Title: Safety of influenza vaccines in pregnant women
Abstract: Prevention of influenza in pregnant women and their newborns through maternal immunization is a safe and effective intervention during seasonal epidemics and a priority during a pandemic. While influenza vaccination of pregnant women has been routine in the United States since the 1950s, coverage rates increased significantly only after the 2009 H1N1 influenza pandemic. Epidemiologic and clinical studies support the safety of inactivated influenza vaccines in pregnant women and their infants. Safety barriers to the use of vaccines during pregnancy can be addressed through research, active surveillance, and education. Prevention of influenza in pregnant women and their newborns through maternal immunization is a safe and effective intervention during seasonal epidemics and a priority during a pandemic. While influenza vaccination of pregnant women has been routine in the United States since the 1950s, coverage rates increased significantly only after the 2009 H1N1 influenza pandemic. Epidemiologic and clinical studies support the safety of inactivated influenza vaccines in pregnant women and their infants. Safety barriers to the use of vaccines during pregnancy can be addressed through research, active surveillance, and education. The American College of Obstetricians and Gynecologists recommends inactivated influenza vaccine as an essential element of prenatal care because pregnant women are known to be at increased risk of serious illness and complications from influenza.1American College of Obstetricians and Gynecologists Committee on Obstetric PracticeACOG committee opinion no. 468: influenza vaccination during pregnancy.Obstet Gynecol. 2010; 116: 1006-1007Crossref PubMed Scopus (98) Google Scholar Influenza vaccination can be administered at any time during pregnancy, before and during the influenza season.2The Centers for Disease Control and PreventionPrevention and control of influenza with vaccines: recommendation of the advisory committee on immunization practices.MMWR Morb Mortal Wkly Rep. 2010; 59: 1-62PubMed Google Scholar These recommendations are supported by the Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention (CDC), and national organizations such as the American Academy of Pediatrics and the American Academy of Family Practitioners. Pregnant women are included in tier 1 as a priority group to receive influenza vaccine during a pandemic. These recommendations are based on the premise that the benefits of vaccinating pregnant women outweigh any potential risks of the vaccine. An important concern for patients and providers when considering influenza vaccination during pregnancy is the safety of the vaccine. Potential risks to the mother include the occurrence of adverse local or systemic reactions to the vaccine, including fever and anaphylaxis, but also potential effects on pregnancy outcomes such as possible induction of labor, preterm birth, or fetal loss. Potential risks to the infant include a theoretical concern for congenital anomalies when the vaccine is administered in the first trimester of gestation, preterm birth, and even tolerance to vaccine antigens or alteration of the infant's immune response to natural infection or active immunization. Adverse events of vaccination during pregnancy can be difficult to evaluate in the context of the risks associated with pregnancy itself; up to 20% of pregnancies end in spontaneous miscarriage, obstetric complications may occur in up to 15% of pregnancies, and 1 in 10 infants are born preterm or with low birthweight.3Schatz M. Chambers C.D. Jones K.L. Louik C. Mitchell A.A. Safety of influenza immunizations and treatment during pregnancy: the vaccines and medications in pregnancy surveillance system.Am J Obstet Gynecol. 