In the United States, influenza immunization

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1 Safety of influenza immunization during pregnancy for the fetus and the neonate Robert A. Bednarczyk, PhD; Dzifa Adjaye-Gbewonyo, MPH; Saad B. Omer, MPH, PhD 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. Key words: fetus, influenza vaccine, neonate, pregnancy, safety, vaccination In the United States, influenza immunization for pregnant women has been recommended for decades, 1 with detailed recommendations for vaccinating pregnant women in all trimesters standardized in the mid- 2000s. 2 During most of the first decade of the 21st century, influenza vaccine From the Center for Health Research- Southeast, Kaiser Permanente (Dr Bednarczyk, Ms Adjaye-Gbewonyo, and Dr Omer); Rollins School of Public Health, Emory University (Drs Bednarczyk and Omer), Atlanta, GA. Received March 17, 2012; revised June 26, 2012; accepted July 2, S.B.O. was awarded the Maurice R. Hilleman Early-stage Career Investigator Award by the National Foundation for Infectious Diseases. The award was funded by an unrestricted educational grant to the National Foundation for Infectious Diseases from Merck and Co, Inc. However, S.B.O. had no direct interaction with Merck. The other authors report no conflict of interest. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the National Vaccine Program Office, the Centers for Disease Control and Prevention, or the Food and Drug Administration. Reprints not available from the authors /$ Mosby, Inc. All rights reserved. uptake among pregnant women was relatively low, often 20%. During the H1N1 pandemic, pregnant women were considered a high-risk group for pandemic influenza infection and were a priority vaccination group. 3 Coverage with the monovalent H1N1 influenza vaccine and the trivalent seasonal influenza vaccine rose to approximately 50%, although it has not increased much since then. 4 After the influenza season, the Centers for Disease Control and Prevention conducted an internet-based survey of pregnant women to estimate influenza vaccine coverage levels and to understand reasons for and against vaccination. The top reason provided for not receiving influenza vaccine was I am concerned about possible safety risks to my baby if I got vaccinated, which was provided by 20% of nonvaccinated women. 5 However, decades of research has documented the safety of influenza vaccine for pregnant women and for the fetus and neonate. This review addresses the underlying concepts behind the safety evaluation of vaccinations in pregnancy and summarizes nearly 4 decades of research on the safety of influenza vaccine that is administered to pregnant women, with a focus on fetal and neonatal outcomes. Time periods relevant to teratogenesis Safety concerns over influenza vaccination in pregnancy often relate to its potential developmental toxicity and possible teratogenic effects on the fetus. Teratogens are agents that cause permanent changes or disruptions to the anatomy, function, or development of an embryo or fetus. 6 The effects of teratogens are highly dependent on the nature of the agent, physiologic and biochemical factors of exposed individuals, and the level, timing, and duration of exposure during pregnancy. 6 Although there is some temporal variation in fetal development, 7 changes that take place typically occur at well-defined time intervals over the course of gestation; thus, exposure to teratogens at certain stages in pregnancy tends to result in specific rather than indiscriminate effects. For example, organogenesis is a time of high teratogen susceptibility during the embryonic phase of pregnancy (embryonic age, 2-9 weeks); each organ has a specific time period of development and specific exposure window in which it is most vulnerable. 8 Teratogenic exposure during this period therefore may lead to anomalies in a particular organ, whereas exposure before this time period is likely to result in either spontaneous abortion (given sufficient cell damage) or compensation for damaged cells and normal development if cell damage is not extensive. 6 Table 1 describes time periods in pregnancy (in terms of embryonic age and not specifically gestational age relative to last menstrual period) and their associated potential teratogenic outcomes. Because inactivated influenza vaccine is recommended for all persons 6 months of age, including pregnant women, 9 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. S38 American Journal of Obstetrics & Gynecology Supplement to SEPTEMBER 2012

