|TERIS Agent Number:||1485||Bibliographic Search Date:||10/2019|
|Agent Name:||INFLUENZA VACCINE, INACTIVATED|
|Conventional influenza vaccine consists of whole or fractionated inactivated (i.e., killed) influenza virus that is administered by injection. PLEASE SEE AGENT SUMMARY ON INFLUENZA VACCINE, LIVE, FOR INFORMATION ON THE ATTENUATED LIVE VIRUS VACCINE THAT IS GIVEN BY INTRANASAL ADMINISTRATION.|
Magnitude of Teratogenic Risk to Child Born After Exposure During Gestation:
Quality and Quantity of Data on Which Risk Estimate is Based:
1) THE FORMULATION OF INFLUENZA VIRUS VACCINE VARIES EACH YEAR.
2) NATIVE INFLUENZA VIRUS IS NOT KNOWN TO BE TERATOGENIC IN HUMANS, ALTHOUGH MATERNAL INFLUENZA INFECTION DURING PREGNANCY HAS BEEN ASSOCIATED WITH FETAL DEATH AND PREMATURE DELIVERY (MALDONADO, 2011; NEWSOME ET AL., 2011; RASMUSSEN ET AL., 2012; HABERG ET AL., 2013). THE FEVER THAT IS ASSOCIATED WITH MATERNAL INFLUENZA MAY ALSO POSE A RISK TO THE DEVELOPING EMBRYO (MORETTI ET AL., 2005; EDWARDS, 2006).
3) INACTIVATED (RATHER THAN LIVE, ATTENUATED) INFLUENZA VACCINE SHOULD BE USED FOR IMMUNIZING WOMEN DURING PREGNANCY (RASMUSSEN ET AL., 2011; HISANO & YAMAGUCHI, 2012; RASMUSSEN & JAMIESON, 2012).
Summary of Teratology Studies:
The prevalence of major malformations selected for reliability of record coding was no greater than expected among 52,856 infants whose mothers had been immunized with inactivated influenza vaccination during the first trimester of pregnancy in a US health-insurance-based record-linkage study (prevalence ratio=1.02, 95% confidence interval 0.94-1.10) (Kharbanda et al., 2017). No increase in the prevalence of 11 principal classes or subclasses of malformations was observed among the infants of women who had received influenza vaccine during after first trimester in this study.
No increase was seen in the frequencies of congenital anomalies in general or of five major classes of congenital anomalies among 1729 infants whose mothers were immunized with inactivated influenza vaccine between the first and ninth weeks of pregnancy in a Swedish population-based record linkage study (Kallen & Olausson, 2012). Major congenital anomalies and five anatomic classes of congenital anomalies were no more frequent than expected among infants whose mothers had been vaccinated during the first trimester of pregnancy. Similarly, the frequencies of congenital anomalies in general, of major malformations, of minor anomalies, and of principal classes of malformations were no greater than expected among the children of 650 women who were immunized with inactivated influenza virus vaccine during the first four lunar months of pregnancy or among the children of 2283 women who had been given inactivated influenza virus vaccine anytime during pregnancy in the Collaborative Perinatal Project (Heinonen et al., 1977). The frequency of major malformations was not increased among 447 infants whose mothers had been immunized with inactivated influenza vaccine in the first trimester of pregnancy or among 8864 infants whose mothers were vaccinated anytime in pregnancy in an obstetrical database study performed at a single large US hospital (Sheffield et al., 2012).
The frequency of congenital anomalies was no greater than expected among 2310 infants whose mothers received immunization with inactivated influenza vaccine during pregnancy in a cohort study performed in three countries by the manufacturer (Heikkinen et al., 2012). The rate of congenital anomalies was similar among the infants of 94 women who were vaccinated in the first trimester in this study and the infants of women who were immunized later in pregnancy. The reported frequency of congenital anomalies was not increased among the infants of 7293 women who had been immunized with inactivated influenza vaccine in a retrospective cohort study performed in Argentina, but congenital anomalies appear to have been seriously underascertained in both the immunized and control groups in this study (Rubinstein et al., 2013). 39.4% of the vaccinated women were immunized during the first trimester of pregnancy.