2011; 204: S64-S68Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar In general, patients and providers must consider the risks of acquiring influenza disease over any potential risks of the vaccine and those of pregnancy itself. Inactivated influenza vaccine has been routinely administered to pregnant women since the 1950s in the United States, and since 1997, pregnancy has been included in the ACIP list of high-risk conditions requiring routine annual influenza vaccination. Therefore, vast experience and clinical data are available for influenza vaccine, the most frequently administered vaccine during pregnancy other than tetanus toxoid. No study conducted to date has shown a harmful consequence of influenza vaccination in pregnant women or their infants. Studies evaluating the safety of influenza vaccine during pregnancy include population-based cohort studies, retrospective and database review studies, clinical trials, and postmarketing surveillance or adverse event reporting systems. Because influenza vaccination during pregnancy has been recommended in the United States for >60 years, prospective, randomized clinical trials are few and of limited statistical power given the small numbers of subjects enrolled. In some studies, influenza vaccine was used as the control intervention when evaluating other vaccines in pregnant women. The 2009 H1N1 influenza pandemic provided an opportunity to prospectively study influenza vaccines in pregnancy. Vaccine safety reporting systems used to identify potential adverse events among vaccine recipients included the Vaccine Adverse Event Reporting System (VAERS) and the Vaccine Safety Datalink in the United States, postmarketing pregnancy registries established by vaccine manufacturers, and databases linking vaccination history and medical outcomes. These systems have limitations, including their passive reporting nature (which may result in underreporting), the difficulty in determining a denominator to calculate attributable risk and evaluate associations, limited statistical power, and the inability to assess for confounders. The Vaccines and Medications in Pregnancy Surveillance System, established in 2009 with funding from the US Department of Health and Human Services, attempts to address these limitations by systematically assessing the safety of vaccines in pregnant women enrolled in prospective cohort and case-control surveillance systems.3Schatz M. Chambers C.D. Jones K.L. Louik C. Mitchell A.A. Safety of influenza immunizations and treatment during pregnancy: the vaccines and medications in pregnancy surveillance system.Am J Obstet Gynecol. 2011; 204: S64-S68Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar Other factors to consider when evaluating the safety of influenza vaccines in pregnancy include: vaccine formulations are different every year, the outcomes evaluated may differ, and pregnancy-related adverse events and safety assessments during pregnancy may not be consistently defined. Furthermore, knowledge of immunologic and inflammatory processes during pregnancy is, in general, also limited. A large prospective cohort study and a few randomized controlled clinical trials provide information on the safety of the early formulations of influenza vaccines. In the Collaborative Perinatal Project conducted from 1959 through 1965 in the United States, >50,000 pregnant women immunized with different vaccines and their children were followed for up to 7 years to evaluate factors associated with central nervous system injury and cerebral palsy.4Heinonen 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, 5Heinonen O.P. Slone D. Shapiro S. Immunizing agents.in: Kaufman D.W. Birth defects and drugs in pregnancy. Littleton Publishing Sciences Group, Boston, MA1977: 314-321Google Scholar Trivalent inactivated vaccine was received by 2291 pregnant women (650 in the first 4 months of pregnancy). This study found no significant increase in adverse outcomes associated with influenza vaccination in mothers or their infants including stillbirths, malformations, neurocognitive disability, hearing loss, or malignancies. In the Asian influenza outbreak study conducted from 1962 through 1963 in Pittsburgh, PA, 225 pregnant women who received 2 injections (19 in the first trimester) of a "polyvalent vaccine" containing 200 U of antigen of the new "Asian" influenza strain were compared to 44 nonpregnant vaccinated women and a group of pregnant (n = 104) and nonpregnant (n = 25) placebo recipients. All obstetric patients, including those with medical complications, were included. There were no maternal deaths. Expected local and systemic reactogenicity was reported in all study groups, and there were no fetal anomalies or miscarriages associated with vaccination.6Hulka J.F. Effectiveness of a polyvalent influenza vaccine in pregnancy: report of a controlled study during an outbreak of Asian influenza.Obstet Gynecol. 