2 Supplement Pregnancy-related labeling of vaccines The 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. 10 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. 10 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 As part TABLE 1 Gestational time periods relevant to teratogenesis 6,8 Period Before implantation Gestational age, wk a Events Potential teratogenic effects 0-2 Fertilization, cell division, blastocyst formation, implantation of a larger study to examine factors that were associated with abnormalities that developed in the prenatal and neonatal periods, Heinonen et al 11 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. 12,13 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 Injury to a large number of cells spontaneous abortion OR injury to a small number of cells survival without abnormalities... Embryonic 2-9 Organogenesis Malformations, altered function... Onset for major defects in organs Central nervous system: 3 wk Heart: 3 wk Sensory organs (eyes, ears): 4 wk Limbs: 4 wk Palate: 6 wk Teeth: 6 wk Genitalia: 7 wk... Fetal 9-term Growth, differentiation, maturation Small for gestational age/intrauterine growth restriction, fetal death, minor malformations and altered function... Continued susceptibility period for minor defects in organs Central nervous system: to end of period Sensory organs: to end of period Palate: through 9 wk Teeth: to end of period Genitalia: to end of period... a Gestational age values, as presented, specifically reference embryonic age and not gestational age as determined from last menstrual period dating. Bednarczyk. Influenza vaccine safety for fetus and neonate. Am J Obstet Gynecol newborn infants exhibited congenital defects, which is a level that was similar to that observed in a matched control group of unvaccinated women. 13 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. 12 Later studies (2000 and later) before H1N1 influenza pandemic After the 1976 influenza immunization campaign, there was little research that Supplement to SEPTEMBER 2012 American Journal of Obstetrics & Gynecology S39

3 Supplement TABLE 2 Licensed influenza vaccine products according to Food and Drug Administration pregnancy categories Category Description 10 Vaccine (manufacturer) a Vaccine type A Adequate 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.... B Animal reproduction studies have not demonstrated a risk to the fetus, and there are no adequate and well-controlled studies in Agriflu (Novartis Vaccines and Diagnostics, Inc, Emeryville, CA) TIV b pregnant women.... OR FluLaval (ID Biomedical Corporation of Quebec, TIV Animal reproduction studies have shown an adverse effect Laval, Quebec, Canada) (other than a decrease in fertility), but adequate and wellcontrolled studies in pregnant women have not demonstrated a... risk to the fetus during the first trimester of pregnancy (and Fluarix (GlaxoSmithKline Biologicals, Brentford, TIV there is no evidence of a risk in later trimesters). Middlesex, UK)... C Animal reproduction studies have shown an adverse effect on the fetus, and there are no adequate and well-controlled studies Afluria (CSL Limited, Parkville, Victoria, Australia) TIV... in humans; however, potential benefits may warrant the use of Fluvirin (Novartis Vaccines and Diagnostics TIV the drug in pregnant women, despite potential risks. Ltd) OR... There are no animal reproduction studies and no adequate and Fluzone (Sanofi Pasteur, Inc, Swiftwater, PA) TIV... well-controlled studies in humans. FluMist (MedImmune, LLC, Gaithersburg, MD) LAIV c... Influenza Virus Vaccine, H5N1 (Sanofi Pasteur, MIV d Inc)... Influenza A (H1N1) 2009 Monovalent Vaccine MIV (CSL Limited, ID Biomedical Corporation of Quebec, Novartis Vaccines and Diagnostics Ltd, Sanofi Pasteur Inc)... Influenza A (H1N1) 2009 Monovalent Vaccine LAIV (MedImmune, LLC)... D There 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.... X Studies 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. a Vaccine pregnancy category data obtained from the most recent influenza vaccine package inserts available on the Food and Drug Administration website (available at: BiologicsBloodVaccines/Vaccines/ApprovedProducts/ucm htm; accessed: Feb. 13, 2012); b Injectable, seasonal (typesa&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. Bednarczyk. Influenza vaccine safety for fetus and neonate. Am J Obstet Gynecol 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 ( ), Black et al 14 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. 14 Another examination of medical records was conducted in a Houston, TX, hospital over 5 influenza seasons ( ). 15 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 S40 American Journal of Obstetrics & Gynecology Supplement to SEPTEMBER 2012

