Pregnant women are at increased risk for serious complications from influenza.1,2 The increased burden of influenza during pregnancy was pronounced during the H1N1 pandemic;3–5 however, even in nonpandemic seasons, pregnant women are more likely than nonpregnant women to have an influenza-related hospitalization.1 Influenza infection during pregnancy also can adversely affect fetal growth and is a risk for preterm delivery.6,7 When administered during pregnancy, the trivalent inactivated influenza vaccine can prevent these adverse outcomes for expectant mothers and their fetuses.8–10
Since 1997, the trivalent inactivated influenza vaccine has been recommended for otherwise healthy women in their second or third trimester of pregnancy. In 2004, the Advisory Committee on Immunization Practices changed its recommendations to include women in any stage of pregnancy.11 These recommendations have been strongly endorsed by the American College of Obstetricians and Gynecologists.12 However, concerns regarding vaccine safety during pregnancy remain a persistent barrier to vaccination.13,14 Data from clinical trials,9,15,16 passive surveillance,17 and observational studies18 have not suggested any associations between the trivalent inactivated influenza vaccine and maternal or fetal adverse events. However, previous studies have been underpowered to detect rare outcomes, and no previous studies have adequately assessed the safety of first-trimester vaccination.19
Using a large, geographically diverse, retrospective cohort of pregnant women, the goals of this study were to estimate the risks for medically attended events occurring within 42 days of receiving trivalent inactivated influenza vaccine and to evaluate specific risks of first-trimester vaccination.
MATERIALS AND METHODS
In this retrospective observational cohort study, we compared rates of medically attended adverse events in pregnant women vaccinated with trivalent inactivated influenza vaccine and unvaccinated pregnant women in the Vaccine Safety Datalink. The Vaccine Safety Datalink is a collaborative effort between the Centers for Disease Control and Prevention Immunization Safety Office and 10 health care systems across the United States. It includes data for 9.5 million individuals, comprising 3% of the United States population.20 The current study is first large cohort study of vaccine safety during pregnancy for the Vaccine Safety Datalink.21
Seven Vaccine Safety Datalink sites (Group Health Cooperative, HealthPartners, Kaiser Permanente Colorado, Kaiser Permanente Northwest, Kaiser Permanente Northern California, Kaiser Permanente Southern California, and Marshfield Clinic Research Foundation) contributed data for this study. This study was approved by the Institutional Review Boards of all involved sites. All data were derived from claims and electronic medical records from the health care organizations. Pregnant women enrolled at those sites were identified using a previously validated algorithm developed by Hornbrook et al22 and data were adapted for use in the Vaccine Safety Datalink by Naleway et al.23 The algorithm uses a hierarchical approach to identify pregnancy episodes, pregnancy outcomes (live births, still births, spontaneous abortions, therapeutic abortions, ectopic pregnancies, and gestational trophoblastic disease), and gestational age at pregnancy outcome. The algorithm calculates a pregnancy start date equivalent to the estimated last menstrual period. The first trimester was defined as less than 14 weeks of gestation, the second trimester was defined as 14 to less than 28 weeks, and the third trimester was defined as 28 weeks or more of gestation. In a recent validation of this algorithm, 99% of live births were confirmed to occur within 30 days of the algorithm-defined dates, and there was 98% agreement in gestational age between the algorithm and manual chart review.23 Additional strategies used in this algorithm to assign gestational age in weeks based on the timing of common prenatal procedures have been previously described.21
Women were retained in the cohort if they had continuous insurance enrollment with no more than a 30-day administrative enrollment gap from 6 months before the start of pregnancy until 2 months after the end of pregnancy. The following pregnancies were excluded: multiple gestation pregnancies; ectopic pregnancies; gestational trophoblastic disease; therapeutic abortions; and pregnancies in which the outcome could not be determined based on available data. In addition, women with no medical encounters during pregnancy were excluded (Appendix 1, available online at http://links.lww.com/AOG/A348).