1964; 23: 830-837PubMed Google Scholar From 1976 through 1989, >300 women received influenza vaccines (monovalent A/New Jersey/8/76 strain, or trivalent inactivated vaccine) in 4 randomized controlled clinical trials, from preconception to the third trimester of gestation. Control groups included nonvaccinated pregnant women, pregnant women receiving tetanus toxoid, and nonpregnant women receiving influenza vaccine. Study follow-up varied from short-term reactogenicity to 8 weeks after delivery. Although mild fever, headache, and influenza-like symptoms were reported by some participants, no significant local or systemic adverse reactions, including high fever, occurred. No fetal, perinatal, or infant complications were associated with administration of the vaccines.7Sumaya C.V. Gibbs R.S. Immunization of pregnant women with influenza A/New Jersery/76 virus vaccine: reactogenicity and immunogenicity in mother and infant.J Infect Dis. 1979; 140: 141-146Crossref PubMed Scopus (143) Google Scholar, 8Murray D.L. Imagawa D.T. Okada D.M. St Geme Jr, J. Antibody response to monovalent A/New Jersey/8/76 influenza vaccine in pregnant women.J Clin Microbiol. 1979; 10: 184-187PubMed Google Scholar, 9Deinard 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, 10Englund J.A. Mbawuike I.N. Hammill H. Holleman M.C. Baxter B.D. Glezen W.P. Maternal immunization with influenza or tetanus toxoid vaccine for passive antibody protection in young infants.J Infect Dis. 1993; 168: 647-656Crossref PubMed Scopus (238) Google Scholar More recently, a study conducted in Bangladesh from 2004 through 2005 enrolled 340 pregnant women who were randomized in a 1:1 ratio to receive the trivalent inactivated influenza vaccine or pneumococcal polysaccharide vaccine in the third trimester of gestation.11Zaman K. Roy E. Arifeen S. et al.Effectiveness of maternal influenza immunization in mothers and infants.N Engl J Med. 2008; 359: 1555-1564Crossref PubMed Scopus (971) Google Scholar No serious adverse events were reported in mothers or their infants. There were no differences in pregnancy outcomes, rate of cesarean section delivery, infant gestational age, birthweight, or Apgar scores. Furthermore, transplacental transfer of antibodies from mothers to infants was documented, and infants of vaccinated mothers were protected against influenza illness in the first few months of life. One other large prospective study enrolling a total of 1169 mothers and their infants in the Southwestern United States from 2002 through 2005 also concluded that maternal influenza vaccination results in higher antibody titers and decreased risk of influenza infection in infants, without safety concerns for the mother or the infant.12Eick A.A. Uyeki T.M. Kilmov A. et al.Maternal influenza vaccination and effect of influenza virus infection in young infants.Arch Pediatr Adolesc Med. 2011; 165: 104-111Crossref PubMed Scopus (247) Google Scholar Furthermore, routine maternal influenza vaccination has been associated with a reduction in infant hospitalization due to influenza in the first 6 months of life.13Benowitz I. Esposito D.B. Gracey K.D. Shapiro E.D. Vazquez M. Influenza vaccine given to pregnant women reduces hospitalization due to influenza in their infants.Clin Infect Dis. 2010; 51: 1355-1361Crossref PubMed Scopus (258) Google Scholar, 14Poehling K.A. Szilagyi P.G. Statt M.A. et al.Impact of maternal immunization on influenza hospitalization in infants.Am J Obstet Gynecol. 2011; 204: S141-S148Abstract Full Text Full Text PDF PubMed Scopus (203) Google Scholar Retrospective studies using established databases to evaluate the occurrence of adverse events that may be associated with influenza vaccination have provided reassuring results in support of the safety of routine administration of influenza vaccine during pregnancy. First, utilizing the California managed care system, France et al15France E.K. Smith-Ray R. McClure D. et al.Impact of maternal influenza vaccination during pregnancy on the incidence of acute respiratory illness among infants.Arch Pediatr Adolesc Med. 2006; 160: 1277-1283Crossref PubMed Scopus (93) Google Scholar found no