. Pregnancy and safety outcomes in women vaccinated with an AS03-adjuvanted split virion H1N1 (2009) pandemic influenza vaccine during pregnancy: a prospective cohort study.Vaccine. 2011; 29: 6358-6365Crossref PubMed Scopus (64) Google Scholar that included pregnant women.Zuccotti et al20Zuccotti G. Pogliani L. Pariani E. Amendola A. Zanetti A. Transplacental antibody transfer following maternal immunization with a pandemic 2009 influenza A(H1N1) MF59-adjuvanted vaccine.JAMA. 2010; 304: 2360-2361Crossref PubMed Scopus (54) Google Scholar reported a small, single-arm trial of 75 Italian women who received monovalent H1N1 influenza vaccine during their third trimester, with no serious adverse events reported in mothers or their neonates. Jackson et al22Jackson L.A. Patel S.M. Swamy G.K. et al.Immunogenicity of an inactivated monovalent 2009 H1N1 influenza vaccine in pregnant women.J Infect Dis. 2011; 204: 854-863Crossref PubMed Scopus (88) Google Scholar conducted a trial that compared 2 formulations of the monovalent H1N1 vaccine that contained either 25 or 49 μg of hemagglutinin antigen and was administered in the second or third trimester. This dosage was higher than the final dosage level of 15 μg of antigen. Sixty women in each group were followed through delivery; the frequency of severe adverse events in both mothers and neonates was relatively balanced across dosage groups; slightly higher frequencies occurred in the lower dosage group. None of the adverse events were considered to be related to vaccine receipt. A clinical trial that involved 210 pregnant women in Japan involved the administration of either 1 dose (n = 82) or 2 doses (n = 128) of monovalent H1N1 influenza vaccine during the period of 8-32 weeks gestation. Among the women who received 2 vaccine doses, a total of 5 infants had congenital anomalies, none of whom had mothers who had been vaccinated in the first trimester. No abortions or fetal losses were documented, and preterm birth rates were comparable with those of the general population.21Horiya M. Hisano M. Iwasaki Y. et al.Efficacy of double vaccination with the 2009 pandemic influenza A (H1N1) vaccine during pregnancy.Obstet Gynecol. 2011; 118: 887-894Crossref PubMed Scopus (19) Google ScholarIn the fall of 2009, a postauthorization safety study of an AS03-adjuvanted monovalent H1N1 influenza vaccine was conducted in the United Kingdom; there were 267 pregnant women in the >9000 individuals in the study. Of the 265 w