Receipt of trivalent inactivated influenza vaccine was identified from the Vaccine Safety Datalink vaccine files. The data sources for these files vary slightly across sites but generally include vaccines captured through claims and site-based vaccine registries. Data of workplace or pharmacy vaccination were available only when manually entered by a health care provider, on the basis of patient report. Exclusions included women receiving trivalent inactivated influenza vaccine within 2 weeks of their estimated pregnancy start (because of some uncertainty regarding dates). To avoid including vaccines administered postpartum, women vaccinated within 1 week of their pregnancy end date also were excluded. In addition, women receiving other vaccines during pregnancy were excluded.
After applying these inclusion and exclusion criteria, all pregnant women 14 through 49 years old retained in the cohort who received trivalent inactivated influenza vaccine during the 2002–2003 through the 2008–2009 influenza seasons were matched 1:2 with replacement to unvaccinated women using a variable optimal matching algorithm.24 The original algorithm was modified so that matched vaccinated and unvaccinated women would be equally likely to be vaccinated during the same risk window. Match variables included age at pregnancy outcome (±1 year), estimated pregnancy start date (±30 days), and Vaccine Safety Datalink site. Unexposed women were assigned an index date equal to the trivalent inactivated influenza vaccine--exposed woman's gestational age at vaccination.
Adverse events were identified from International Classification of Diseases 9th Edition, Clinical Modification (ICD-9-CM) codes from inpatient, outpatient, or emergency department visits. Events on the day of vaccination (day 0) were included only if diagnosed at an inpatient or emergency department visit. Specific outcomes and windows were selected a priori based on biologic plausibility and past Vaccine Safety Datalink research on influenza vaccine safety in nonpregnant populations.25–28 For the first 3 days after vaccination, outcomes included allergic reactions, cellulitis, fever or malaise, limb soreness or swelling, rash, seizures, and altered mental status.
For the first 42 days after vaccination, outcomes included autonomic disorders, cranial nerve disorders, degeneration of the central nervous system, demyelinating disease, peripheral neuropathy or neuritis, Guillain-Barré syndrome, meningoencephalitides, movement disorders, myoneural disorders, paralytic syndromes, psychoses, spinocerebellar disease, myocarditis or pericarditis, and thrombocytopenia. To improve specificity for Guillain-Barré syndrome, only inpatient diagnoses were included. Appendix 2 (http://links.lww.com/AOG/A349) provides a complete listing of outcomes and their specific ICD-9-CM codes. Outcomes were included only if they represented new events. Washout periods to exclude pre-existing conditions were applied, and they varied by outcome (Appendix 2, available online at http://links.lww.com/AOG/A349).
As previously described, vaccinated and unvaccinated cohorts were matched by age, site, and estimated pregnancy start date. Data of additional covariates that may have differed between these cohorts also were gathered.14 Pre-existing conditions (diabetes mellitus, heart disease, hypertension, neurologic disease, and pulmonary disease) and pregnancy-related conditions (gestational diabetes, gestational hypertension, and preeclampsia) were identified from automated claims data from 6 months before pregnancy through the date of vaccination or index date. Receipt of medical care during the first trimester and hospitalization before the vaccination or index date also were recorded. In the absence of socioeconomic variables at the individual level, we used geocode files to describe, for each participant, the percentage of families in their census tract whose income was less than 150% of the federal poverty level.29 In the absence of a geocode, data for poverty was imputed using the expectation maximization algorithm.30
We used χ2 and Mann-Whitney U tests to compare baseline characteristics in vaccinated and unvaccinated populations (Tables 1). We report 0-day to 3-day and 1-day to 42-day rates for potential adverse events in our exposed and unexposed cohorts per 10,000 pregnancies. Crude associations between individual outcomes and trivalent inactivated influenza vaccine were analyzed using exact χ2 tests.