4 Supplement adverse outcomes was an elevated level of congenital anomalies among infants born to unvaccinated mothers; all other neonatal outcomes were similar across groups. 15 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. 16 In 2011, Moro et al 17 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. 17 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. 18 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. 17 Although the trimester of vaccination was reported, there was not a systematic evaluation of adverse events by vaccination timing. 17 A randomized controlled trial of influenza immunization in pregnant women was conducted in 340 pregnant women in Bangladesh between August 2004 and December 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. 19 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 H1N1 pandemic influenza vaccine studies After 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. 3 During the development and testing of these monovalent vaccines, there were a number of clinical trials and observational studies that included pregnant women. Zuccotti et al 20 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 al 22 conducted a trial that compared 2 formulations of the monovalent H1N1 vaccine that contained either 25 or 49 gof hemagglutinin antigen and was administered in the second or third trimester. This dosage was higher than the final dosage level of 15 g 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. 21 In 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 women for whom pregnancy outcomes were known, there were 261 live births and 4 spontaneous abortions (3 among mothers who had been vaccinated in the first trimester and 1 whose mother was vaccinated in the second trimester), none of which had evidence of congenital anomalies. Six live births had congenital anomalies (5 after secondtrimester vaccination and 1 after thirdtrimester vaccination). Overall, fetal outcome rates corresponded to those observed in the general population. 26 Another safety surveillance study was conducted in Scotland during the pandemic and involved 3754 vaccinated individuals and 312 individuals who were not vaccinated. Within the full cohort, there were 128 pregnant women and 130 separate pregnancy episodes; 117 pregnancy episodes involved exposure to H1N1 vaccine, and 13 did not. There were no differences in birth outcomes across vaccinated or unvaccinated women, nor were there differences when compared across trimester of vaccination. Among women who had been vaccinated either before their last menstrual Supplement to SEPTEMBER 2012 American Journal of Obstetrics & Gynecology S41

5 S42 American Journal of Obstetrics & Gynecology Supplement to SEPTEMBER 2012 TABLE 3 Summary of studies of safety of influenza vaccination in pregnancy for fetal and neonatal outcomes Study Design Study vaccine Study group Control group Follow-up period Fetal outcome Neonatal adverse outcome Omon et al, Prospective descriptive study of pregnant women with no unvaccinated group H1N1 monovalent vaccine, nonadjuvanted; all administered in 2nd or 3rd trimester, none in 1st trimester 569 pregnant women in southwestern France who were vaccinated against H1N1 in vaccination clinics or maternity wards and monitored through delivery None (comparisons with previous published surveys) Through delivery Similar rates to previous published studies of French pregnancies for premature rupture of membranes, preterm labor, hypertension, gestational diabetes mellitus, intrauterine growth retardation, fetal deaths, stillbirths, prematurity, severe prematurity, low Apgar score, weight, length; significantly elevated congenital anomalies (4.5% vs 2.2%); no difference in major anomalies (3% vs 2.4-3%); all vaccinations given in 2nd or 3rd trimester after embryogenesis No direct measures of infant AE/SAE after delivery Mackenzie et al, Cohort Monovalent H1N1 vaccine 128 pregnant women, with 130 pregnancies;117 women who were exposed to H1N1 vaccine 13 women who were not exposed to H1N1 vaccine No direct measures of infant AE/SAE after delivery Through delivery 13 women who were vaccinated before last menstrual period (5 uncomplicated vaginal births [1 with hypospadias], 3 cesarean deliveries, 3 unknown birth type, 2 miscarriages);19 women who were vaccinated in 1st trimester (9 women with uncomplicated vaginal births [1 with skin tag on finger], 2 cesarean deliveries, 2 forceps deliveries, 4 unknown delivery type, 2 miscarriages); 83 women who were vaccinated in 2nd/3rd trimesters (45 uncomplicated vaginal births [1 Down Syndrome, 1 hydrocephalus, 1 umbilical hernia, 1 cleft palate]; 16 cesarean deliveries [4 forceps deliveries, 18 unknown delivery type, 0 miscarriages]); 2 women with uncertain vaccination time and unknown birth outcome; 13 women who were not vaccinated (7 uncomplicated vaginal births, 3 cesarean deliveries, 1 forceps delivery, 2 unknown birth type); no differences in birth outcomes from control group or national levels; no difference in congenital anomalies compared with national estimates Moro et al, Review of reports to Vaccine Adverse Events Reporting System Pregnant women with reports in VAERS No direct measures of infant AE/SAE after delivery H1N1 monovalent vaccines; trimester of vaccination recorded but AE measurement not analyzed against trimester except to rule out associations (eg, vaccination at 17 weeks gestation could not have