differences in birthweight, gestational age, or length of hospitalization after delivery among 3160 infants born to women who received influenza vaccine during pregnancy, compared to 37,969 infants born to unvaccinated mothers from 1995 through 2001. Similarly, Black et al16Black 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 differences in the rate of cesarean section or preterm birth among 3719 vaccinated pregnant women vs 45,866 controls from 1997 through 2002. In Houston, TX, 2 retrospective studies conducted in a multidisciplinary clinic evaluating multiple influenza seasons from 1998 through 2005 and including 252 pregnant women vaccinated with trivalent inactivated vaccine vs 826 unvaccinated pregnant women matched by age and date of delivery; and 1006 vaccinated pregnant women vs 1495 unvaccinated matched controls, respectively, found no differences in serious adverse events in mothers within 42 days of vaccination, and no differences in pregnancy outcomes, including rate of cesarean section and preterm birth, or infant medical complications in the first 6 months of life.17Munoz 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, 18Munoz FM, Mouzoon ME, Smith FA, et al. Safety and effectiveness of influenza vaccine in pregnant women and their infants. Presented at the Pediatric Academic Societies meeting, Toronto, Canada; May 5-8, 2007.Google Scholar The most extensive and recent retrospective studies come from VAERS. During the 2000 through 2003 influenza seasons, 26 reports were submitted to the CDC among an estimated 2 million pregnant women vaccinated with trivalent inactivated vaccine.19Pool V. Iskander J. Safety of influenza vaccination during pregnancy.Am J Obstet Gynecol. 2006; 194: 1200Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar No unexpected adverse events were reported. There were 5 reports of "inadvertent" vaccine administration during pregnancy, but no vaccine-associated adverse events occurred among them. Nine events were self-limited injection-site reactions and there were 8 reports of systemic symptoms such as fever, headache, malaise, nausea, vomiting, and diarrhea. There were 3 reports of miscarriages, although none known to be caused by vaccination. A more comprehensive VAERS report encompassing 19 years, from 1990 through 2009, when an estimated 11.8 million pregnant women were vaccinated with influenza vaccine, includes 148 reports after receipt of inactivated vaccine and 27 after receipt of live inactivated vaccine (which is currently contraindicated during pregnancy).20Moro P.L. Broder K. Zheteyeva Y. et al.Adverse events in pregnant women following administration of trivalent inactivated vaccine and live attenuated influenza vaccine in the Vaccine Adverse Event Reporting System, 1990-2009.Am J Obstet Gynecol. 2010; 204: 146.e1-146.e7Google Scholar No specific adverse events were described in 30 of 148 (20.3%) reports involving inactivated vaccine, and in 16 of 27 (59.3%) reports involving live vaccine. There were no maternal deaths. Serious adverse events occurred in 20 (13.5% of reports) women who received trivalent inactivated vaccine (including 1 case of anaphylactic reaction), and in 1 (4% of reports) woman who received live inactivated vaccine–a miscarriage at 16 weeks of gestation. The most common pregnancy-specific adverse event was spontaneous abortion, which occurred in 17 (11.5%) recipients of inactivated vaccine and 3 (11%) recipients of live vaccine, with an overall rate of 1.9 cases/million patients, which is lower than the expected rate of 5.5 cases/million in the general population. Of note, vaccine was administered in all trimesters of pregnancy among those with events reported to VAERS. Overall, this study evaluating the experience in the United States during an extensive period of time when seasonal influenza vaccine was routinely recommended for pregnant women concluded that influenza vaccination during pregnancy did not result in an increased risk of adverse pregnancy outcomes when compared to background rates. The 2009 H1N1 influenza pandemic brought influenza vaccination of pregnant women to the forefront of research and public health implementation efforts. Facing a high rate of complications and mortality, pregnant women were among the first to receive the 2009 H1N1 inactivated monovalent vaccine. Thousands of pregnant women were vaccinated around the world. Clinical trials were performed simultaneously in pregnant and nonpregnant adults, and the clinical experience of maternal immunization has been described in numerous publications from the United States, Europe, and Asia.21Jackson 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, 22Hanquet G. VanDamme P. Brasseur D. et al.Lessons learnt from pandemic A(H1N1) 2009 influenza vaccination: highlights of a European workshop in Brussels (March 22, 2010).Vaccine. 