Using the generalized estimating equation method to account for the matching effect, with a Poisson distribution and log link, we calculated maternal incident rate ratios for the following composite safety outcomes: any event occurring 0–3 days after vaccination (Table 2); any neurologic event occurring 1–42 days after vaccination; and thrombocytopenia (Table 3). Incident rate ratios were adjusted for receipt of medical care during the first trimester, hospitalization, and high-risk conditions before the vaccination or index date. Associations are presented as 0-day to 3-day or 1-day to 42-day adjusted incident rate ratios and 95% confidence intervals (CIs). Analyses were conducted for the entire cohort and for the subset of women vaccinated during the first trimester. In addition, we evaluated whether a cluster effect was present because of women with multiple pregnancies over the 7-year period or because of sampling controls with replacement. Results did not differ from our main analysis. Because the intraclass correlation was minimal for most models (<.001), and some models did not converge; these effects were ignored in the main analyses.31
Most of the acute safety outcomes undergoing investigation (groups of ICD-9-CM codes) were expected to have 42-day incident background rates of approximately 1 per 10,000 women.32 Analyses for these outcomes had 80% power to detect a difference of 0.05% or an adjusted incident rate ratio of 1.5 with an α of 0.05. All analyses were performed using SAS 9.2.
Across the seven participating sites, from 1 June 2002 through 31 July 2009, a total of 807,563 pregnancies among women aged 14 through 49 years were identified from administrative and claims data. After applying exclusions, 407,745 pregnancies remained; 19% received trivalent inactivated influenza vaccine while pregnant. Our final cohort consisted of 75,906 trivalent inactivated influenza vaccine--exposed pregnancies matched by age, Vaccine Safety Datalink site, and estimated pregnancy start date with 147,992 unvaccinated women (Appendix 1 [http://links.lww.com/AOG/A348] provides a detailed diagram of inclusions and exclusions.)
The mean age of our cohort was 30.8±5.6 years. Vaccination occurred in all three trimesters, including 21,553 women (28.4%) vaccinated during their first trimester, 33,553 (44.2%) vaccinated during their second trimester, and 20,800 (27.4%) vaccinated during their third trimester. Although most women received medical care in the first trimester, rates were slightly higher among vaccinated women (88.8% compared with 86.4%). Compared with the unexposed, trivalent inactivated influenza vaccine--exposed women were more likely to have a pre-existing condition (14.5% compared with 11.7%), but they were somewhat less likely to be hospitalized before their vaccination or index date (5.3% compared with 5.7%).
Rates for medically attended allergic reactions, skin infections, fever and malaise, rash, seizures, or altered mental status events 0–3 days after vaccination were low; none exceeded 2 per 10,000 among both the vaccinated and unvaccinated women. Compared with unvaccinated women, no increase was observed in the incidence of 0-day to 3-day events among vaccinated women (Table 1). In multivariable regression models, after accounting for the matching effect and adjusting for pre-existing conditions, receipt of care in the first trimester, and hospitalization before their vaccination or index date, in the first 3 days after vaccination, receipt of trivalent inactivated influenza vaccine was not associated with having a medically attended event (adjusted incident rate ratio 1.12, 95% CI 0.81–1.55; P=.48). Similarly, in a regression model restricted to first-trimester vaccinees and their unexposed matches, in the first 3 days after vaccination, trivalent inactivated influenza vaccination was not associated with having a medically attended event (adjusted incident rate ratio 0.97, 95% CI 0.53–1.78; P=.93).
The most common safety outcome in the 42 days after vaccination or index date among both vaccinated and unvaccinated pregnant women was thrombocytopenia, which occurred at a rate of 10.4 per 10,000 vaccinees and 11.5 per 10,000 unexposed women. Among vaccinated women, there were no cases of Guillian-Barré syndrome, optic neuritis, Bells palsy, or transverse myelitis. For most other outcomes during the first 42 days, incident rates were less than 1 per 10,000 vaccinees or unexposed women. We found no evidence of increased risk in the 42 days after receiving the trivalent inactivated influenza for any prespecified neurologic outcome, myocarditis or pericarditis, or thrombocytopenia (Table 2). After accounting for the matching effect and adjusting for pre-existing conditions, receipt of care in the first trimester, and hospitalization before the vaccination or index date, in the first 42 days trivalent inactivated influenza vaccination was not associated with receiving a new diagnosis of thrombocytopenia (adjusted incident rate ratio 0.90, 95% CI 0.68–1.19; P=.45) or an acute neurologic event (adjusted incident rate ratio 0.92, 95% CI 0.54–1.56; P=.75) Similarly, in analyses restricted to women receiving trivalent inactivated influenza vaccine during their first trimester and their unexposed matches, trivalent inactivated influenza vaccination was not associated with a new episode of thrombocytopenia (adjusted incident rate ratio 0.56, 95% CI 0.22–1.39; P=.21) or an acute neurologic event (adjusted incident rate ratio 1.05, 95% CI 0.46–2.38; P=.91).