caused cleft lip given the timing of cleft development) None Not applicable 294 total VAERS reports after H1N1 vaccination (288 after inactivated and 6 after live attenuated vaccines); 165 pregnancyspecific outcomes (131 verified):121 spontaneous abortions a 20 wk gestation;19 stillbirths at 20 wk gestation; 7 preterm deliveries; 4 threatened abortions; 3 preterm labor; 2 each preeclampsia, maternal death, and intrauterine growth retardation; 1 each of fetal hydronephrosis, fetal tachycardia, cleft lip, neonatal intraparenchymal hemorrhage, and intrauterine fetal death; no evidence of higher rates than in general population; increased reporting rate of spontaneous abortion compared with rates after trivalent influenza vaccination may be due to enhanced and stimulated reporting Moro et al, Review of reports to Vaccine Adverse Events Reporting System among pregnant women from Trivalent influenza vaccine; trimester of vaccination recorded, but AE measurement not analyzed against trimester Pregnant women with reports in VAERS None Not applicable 175 total reports (148 after TIV, 27 after LAIV); 20 spontaneous abortions reported (17 after TIV, 3 after LAIV); after TIV (6 stillbirth, 3 oligohydramnios, 2 polyhydramnios); congenital anomalies (1 each of upper limb reduction, multiple malformations, agenesis of the corpus callosum, cystic adenomatoid malformation, fetal arrhythmias, patent foramen ovale and peripheral pulmonic stenosis, spina bifida, pyloric stenosis and pneumonia); no evidence of increased or 4 adverse neonatal outcomes (1 each of meningitis, developmental disability, jaundice, autism); no evidence of increased or unexpected patterns of adverse events unexpected patterns of adverse events Bednarczyk. Influenza vaccine safety for fetus and neonate. Am J Obstet Gynecol (continued ) Supplement

6 Supplement to SEPTEMBER 2012 American Journal of Obstetrics & Gynecology S43 TABLE 3 Summary of studies of safety of influenza vaccination in pregnancy for fetal and neonatal outcomes (continued) Study Design Study vaccine Study group Control group Follow-up period Fetal outcome Neonatal adverse outcome Tavares et al, Prospective, observational, postauthorization safety study GlaxoSmithKline Biologicals (Brentford, Middlesex, UK) monovalent H1N1 vaccine with ASO3 adjuvant; sodium deoxycholate splitting agent; given in all trimesters 267 pregnant women None; comparisons made across trimester of vaccination Through delivery 265 known pregnancy outcomes (261 live births and 4 spontaneous abortions [no evidence of congenital anomalies; occurred at 10, 16, 17, and 22 wk gestation], with no stillbirths; 6 live births with congenital anomalies [1 diagnosed before vaccination]); fetal outcomes corresponded to population-level expected levels (preterm birth [5.4%] and low birthweight [8.1%] comparable with expected rates; 42 1st-trimester vaccinations (38 live births, 3 spontaneous abortions, 1 lost to follow up); 115 2nd-trimester vaccinations (108 live births, 5 live births with congenital anomalies, 1 spontaneous abortion, 1 lost to follow up); 110 3rd-trimester vaccinations (109 live births, 1 live birth with a congenital anomaly) No AE recorded or monitored after delivery Horiya et al, Controlled trial (no indication of randomization) 128 pregnant women who received 2 doses of H1N1 vaccine 82 pregnant women who received 1 dose of H1N1 vaccine Through delivery No AE recorded or monitored after delivery Kitasato Institute Research Center for Biologicals (Tokyo, Japan) monovalent H1N1 vaccine; no adjuvant; splitting agent not available No abortions; incidence of preterm birth comparable with general population; Apgar scores within standard range; 5 congenital anomalies noted, comparable with general population (3 women who were vaccinated in 2nd trimester; 2 women who were vaccinated in 3rd trimester) Jackson et al Randomized, Through delivery No AE recorded or monitored controlled trial after delivery Sanofi Pasteur, Inc (Swiftwater, PA) monovalent H1N1 vaccine; no adjuvant; octylphenol ethoxylate (Triton X-100) splitting agent; vaccinated in 2nd and 3rd trimester 60 pregnant women who received 49 g hemagglutinin antigen dose influenza vaccine 60 pregnant women who received 25 g hemagglutinin antigen dose influenza vaccine 18 SAEs in 15 women; 24 SAEs in 20 infants; frequency balanced across exposure group (9/15 maternal and 13/20 infant in 25- g group); maternal SAE (6 postpartum hemorrhages, 2 preterm contractions, 2 severe preeclampsia, 1 each abdominal myomectomy, exacerbation of asthma, gestational hypertension at term, fetal loss at 20 wk gestation, nonelective cesarean delivery, premature delivery, retained placenta, vaginal bleeding); infant SAE (5 premature births, 4 sacral dimples, 3 atrial septal defects, 1 each of congenital heart disease, hyperbilirubinemia, possible Hirschsprung s disease, postaxial polydactyly, pulmonic stenosis, respiratory