2011; 29: 370-377Crossref PubMed Scopus (36) Google Scholar, 23Tavares F. Nazareth I. Sawchik M. Kolte I. Verstraeten T. Bauchau V. Pregnancy and safety outcomes in women vaccinated with an ASO3-adjuvanted split virion H1N1(2009) pandemic influenza vaccine during pregnancy: a prospective cohort study.Vaccine. 2011; 29: 6358-6365Crossref PubMed Scopus (64) Google Scholar, 24Folkenberg M. Callreus T. Svanstrom H. Vanlentiner-Branth P. Hviid A. Spontaneous reporting of adverse events following immunization against pandemic influenza in Denmark November 2009-March 2010.Vaccine. 2011; 29: 1180-1184Crossref PubMed Scopus (25) Google Scholar, 25Parretta E. Ianniello B. Ferrazin F. Rossi F. Capuano A. Italian post-marketing surveillance for adverse event reports after MF59-adjuvanted H1N1v vaccination.Vaccine. 2011; 29: 3708-3713Crossref PubMed Scopus (33) Google Scholar, 26Tsai T. Kyaw M.H. Novicki D. Nacci P. Rai S. Clemens R. Exposure to MF59-adjuvanted influenza vaccines during pregnancy–a retrospective analysis.Vaccine. 2011; 28: 1877-1880Crossref Scopus (47) Google Scholar, 27Zuccotti G.V. 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, 28Lim S.H. Lee J.H. Kim B.C. Jung S.U. Park Y.B. Lee C.S. Adverse reaction of influenza A(H1N1) 2009 virus vaccination in pregnant women and its effect on newborns.Vaccine. 2010; 28: 7455-7456Crossref PubMed Scopus (19) Google Scholar Importantly, 2009 H1N1 vaccines were produced by multiple manufacturers nationally and internationally, using different dosages of antigen, formulations (with and without adjuvant), and regimens of administration (1 or 2 doses).21Jackson 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, 22Hanquet G. VanDamme P. Brasseur D. et al.Lessons learnt from pandemic A(H1N1) 2009 influenza vaccination: highlights of a European workshop in Brussels (March 22, 2010).Vaccine. 2011; 29: 370-377Crossref PubMed Scopus (36) Google Scholar In the United States, only vaccines without adjuvant were approved, while European countries and Canada also licensed monovalent vaccines with various adjuvants such as MF59, ASO3, and aluminum phosphate.23Tavares F. Nazareth I. Sawchik M. Kolte I. Verstraeten T. Bauchau V. Pregnancy and safety outcomes in women vaccinated with an ASO3-adjuvanted split virion H1N1(2009) pandemic influenza vaccine during pregnancy: a prospective cohort study.Vaccine. 2011; 29: 6358-6365Crossref PubMed Scopus (64) Google Scholar, 24Folkenberg M. Callreus T. Svanstrom H. Vanlentiner-Branth P. Hviid A. Spontaneous reporting of adverse events following immunization against pandemic influenza in Denmark November 2009-March 2010.Vaccine. 2011; 29: 1180-1184Crossref PubMed Scopus (25) Google Scholar, 25Parretta E. Ianniello B. Ferrazin F. Rossi F. Capuano A. Italian post-marketing surveillance for adverse event reports after MF59-adjuvanted H1N1v vaccination.Vaccine. 2011; 29: 3708-3713Crossref PubMed Scopus (33) Google Scholar, 26Tsai T. Kyaw M.H. Novicki D. Nacci P. Rai S. Clemens R. Exposure to MF59-adjuvanted influenza vaccines during pregnancy–a retrospective analysis.Vaccine. 2011; 28: 1877-1880Crossref Scopus (47) Google Scholar In general, fewer pregnant women have received influenza vaccines with adjuvant, which are relatively new. Nevertheless, studies in pregnant women consistently showed that the 2009 H1N1 vaccines had a safety profile and immunogenicity comparable to that of the seasonal influenza vaccine in nonpregnant adults.21Jackson 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, 27Zuccotti G.V. 