Many smaller studies also found no association between maternal influenza immunization during pregnancy, usually after the first trimester, and congenital anomalies in the infants (Tavares et al., 2011; Launay et al., 2012; Oppermann et al., 2012; Pasternak et al., 2012; Chambers et al., 2013; Moro et al., 2017; Vesikari et al., 2019). Reviews and meta-analyses that include these and many earlier studies conclude that there is no evidence that infants whose mothers are immunized with influenza vaccine during pregnancy have a greater than expected risk of congenital anomalies (Bednarczyk et al., 2012; Munoz, 2012; Polyzos et al., 2015; Jeong et al., 2019).
OTHER ADVERSE PREGNANCY OUTCOMES
Some studies suggest that maternal immunization with inactivated influenza vaccine during the second or third trimester of pregnancy may decrease the frequency of low birth weight infants, preterm birth, or fetal death (Nunes et al., 2016), but a recent meta-analysis of 48 studies that included over two million pregnant women or their infants does not support a beneficial effect of influenza immunization on fetal growth or survival or on preterm birth (Jeong et al., 2019). A suggested association between inactivated influenza vaccination during pregnancy and spontaneous abortion (Donahue et al., 2017) was not replicated in a subsequent larger study by the same researchers (Donahue et al., 2019).
Maternal immunization with influenza vaccine during pregnancy does appear to reduce the risk of influenza occurring among the infants in the first few months of life (Nunes & Madhi, 2018). Rates of childhood lung and ear infections, sensory disorders, chronic pediatric disease, mortality, and neoplasms were similar among 31,295 children whose mothers were vaccinated against influenza during pregnancy and among the children of whose mothers were not vaccinated in a study performed through a Canadian birth registry (Walsh et al., 2019).
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Bednarczyk RA, Adjaye-Gbewonyo D, Omer SB: Safety of influenza immunization during pregnancy for the fetus and the neonate. Am J Obstet Gynecol 207(3 Suppl):S38-S46, 2012. [R]
Chambers CD, Johnson D, Xu R, Luo Y, Louik C, Mitchell AA, Schatz M, Jones KL: Risks and safety of pandemic H1N1 influenza vaccine in pregnancy: birth defects, spontaneous abortion, preterm delivery, and small for gestational age infants. Vaccine 31(44):5026-5032, 2013. [E]
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Heikkinen T, Young J, van Beek E, Franke H, Verstraeten T, Weil JG, Della Cioppa G: Safety of MF59-adjuvanted A/H1N1 influenza vaccine in pregnancy: a comparative cohort study. Am J Obstet Gynecol 207(3):177.e1-177.e8, 2012. [E]
Heinonen OP, Slone D, Shapiro S: Birth Defects and Drugs in Pregnancy. Littleton, Mass.: John Wright-PSG, 1977, pp 314-316, 318-319, 436, 474, 488. [E]
Jeong S, Jang EJ, Jo J, Jang S: Effects of maternal influenza vaccination on adverse birth outcomes: a systematic review and Bayesian meta-analysis. PLoS One 14(8):e0220910, 2019. [R]
Kallen B, Olausson PO: Vaccination against H1N1 influenza with Pandemrix® during pregnancy and delivery outcome: a Swedish register study. BJOG 119(13):1583-1590, 2012. [E]
Kharbanda EO, Vazquez-Benitez G, Romitti PA, Naleway AL, Cheetham TC, Lipkind HS, Klein NP, Lee G, Jackson ML, Hambidge SJ, McCarthy N, DeStefano F, Nordin JD: First trimester influenza vaccination and risks for major structural birth defects in offspring. J Pediatr 187:234-239.e4, 2017. [E]