In this observational multisite study of 75,906 women who received trivalent inactivated influenza vaccine during pregnancy, no increased risk for adverse events after vaccination was observed in the first 6 weeks after vaccination. In the United States, it is estimated that six million women become pregnant each year.33 Most are pregnant for at least a portion of the influenza season and therefore are strongly encouraged to be vaccinated. This study should reassure these women and their health care providers of the safety of influenza vaccination for the outcomes we studied.
Our study is unique because we report on a large geographically diverse cohort of women, including more than 20,000 women vaccinated during the first trimester. Thus, our findings greatly expand on previous observational studies by Deinard et al34 and Munoz et al.18 In 1981, Deinard et al studied 189 trivalent inactivated influenza vaccine--exposed and 517 unexposed pregnant women and found no differences in maternal, perinatal, or neonatal complications.34 More recently, in 2005, Munoz et al evaluated the safety of trivalent inactivated influenza vaccine administered to 252 pregnant women during their second trimester or third trimester of pregnancy. When compared with 826 matched unvaccinated pregnant women, no increased risk for adverse events in the first 42 days after vaccination was observed. In addition, Munoz et al18 reported no difference in pregnancy or neonatal outcomes between the trivalent inactivated influenza vaccine-exposed and unexposed women.
Our findings complement and expand on results recently reported from the Vaccine Adverse Event Reporting System. Moro and colleagues reviewed the Vaccine Adverse Event Reporting System reports among pregnant women who received the trivalent inactivated influenza vaccine from 1 July 1990 through 30 June 2009. In this 20-year period, only 148 adverse events after receiving the trivalent inactivated influenza vaccine in pregnancy were identified; 20 (13.5%) reports were classified as serious. No unusual patterns of pregnancy complications or fetal outcomes were observed. Three reports of Guillain-Barré syndrome in pregnant women who received the trivalent inactivated influenza vaccine were noted in the Vaccine Adverse Event Reporting System; two of these cases were confirmed by chart review.35 As a passive reporting system, these reports are from an unknown denominator of pregnant vaccinated women. Background rates of Guillain-Barré syndrome in women of reproductive age range from 1.5 to 2.3 per 100,000 person-years;32 risks for Guillain-Barré may increase up to threefold for women during the first 30 days postpartum.36 Although we were underpowered to detect differences in rates of Guillain-Barré syndrome between trivalent inactivated influenza vaccine--exposed and unexposed women, it is reassuring that we had no incident cases in more than 76,000 vaccinated women.
Several limitations to this study should be noted. First, as with all observational studies, there was potential for confounding by indication. At baseline, vaccinated women were more likely to have a chronic medical condition such as asthma and diabetes, whereas unvaccinated women were slightly more likely to have been hospitalized during the baseline period. We were able to adjust for these baseline differences in our multivariable models. However, it is likely that, similar to nonpregnant populations, other unmeasured confounders differed between vaccinated and unvaccinated women.37
Second, data regarding whether women received the trivalent inactivated influenza vaccine were from claims or electronic medical record--based registries. Women vaccinated at nonmedical sites may have been misclassified as unexposed, potentially biasing our results. In a recent survey, up to 13% of women receiving the trivalent inactivated influenza vaccine while pregnant during the 2010–2011 influenza season did so at a pharmacy, other store, school, or workplace.38 Rates for women in our cohort to receive the trivalent inactivated influenza vaccine at alternative sites were likely to be lower, but data about the site of vaccination among pregnant women for 2002–2009 is limited. Third, our choice of ICD-9-CM codes and outcomes were based on extensive previous research in the Vaccine Safety Datalink. However, these outcomes are still prone to misclassification because of errors in coding. Both of these limitations may have reduced our power to detect acute safety signals. In addition, we were able to assess only medically attended adverse events. Thus, our estimated rates for mild events such as malaise or limb soreness are probably underestimates of their true rates. Furthermore, despite the large size of our cohort, we had insufficient power to detect increased risks for rare events or to conduct subgroup analyses by year or vaccine manufacturer.