distress, simple complete syndactyly, teratology of Fallot, thickened nuchal fold, fetal distress resulting in emergency cesarean delivery); no analysis of AE by trimester of vaccination Zuccotti et al, Prospective, singlearm trial None Through delivery No serious adverse events noted No serious adverse events noted 2009 monovalent H1N1 vaccine (7.5 g hemagglutinin antigen dose), MF-59 adjuvanted; splitting agent unknown (manufactured by Novartis Vaccines and Diagnostics, Inc, Emeryville, CA) but may be cetyltrimethylammonium bromide 75 pregnant women who were vaccinated in the 3rd trimester Prospective, Sheffield et al, Not reported 439 pregnant women 8251 pregnant Through delivery Two percent of infants in first-trimester group had major No AE/SAE monitored beyond population-based surveillance who were vaccinated in the 1st trimester women who were vaccinated in 2nd congenital anomalies (the same level as in 2nd/3rd trimester group; no significant difference in minor anomalies malformations that were identified at birth and 3rd trimesters Zaman et al, Prospective, 7 d after vaccination; 3 stillbirths that were recorded; no significant difference in No statistical differences in randomized doubleblind mother-infant pairs serious adverse events between vaccine groups newborn infant or infant AE controlled trial observed to 24 wk old through 24 wk old Fluarix (GlaxoSmithKline Biologicals); no adjuvant; sodium deoxycholate splitting agent; vaccinated in 3rd trimester 172 pregnant women 168 pregnant women who received 23- valent pneumococcal polysaccharide vaccine Bednarczyk. Influenza vaccine safety for fetus and neonate. Am J Obstet Gynecol (continued ) Supplement

7 Supplement TABLE 3 Summary of studies of safety of influenza vaccination in pregnancy for fetal and neonatal outcomes (continued) Study Design Study vaccine Study group Control group Follow-up period Fetal outcome Neonatal adverse outcome Medical outcomes in infants similar between vaccinated and unvaccinated mothers No significant differences in cause of maternal hospitalization related to infant health between vaccinated and unvaccinated women Maternal follow-up until delivery; infants observed until 6 mo old 826 pregnant women who were not vaccinated 225 pregnant women who were vaccinated in 2nd and 3rd trimesters Not applicable; database review Munoz et al, Retrospective, matched cohort No AE/SAE beyond cesarean/ preterm delivery 45,866 women End of influenza season No maternal deaths; no significant difference in rate of preterm birth; cesarean delivery similar between vaccinated and unvaccinated women after adjustment for maternal age pregnant women who were vaccinated Black et al, Retrospective cohort Not applicable; database review; vaccinated in 2nd or 3rd trimester Deinard and Ogburn, Prospective cohort 1976 A/NJ influenza vaccine Through 8 wk old No complications No teratogenicity or infant outcomes; no difference in physical or neurologic assessments at birth or 8 wk old 517 pregnant women who did not receive the vaccine 189 women who were vaccinated before or during pregnancy Sumaya and Gibbs, Retrospective, 56 pregnant women Up to 6 mo after No AE/SAE during infancy matched cohort who were vaccinated immunization All immunized mothers had live births; 3 newborn infants had congenital defects (inguinal hernia, phalangeal tag, club feet), which was similar to the general control group 40 pregnant women who were not vaccinated Inactivated influenza A/NJ/ 76; vaccinated in 2nd and 3rd trimesters Heinonen et al, Prospective cohort Not specified 2291 women who None Through 1 y Not applicable 1 child who had astrocytoma of the spinal medulla; mother who also received polio vaccine during pregnancy were vaccinated against influenza AE, adverse event; LAIV, live attenuated influenza vaccine; SAE, serious adverse event; TIV, trivalent inactivated vaccine; VAERS, Vaccine Adverse Events Reporting System. Bednarczyk. Influenza vaccine safety for fetus and neonate. Am J Obstet Gynecol period or during pregnancy, there were 59 uncomplicated vaginal deliveries, 21 cesarean deliveries, 6 forceps deliveries, 4 miscarriages, and 25 deliveries of unknown type, with 2 pregnancy episodes with unknown trimester of vaccination and unknown birth outcome. Among women who were not vaccinated against H1N1 influenza, there were 7 uncomplicated vaginal deliveries, 3 cesarean deliveries, 1 forceps delivery, and 2 deliveries of unknown type. Six congenital anomalies were identified in births to vaccinated mothers, with no patterns in type (1 each of hypospadias, skin tag on finger, Down syndrome, hydrocephalus, umbilical hernia, cleft palate) and little biologic plausibility (eg, Down syndrome and cleft palate in children who were born to mothers who had been vaccinated in the second or third trimester). Additionally, the levels of congenital anomalies that were identified were similar across vaccination type and compared with national estimates. 