Launay O, Krivine A, Charlier C, Truster V, Tsatsaris V, Lepercq J, Ville Y, Avenell C, Andrieu T, Rozenberg F, Artiguebielle F, Treluyer J-M, Goffinet F: Low rate of pandemic A/H1N1 2009 influenza infection and lack of severe complication of vaccination in pregnant women: a prospective cohort study. PLoS One 7(12):e52303, 2012. [E]
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Moretti ME, Bar-Oz B, Fried S, Koren G: Maternal hyperthermia and the risk for neural tube defects in offspring: systematic review and meta-analysis. Epidemiology 16(2):216-219, 2005. [R]
Moro P, Baumblatt J, Lewis P, Cragan J, Tepper N, Cano M: Surveillance of adverse events after seasonal influenza vaccination in pregnant women and their infants in the Vaccine Adverse Event Reporting System, July 2010-May 2016. Drug Saf 40(2):145-152, 2017. [S]
Munoz FM: Safety of influenza vaccines in pregnant women. Am J Obstet Gynecol 207(3 Suppl):S33-S37, 2012. [R]
Nunes MC, Aqil AR, Omer SB, Madhi SA: The effects of influenza vaccination during pregnancy on birth outcomes: a systematic review and meta-analysis. Am J Perinatol 33(11):1104-1014, 2016. [R]
Nunes MC, Madhi SA: Influenza vaccination during pregnancy for prevention of influenza confirmed illness in the infants: a systematic review and meta-analysis. Hum Vaccin Immunother 14(3):758-766, 2018. [R]
Oppermann M, Fritzsche J, Weber-Schoendorfer C, Keller-Stanislawski B, Allignol A, Meister R, Schaefer C: A(H1N1)v2009: a controlled observational prospective cohort study on vaccine safety in pregnancy. Vaccine 30(30):4445-4452, 2012. [E]
Pasternak B, Svanstrom H, Molgaard-Nielsen D, Krause TG, Emborg H-D, Melbye M, Hviid A: Risk of adverse fetal outcomes following administration of a pandemic influenza A(H1N1) vaccine during pregnancy. JAMA 308(2):165-174, 2012. [E]
Polyzos KA, Konstantelias AA, Pitsa CE, Falagas ME: Maternal influenza vaccination and risk for congenital malformations: a systematic review and meta-analysis. Obstet Gynecol 126(5):1075-1084, 2015. [R]
Rubinstein F, Micone P, Bonotti A, Wainer V, Schwarcz A, Augustovski F, Pichon Riviere A, Karolinski A: Influenza A/H1N1 MF59 adjuvanted vaccine in pregnant women and adverse perinatal outcomes: multicentre study [published erratum appears in BMJ 346:f990, 2013]. BMJ 346:f393, 2013. [E]
Sheffield JS, Greer LG, Rogers VL, Roberts SW, Lytle H, McIntire DD, Wendel GD Jr: Effect of influenza vaccination in the first trimester of pregnancy. Obstet Gynecol 120(3):532-537, 2012. [E]
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Tavares F, Nazareth I, Monegal JS, 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 29(37):6358-6365, 2011. [S]
Vesikari T, Virta M, Heinonen S, Eymin C, Lavis N, Chabanon AL, Gresset-Bourgeois V: Immunogenicity and safety of a quadrivalent inactivated influenza vaccine in pregnant women: a randomized, observer-blind trial. Hum Vaccin Immunother. 2019 Oct 7 (Epub ahead of print). [E]
Walsh LK, Donelle J, Dodds L, Hawken S, Wilson K, Benchimol EI, Chakraborty P, Guttmann A, Kwong JC, MacDonald NE, Ortiz JR, Sprague AE, Top KA, Walker MC, Wen SW, Fell DB: Health outcomes of young children born to mothers who received 2009 pandemic H1N1 influenza vaccination during pregnancy: retrospective cohort study. BMJ 366:l4151, 2019. [E]