In this large observational cohort study, receipt of the trivalent inactivated influenza vaccine during pregnancy was not associated with increased risk of medically attended acute adverse events in the 6 weeks after immunization. These findings should reassure pregnant women and their health care providers that the seasonal influenza vaccination is unlikely to cause the complications included in our study.
1. Neuzil KM, Reed GW, Mitchel EF, Simonsen L, Griffin MR. Impact of influenza on acute cardiopulmonary hospitalizations in pregnant women. Am J Epidemiol 1998;148:1094–102.
2. Dodds L, McNeil SA, Fell DB, Allen VM, Coombs A, Scott J, et al.. Impact of influenza exposure on rates of hospital admissions and physician visits because of respiratory illness among pregnant women. CMAJ 2007;176:463–8.
3. Creanga AA, Johnson TF, Graitcer SB, Hartman LK, Al-Samarrai T, Schwarz AG, et al.. Severity of 2009 pandemic influenza A (H1N1) virus infection in pregnant women. Obstet Gynecol 2010;115:717–26.
4. Louie JK, Acosta M, Jamieson DJ, Honein MA. Severe 2009 H1N1 influenza in pregnant and postpartum women in California. N Engl J Med 2010;362:27–35.
5. Siston AM, Rasmussen SA, Honein MA, Fry AM, Seib K, Callaghan WM, et al.. Pandemic 2009 influenza A(H1N1) virus illness among pregnant women in the United States. JAMA 2010;303:1517–25.
6. Maternal and infant outcomes among severely ill pregnant and postpartum women with 2009 pandemic influenza A (H1N1)–United States, April 2009-August 2010. MMWR Morb Mortal Wkly Rep 2011;60:1193–6.
7. Pierce M, Kurinczuk JJ, Spark P, Brocklehurst P, Knight M. Perinatal outcomes after maternal 2009/H1N1 infection: national cohort study. BMJ 2011;342:d3214.
8. Fell DB, Sprague AE, Liu N, Yasseen AS 3rd, Wen SW, Smith G, et al.. H1N1 influenza vaccination during pregnancy and fetal and neonatal outcomes. Am J Public Health 2012;102:e33–40.
9. Zaman K, Roy E, Arifeen SE, Rahman M, Raqib R, Wilson E, et al.. Effectiveness of maternal influenza immunization in mothers and infants. N Engl J Med 2008;359:1555–64.
10. Omer SB, Goodman D, Steinhoff MC, Rochat R, Klugman KP, Stoll BJ, et al.. Maternal influenza immunization and reduced likelihood of prematurity and small for gestational age births: a retrospective cohort study. PLoS Med 2011;8:e1000441.
11. Harper SA, Fukuda K, Uyeki TM, Cox NJ, Bridges CB. Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2004;53:1–40.
12. Influenza vaccination during pregnancy. Committee Opinion No. 468. American College of Obstetricians and Gynecologists. Obstet Gynecol 2010;116:1006–7.
13. Ahluwalia IB, Singleton JA, Jamieson DJ, Rasmussen SA, Harrison L. Seasonal influenza vaccine coverage among pregnant women: pregnancy risk assessment monitoring system. J Womens Health (Larchmt) 2011;20:649–51.
14. Ding H, Santibanez TA, Jamieson DJ, Weinbaum CM, Euler GL, Grohskopf LA, et al.. Influenza vaccination coverage among pregnant women—National 2009 H1N1 Flu Survey (NHFS). Am J Obstet Gynecol 2011;204:S96–106.
15. Sumaya CV, Gibbs RS. Immunization of pregnant women with influenza A/New Jersey/76 virus vaccine: reactogenicity and immunogenicity in mother and infant. J Infect Dis 1979;140:141–6.
16. 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 2011;29:6358–65.
17. Moro PL, Broder K, Zheteyeva Y, Walton K, Rohan P, Sutherland A, 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.e1–7.