23 In southwestern France, 651 pregnant women who received H1N1 influenza vaccine during the pregnancy were enrolled in a prospective follow-up study; full information was available on pregnancy outcomes for 569 women. 25 Of these 569 women, there were 580 live births (12 sets of twins) and 1 fetal death, with no stillbirths. Although there was not an unvaccinated group for comparison, pregnancy and birth outcomes were compared with existing historic data from previous French population surveys. 25 Similar to the study described earlier for seasonal influenza vaccine, reports to VAERS after administration of H1N1 influenza vaccine were also studied. 24 Given the strong emphasis on the vaccination of pregnant women against H1N1 influenza 3 and the high public awareness of the vaccine, it is not surprising that there were more VAERS reports related to H1N1 influenza vaccine than for seasonal influenza vaccine. 27 Related to the H1N1 influenza vaccination campaign, there were a total of 294 VAERS reports after the vaccination of pregnant women (288 after inactivated vaccine and 6 after live attenuated vaccine). Of these reports, spontaneous S44 American Journal of Obstetrics & Gynecology Supplement to SEPTEMBER 2012

8 Supplement abortion was the most common (121 reports), with an additional 19 stillbirths reported. 24 Similar to the seasonal influenza vaccine, 17 there did not appear to be an increase over expected levels of these outcomes. 24 Although the trimester of vaccination was recorded, there was not a systematic assessment of outcomes by vaccination time because of small numbers. However, for some cases, this information was useful to determine that vaccination could not have led to the development of a specified outcome, such as the birth with a cleft lip to a mother who had been vaccinated at 17 weeks gestation, which is after the time period of development when such an anomaly would occur. 24 For this evaluation, there was no assessment of adverse events in the neonatal period. 24 A summary of these studies that have described the safety of influenza vaccine to the fetus and neonates is given in Table 3. Summary and considerations for future evaluations The available data suggest that influenza vaccination in pregnancy has an overall good safety record for fetal and neonatal outcomes. However, there are several ongoing analyses (for example, within the Vaccine Safety Datalink project) that have focused on the safety of seasonal and pandemic influenza vaccines that are administered during pregnancy. These ongoing analyses might yield new insights into the safety of maternal influenza immunization for fetal and neonatal outcomes. Future research in this area should have a greater focus on safety data for the first trimester of pregnancy. The first trimester is a period of relatively high vulnerability for the developing fetus, and there are limited data on the safety of maternal influenza immunization in early pregnancy. The reasons for limited first-trimester data include difficulty in enrolling in safety studies before pregnancy, difficulty in the assignment of a start of pregnancy date in retrospective studies, and low rates of recognition of some outcomes (eg, spontaneous abortions in early pregnancy). Historically, studies (particularly studies not sponsored by vaccine manufacturers) have focused on influenza vaccine as a single entity without focusing on product-specific analyses. There are differences between the inactivated influenza vaccines that are produced by various manufacturers. These differences include (1) split virus vs subunit antigens, (2) differences in the chemical splitting agent that is used to convert whole virus to split virus particles, (3) the absence or presence of adjuvants, and (4) the specific adjuvant that is used, if any. There is increasing recognition of product-specific adverse events for influenza vaccine. For example, in Australia during the 2010 Southern Hemisphere influenza season, an increased rate of febrile seizures in children 5 years old was observed after the administration of influenza vaccine from 1 specific manufacturer Comparisons with historic data identified adverse event clusters that were associated with the receipt of an influenza vaccine that used the same splitting agent as used in the vaccine that was associated with febrile seizures in Australia. 30 Therefore, there is a need for the evaluation of the safety of specific vaccine products for maternal immunization. Similarly, different congenital anomalies have different causal pathways. Many studies are powered to evaluate composite birth defect outcomes. Future research should focus on discrete outcomes or group of outcomes with common etiologic pathways. In summary, maternal influenza immunization has a good record for fetal and neonatal outcomes. 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