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 Reactogenicity of the vaccine in pregnant women was as expected, mostly mild and self-limited, and there was no evidence of teratogenicity or adverse impact on pregnancy outcomes.21Jackson 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, 23Tavares F. Nazareth I. Sawchik M. Kolte I. Verstraeten T. Bauchau V. Pregnancy and safety outcomes in women vaccinated with an ASO3-adjuvanted split virion H1N1(2009) pandemic influenza vaccine during pregnancy: a prospective cohort study.Vaccine. 2011; 29: 6358-6365Crossref PubMed Scopus (64) Google Scholar, 24Folkenberg M. Callreus T. Svanstrom H. Vanlentiner-Branth P. Hviid A. Spontaneous reporting of adverse events following immunization against pandemic influenza in Denmark November 2009-March 2010.Vaccine. 2011; 29: 1180-1184Crossref PubMed Scopus (25) Google Scholar, 25Parretta E. Ianniello B. Ferrazin F. Rossi F. Capuano A. Italian post-marketing surveillance for adverse event reports after MF59-adjuvanted H1N1v vaccination.Vaccine. 2011; 29: 3708-3713Crossref PubMed Scopus (33) Google Scholar, 26Tsai T. Kyaw M.H. Novicki D. Nacci P. Rai S. Clemens R. Exposure to MF59-adjuvanted influenza vaccines during pregnancy–a retrospective analysis.Vaccine. 2011; 28: 1877-1880Crossref Scopus (47) Google Scholar, 28Lim S.H. Lee J.H. Kim B.C. Jung S.U. Park Y.B. Lee C.S. Adverse reaction of influenza A(H1N1) 2009 virus vaccination in pregnant women and its effect on newborns.Vaccine. 2010; 28: 7455-7456Crossref PubMed Scopus (19) Google Scholar In the United States, uptake of the 2009 H1N1 vaccine among pregnant women was estimated to be approximately 46.6%, 3 times higher than the annual average of ∼13% for the seasonal vaccine.29Centers for Disease Control and PreventionSeasonal influenza and 2009 H1N1 influenza vaccination coverage among pregnant women–10 states, 2009-10 influenza season.MMWR Morb Mortal Wkly Rep. 2010; 59: 1541-1545PubMed Google Scholar It is estimated that 2.4 million pregnant women received the vaccine from October 2009 through February 2010. Among this group, there were 294 reports of adverse events submitted to VAERS.30Moro 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 (87) Google Scholar Most (n = 288) occurred after trivalent inactivated vaccine, and only 6 after receipt of live vaccine. Vaccinations occurred mostly in the first trimester of pregnancy (53.8%) or in the second trimester (27.1%). There were 60 reports of serious adverse events, including 2 maternal deaths (unrelated to vaccination; hemorrhagic shock due to uterine atony, and ruptured aortic aneurysm), 59 hospitalizations, and 1 congenital anomaly (cleft lip). Among 131 prespecified pregnancy outcomes, the majority (95 or 42.4%) were spontaneous abortions in the first 20 weeks of pregnancy, and 18 (6.5%) were stillbirths. Less frequently seen were preterm birth (n = 7), threatened abortion (n = 3), preterm labor (n = 2), preeclampsia (n = 2), and infant events (1 each of hydronephrosis, intrauterine growth retardation, fetal tachycardia, and cleft lip). The authors concluded that there were no concerning patterns of abnormal maternal or fetal outcomes. Nonpregnancy-related events included 1 episode of anaphylaxis, 5 episodes of Bell palsy, 10 local injection-site reactions, 28 reports of nonspecific constitutional symptoms, and 36 allergic reactions. Similar results were reported from a prospective cohort study in the United Kingdom during the 2009 pandemic.23Tavares F. Nazareth I. Sawchik M. Kolte I. Verstraeten T. Bauchau V. Pregnancy and safety outcomes in women vaccinated with an ASO3-adjuvanted split virion H1N1(2009) pandemic influenza vaccine during pregnancy: a prospective cohort study.Vaccine. 2011; 29: 6358-6365Crossref PubMed Scopus (64) Google Scholar One dose of ASO3-adjuvanted split virion H1N1 2009 vaccine was given to 267 pregnant women, the majority (83%) with no underlying medical conditions, and during all trimesters of pregnancy (42 were in the first trimester, 115 in the second, and 110 in the third). The investigators present clear definitions of pregnancy outcomes and congenital anomalies, as well as of medically attended adverse events, serious adverse events, and adverse events of special interest to evaluate over time; and analyzed their frequency in pregnant women compared to known background rates. Safety evaluations were performed for 31 days and 6 months postvaccination in pregnant mothers and until 6 months of life for their infants. No increase in the risk of maternal complications or adverse pregnancy outcomes, including spontaneous abortion, congenital anomalies, preterm birth, and low birthweight, was identified. In a retrospective database review of pregnancy outcomes of women receiving MF59-adjuvanted 2009 H1N1 influenza vaccine or exposed to other MF59-adjuvanted vaccines from 1991 through 2009, Tsai et al26Tsai T. Kyaw M.H. Novicki D. Nacci P. Rai S. Clemens R. Exposure to MF59-adjuvanted influenza vaccines during pregnancy–a retrospective analysis.Vaccine. 