18. Munoz FM, Greisinger AJ, Wehmanen OA, Mouzoon ME, Hoyle JC, Smith FA, , et al.. Safety of influenza vaccination during pregnancy. Am J Obstet Gynecol 2005;192:1098–106.
19. Skowronski DM, De Serres G. Is routine influenza immunization warranted in early pregnancy? Vaccine 2009;27:4754–70.
20. Baggs J, Gee J, Lewis E, et al.. The Vaccine Safety Datalink: a model for monitoring immunization safety. Pediatrics 2011;127(Suppl 1):S45–53.
21. Kharbanda E, Vazquez-Benitez G, Shi WX, Lipkind H, Naleway A, Molitor B, et al.. Assessing the safety of influenza immunization during pregnancy: the Vaccine Safety Datalink. Am J Obstet Gynecol 2012;207:S47–51.
22. Hornbrook MC, Whitlock EP, Berg CJ, et al.. Development of an algorithm to identify pregnancy episodes in an integrated health care delivery system. Health Serv Res 2007;42:908–27.
23. Naleway A, Gold R, Henninger M, Kurosky S, et al.. Identifying pregnancy episodes in the vaccine safety datalink. Clin Med Res 2012;10:179.
24. Bergstralh EJ, Kosanke JL, Jacobsen SJ. Software for optimal matching in observational studies. Epidemiology 1996;7:331–2.
25. Hambidge SJ, Glanz JM, France EK, et al.. Safety of trivalent inactivated influenza vaccine in children 6 to 23 months old. JAMA 2006;296:1990–7.
26. Glanz JM, Newcomer SR, Hambidge SJ, et al.. Safety of trivalent inactivated influenza vaccine in children aged 24 to 59 months in the vaccine safety datalink. Arch Pediatr Adolesc Med 2011;165:749–55.
27. Lee GM, Greene SK, Weintraub ES, Baggs J, Kulldorff M, Fireman BH, et al.. H1N1 and seasonal influenza vaccine safety in the vaccine safety datalink project. Am J Prev Med 2011;41:121–8.
29. Minnesota Population Center. National Historical Geographic Information System: Version 2.0. Minneapolis (MN): University of Minnesota; 2011. Available at: http://www.nhgis.org/
. Retrieved November 28, 2012.
30. Little R, Rubin DB. Statistical analysis with missing data. 2nd ed. New York (NY): John Wiley; 2002.
31. Sauzet O, Wright KC, Marston L, Brocklehurst P, Peacock JL. Modelling the hierarchical structure in datasets with very small clusters: a simulation study to explore the effect of the proportion of clusters when the outcome is continuous. Stat Med 2012 Oct 1. [Epub ahead of print].
32. Black S, Eskola J, Siegrist CA, Halsey N, Macdonald N, Law B, et al.. Importance of background rates of disease in assessment of vaccine safety during mass immunisation with pandemic H1N1 influenza vaccines. Lancet 2009;374:2115–22.
33. Ventura SJ, Mosher WD, Curtin SC, Abma JC, Henshaw S. Trends in pregnancies and pregnancy rates by outcome: estimates for the United States, 1976-96. Vital Health Stat 21 2000;56:1–47.
34. Deinard AS, Ogburn P Jr. A/NJ/8/76 influenza vaccination program: effects on maternal health and pregnancy outcome. Am J Obstet Gynecol 1981;140:240–5.
35. Moro PL, Broder K, Zheteyeva Y, Walton K, Rohan P, Sutherland A, 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 e1–7.
36. Cheng Q, Jiang GX, Fredrikson S, Link H, de Pedro-Cuesta J. Increased incidence of Guillain-Barre syndrome postpartum. Epidemiology 1998;9:601–4.
37. Fireman B, Lee J, Lewis N, Bembom O, van der Laan M, Baxter R. Influenza vaccination and mortality: differentiating vaccine effects from bias. Am J Epidemiol 2009;170:650–6.
38. Influenza vaccination coverage among pregnant women—United States, 2010-11 influenza season. MMWR Morb Mortal Wkly Rep 2011;60:1078–82.
Supplemental Digital Content
© 2013 by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.