The objective of the study was to characterize reports to the Vaccine Adverse Event Reporting System (VAERS) in pregnant women who received seasonal influenza vaccines to assess for potential vaccine safety concerns.
We searched VAERS for reports of adverse events (AEs) in pregnant women who received trivalent inactivated influenza vaccine (TIV) from July 1, 1990 through June 30, 2009, or live attenuated influenza vaccine (LAIV) from July 1, 2003, through June 30, 2009.
A total of 148 reports after TIV and 27 reports after LAIV were identified. Twenty TIV (13.5%) and 1 LAIV (4%) reports were classified as serious. No specific AEs were reported in 30 TIV (20.3%) and 16 LAIV (59%) reports. The most common pregnancy-specific AE was spontaneous abortion: 17 after TIV (11.5%) and 3 after LAIV (11%). The reporting rate of spontaneous abortion was 1.9 per million pregnant women vaccinated.
No unusual patterns of pregnancy complications or fetal outcomes were observed in the VAERS reports of pregnant women after the administration of TIV or LAIV.
Pregnant women have a higher risk for serious complications from influenza than nonpregnant women of reproductive age. The physiological and hormonal changes that take place during pregnancy are believed to place pregnant women at increased risk of complications from influenza infection. To reduce maternal morbidity, in 1997 the Advisory Committee on Immunization Practices recommended routine immunization of pregnant women with trivalent inactivated influenza vaccine (TIV) after the first trimester; in 2004 the recommendation was expanded to cover all trimesters.
Despite these recommendations, it is estimated that only 12-24% of pregnant women received the influenza vaccine during the 2005-2008 influenza season. Patient and health care providers’ concern about the safety of the influenza vaccine during pregnancy may partly explain this low coverage. Although available data support the safety of seasonal influenza vaccine in pregnant women, few studies have assessed the safety of TIV in large populations of pregnant women. The Vaccine Adverse Event Reporting System (VAERS) is the largest US postlicensure surveillance system and has provided useful information on the safety profile of TIV in the general population of adults and children. Because it is national in scope, VAERS may provide information on rare adverse events. We reviewed reports to VAERS to describe the safety profile of TIV and live attenuated influenza vaccine (LAIV) in pregnant women.
Materials and Methods
Vaccine Adverse Events Reporting System
VAERS is a passive surveillance system for vaccine safety created in 1990 and jointly administered by the Centers for Disease Control and Prevention and the Food and Drug Administration. VAERS accepts reports from vaccine manufacturers, health care providers, and vaccine recipients. Reports can be classified as serious or nonserious. Reports are classified as serious based on the code of federal regulations if they result in death, life-threatening illness, hospitalization or prolongation of hospitalization, or permanent disability, or if a congenital anomaly is reported. Medical records for serious reports are normally collected as part of routine surveillance activities in VAERS, regardless of vaccine administered. VAERS generally cannot assess whether a vaccination caused an adverse event (AE) but can identify possible vaccine safety concerns.
Review of reports
We analyzed VAERS reports of pregnant women vaccinated with TIV during July 1, 1990, through June 30, 2009, and with LAIV during the period from July 1, 2003, through June 30, 2009 (LAIV is not recommended for use in pregnant women). Non-US reports were excluded. We used Medical Dictionary for Regulatory Activities (MedDRA), a clinically validated, internationally standardized terminology, to search outcomes of interest in VAERS data. One AE report may have 1 or more MedDRA terms. To search for pregnancy reports, we used MedDRA terms that fall under two system organ classes: pregnancy, puerperium, and perinatal conditions and congenital, familial, and genetic disorders, and the text string search with the term “preg” in the variables for symptoms, laboratory data, illnesses at the time of vaccination, and preexisting conditions. If a VAERS report described AEs in more than 1 person, we treated each person as a separate report.
Two medical officers (P.L.M. and Y.Z.) conducted an independent clinical review of all VAERS reports retrieved using this search strategy to distinguish between pregnancy-related and non-pregnancy-related reports. Reports indicating that influenza vaccine was administered prior to conception or last menstrual period were excluded. A review of the medical records of the AEs in serious reports was also conducted to verify the diagnosis and obtain additional information. The system does not allow for active follow-up of adverse events among pregnant women; thus, pregnancy outcome data are not available for women who had an adverse pregnancy event.
We collected information on the following variables: state of residence, maternal date of birth, maternal age, gestational age, time between vaccination and onset of adverse event, major symptoms, seriousness, laboratory data, concomitant vaccinations, illness at the time of vaccination, and preexisting medical conditions. We used gestational age provided in the VAERS form or estimated gestational age at the time of vaccination if the last menstrual period or estimated date of delivery was provided. If applicable, the sex of the infant or fetus and type of congenital anomaly were collected from the VAERS form.
We used the following definitions for trimesters: first (0-13 weeks), second (14-27 weeks), and third (28 or more weeks). Spontaneous abortion was defined as fetal demise occurring before 20 weeks’ gestation. Stillbirths were defined as fetal demise that occurred at 20 or more weeks’ gestation. For confirmation of cases of anaphylaxis and Guillain-Barré syndrome, we reviewed medical records if available and used the attending physician’s assessment or the Brighton Collaboration definition for these conditions. When more than 1 AE was reported for the same person, we selected what we believed to be the primary clinical event of concern.
Frequencies of the most common coding terms and selected pregnancy and fetal outcomes were calculated using SAS version 9.2 (SAS Institute Inc, Cary, NC).
Reporting rates of AEs and reported spontaneous abortions
We calculated AE reporting rates using the estimated number of pregnant women immunized with seasonal influenza vaccine during the time period covered in this review as the denominator. We calculated reporting rates of spontaneous abortion by dividing the number of VAERS spontaneous abortion reports (for TIV and LAIV) by the estimated number of pregnant women immunized with seasonal influenza vaccine during each influenza season. To estimate the number of pregnant women vaccinated with influenza vaccine, we used published estimates of the pregnant population in the United States and influenza vaccination coverage rates for pregnant women for each influenza season.
Because VAERS is a routine surveillance program that does not meet the definition of research, it is not subject to institutional review board review and informed consent requirements.
Reported adverse events following trivalent inactivated influenza vaccine (TIV) administration in pregnant women
From July 1, 1990, through June 30, 2009, VAERS received 148 reports of AEs in pregnant women after TIV vaccination. Twenty reports (13.5%) were coded as serious and 128 (86.5%) as nonserious. No maternal deaths were reported. Most reports occurred after 2000 with the highest number of reports in 2008-2009 ( Figure ). Characteristics of the reported cases are shown in Table 1 . Among reported cases, TIV had been administered mostly (75.9%) during the first and second trimester of pregnancy. In 119 reports (80.4%), TIV was the only vaccine administered on the day of vaccination. No AEs were reported in 30 reports (20.3%) (eg, incorrect dose administered); rather these reports indicated only that the influenza vaccine was received by a pregnant woman.
|Serious reports, n (%)||20 (13.5)|
|Reports with no AEs, n (%)||30 (20.3)|
|Mean (median) age, y a||28.2 (29.0)|
|Mean (median) onset interval, d b||35.4 (8.0)|
|Mean (median) gestational age at time of AE, wks c||18.5 (18.0)|
|Gestational age at time of vaccination (n = 91), n (%)|
|First trimester (0-13 wks)||28 (30.8)|
|Second trimester (14-27 wks)||41 (45.1)|
|Third trimester (≥28 wks)||22 (24.2)|
|TIV given alone (%)||119 (80.4)|
|MedDRA terms coded for all reports, n d||230|
|Mean number of codes per report||3.4|