2011; 28: 1877-1880Crossref Scopus (47) Google Scholar reported that the distribution of pregnancy outcomes categorized as normal, abnormal, or ending in induced abortion was similar in women exposed to MF59-adjuvanted and unadjuvanted vaccine at any time in pregnancy. Efforts to evaluate the safety of influenza vaccines during pregnancy are ongoing. Manufacturers have established pregnancy registries and active postlicensure studies to continuously assess the safety and clinical efficacy of influenza vaccines, particularly novel adjuvanted vaccines. In the United States, established surveillance systems such as VAERS and the Vaccine Safety Datalink, and networks created in response to the H1N1 pandemic, will continue to monitor adverse events that could be associated with influenza vaccination in pregnant women and their newborns. These include the Vaccines and Medications in Pregnancy Surveillance System funded by the US Department of Health and Human Services, the Pregnancy Risk Assessment Monitoring System of the CDC, and the Medication Exposure in Pregnancy Risk Evaluation Program of the Food and Drug Administration.3Schatz M. Chambers C.D. Jones K.L. Louik C. Mitchell A.A. Safety of influenza immunizations and treatment during pregnancy: the vaccines and medications in pregnancy surveillance system.Am J Obstet Gynecol. 2011; 204: S64-S68Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar In addition, conducting research to address critical knowledge gaps on the biologic effects of influenza vaccination in pregnancy, and particularly on the mechanisms of inflammation and immunity in the pregnant woman, can provide data to further advance the field of maternal immunization. Christian et al31Christian L.M. Iams J.D. Porter K. Glaser R. Inflammatory responses to trivalent influenza virus vaccine among pregnant women.Vaccine. 2011; 29: 8982-8987Crossref PubMed Scopus (46) Google Scholar recently evaluated maternal inflammatory responses to trivalent inactivated vaccine to try to understand the role of vaccine-related responses in clinical outcomes thought to be associated with inflammation, such as preeclampsia and preterm labor. Although responses were variable, pregnant women who received influenza vaccine had increases in measurable inflammatory markers such as C-reactive protein and tumor necrosis factor-alfa but only in the first 2 days postvaccination. Importantly, the inflammatory response elicited by influenza vaccination was milder and more transient than that seen with natural influenza infection. These results are reassuring and important when considering the potential of maternal immunization as a public health intervention to protect both the mother and her infant against serious infectious diseases for which other available interventions are ineffective or where resources are limited and infant mortality is high. Prospective and retrospective studies evaluating the safety of influenza vaccines must consistently and uniformly evaluate adverse events by using clear definitions of outcomes, relatedness, and severity; and carefully consider the biologic plausibility of specific events in relation to vaccination. A well-matched comparison group and/or population-specific background rates of specific pregnancy, maternal, and infant outcomes should be included when assessing the safety of licensed and candidate vaccines for pregnant women. Education of the public and providers on the safety and benefits of the influenza vaccine is critical to improve acceptance and coverage, the key message being that all data available to date support the safety of vaccination of pregnant women with inactivated influenza vaccine, an intervention with the potential to protect both the mother and her infant.