Objective
The objective of the study was to evaluate and summarize reports to the Vaccine Adverse Event Reporting System (VAERS), a spontaneous reporting system, in pregnant women who received influenza A (H1N1) 2009 monovalent vaccine to assess for potential vaccine safety problems.
Study Design
We reviewed reports of adverse events (AEs) in pregnant women who received 2009-H1N1 vaccines from Oct. 1, 2009, through Feb. 28, 2010.
Results
VAERS received 294 reports of AEs in pregnant women who received 2009-H1N1 vaccine: 288 after inactivated and 6 after the live attenuated vaccines. Two maternal deaths were reported. Fifty-nine women (20.1%) were hospitalized. We verified 131 pregnancy-specific outcomes: 95 spontaneous abortions (<20 weeks); 18 stillbirths (≥20 weeks); 7 preterm deliveries (<37 weeks); 3 threatened abortions; 2 preterm labor; 2 preeclampsia; and 1 each of fetal hydronephrosis, fetal tachycardia, intrauterine growth retardation, and cleft lip.
Conclusion
Review of reports to VAERS following H1N1 vaccination in pregnant women did not identify any concerning patterns of maternal or fetal outcomes.
Pregnant women are at higher risk for complications of influenza than nonpregnant women. Since 1997 the Advisory Committee on Immunization Practices (ACIP) has recommended trivalent inactivated influenza vaccine (TIV) for pregnant women. In 2004, the recommendation was expanded to cover all trimesters of pregnancy.
In April 2009, pandemic H1N1 2009 influenza A (H1N1) virus infections (2009 H1N1) were identified in the United States. The second documented death associated with 2009 H1N1 virus was in a previously healthy pregnant woman, and enhanced surveillance for 2009 H1N1 infection in pregnant women in the United States was initiated. Analyses of these cases showed that pregnant women had a higher rate of complications from 2009 H1N1 infection than the general population.
The ACIP recommended that pregnant women (in any trimester) be included as an initial target group for 2009 H1N1 vaccination. On Sept. 15, 2009, the Food and Drug Administration (FDA) licensed the first 2009 influenza A (H1N1) vaccines, which were initially available as live, attenuated vaccine (live H1N1) for intranasal administration (although live vaccines are not recommended for pregnant women ) and as inactivated, split-virus, or subunit vaccines for injection (inactivated H1N1). Because the licensure and manufacturing process for the 2009 H1N1 vaccines was the same as that used for seasonal influenza vaccines, the safety profile of licensed 2009 H1N1 vaccine was anticipated to be similar to that of seasonal influenza vaccine, which has an excellent safety record.
Monitoring adverse events (AEs) following 2009 H1N1 vaccine administration in pregnant women was a priority for the Centers for Disease Control and Prevention (CDC) in collaboration with the FDA. 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 of its size and national scope, VAERS can provide information on rare AEs that may not be detected in prelicensure clinical trials.
As part of the national 2009 H1N1 vaccine safety monitoring, we conducted rapid surveillance for AEs reported to VAERS in pregnant women who received H1N1 vaccines to assess for potential vaccine safety problems.
Materials and Methods
Vaccine Adverse Events Reporting System
VAERS is a spontaneous reporting system used to monitor vaccine safety. It was established in 1990 and is jointly administered by the CDC and FDA. VAERS accepts reports of AEs after vaccination from vaccine manufacturers, health care providers, vaccine recipients, and others. VAERS generally cannot assess whether a vaccination caused an AE but can identify possible vaccine safety problems for further investigation.
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, permanent disability, or congenital anomaly.
This regulatory definition of a serious report does not always reflect the severity of an outcome. Thus, some reports describing severe clinical conditions could be classified as nonserious if none of the above-mentioned situations are met.
As part of the federal response to monitor the safety of 2009 H1N1 vaccine, VAERS was enhanced in several ways: providing VAERS contact information on influenza vaccination cards given to vaccinees at the time of vaccination; advertising in medical journals and on the Internet; communicating with professional associations (such as the American College of Obstetricians and Gynecologists, American Academy of Pediatrics, American Medical Association) and state vaccine safety coordinators; and, increasing the capacity to process reports and obtain and review medical records.
Review of reports
We analyzed VAERS reports received through March 1, 2010, on pregnant women who were vaccinated with the 2009 H1N1 vaccine during Oct. 1, 2009, through Feb. 28, 2010. Non-US reports were excluded. We included reports of AEs in neonates if the report indicated that their mothers had received 2009 H1N1 vaccine during pregnancy.
The Medical Dictionary for Regulatory Activities (MedDRA) is an internationally standardized terminology used for coding clinical signs, symptoms, and diagnoses. An individual VAERS report may be coded with 1 or more MedDRA terms. We manually reviewed all VAERS reports for pregnant cases. Additionally, we identified reports by searching for MedDRA terms in 2 system organ classes: pregnancy, puerperium, and perinatal conditions and congenital, familial and genetic disorders, and a text string search for the term PREG in the report.
Medical records were requested for all reports that suggested the vaccinee was pregnant at the time of receipt of the 2009 H1N1 vaccine or that were from infants born to mothers who received the 2009 H1N1 vaccine during pregnancy. One medical officer (P.L.M.) conducted a clinical review of all VAERS reports retrieved using both search strategies described in the previous text to distinguish between pregnancy- and nonpregnancy-related reports. Medical officers with obstetrical expertise reviewed medical records of case reports presenting more specialized pregnancy information (D.K., F.B., N.R., N.T., Y.Z.).
Reports indicating that influenza vaccine was administered prior to the last menstrual period were excluded. Prespecified pregnancy outcomes under surveillance included spontaneous abortion (SAB) defined as a fetal death occurring less than 20 weeks’ gestation, stillbirth defined as a fetal death occurring at a gestation of 20 weeks or later, preterm delivery occurring less than 37 weeks, preeclampsia, and eclampsia.
We reviewed the medical records of all reports to verify the diagnosis and to obtain additional data, including state of residence, maternal date of birth, maternal age, gestational age at the time of vaccination and at the time of event, time between vaccination and onset of AE (onset interval), major symptoms, laboratory data, concomitant vaccinations, illness(es) at the time of vaccination, and preexisting medical conditions.
We also reviewed medical records of women who reported a spontaneous abortion or a stillbirth to identify risk factors (as reported in literature or identified by expert opinion) for these conditions. Gestational age at the time of vaccination and at the time of the AE was calculated based on the following: (1) clinical determination of the health care provider; (2) the earliest ultrasound assessment (if the former was not available); or (3) the last menstrual period, estimated delivery date, or estimated date of conception (if the first 2 options were not available). If applicable, the sex of the infant or fetus and the type of congenital anomaly were collected.
We defined trimesters by gestational age as the following: first (0-13 weeks), second (14-27 weeks), and third (≥28 weeks). Reports of anaphylaxis or Guillain-Barré syndrome were verified based on the attending physician’s assessment or criteria established by the Brighton Collaboration definition, an international collaboration for establishing standardized case definitions for AEs following vaccination. When more than 1 AE was reported for the same person, we selected what we believed to be the primary clinical event of concern determined after medical record review. We did not assess causality of AEs. 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.
Reporting rates
We estimated the number of pregnant women during the period of our surveillance by adapting previously published methods. To estimate the number of pregnant women vaccinated with inactivated 2009 H1N1 vaccine, we used influenza vaccination coverage data from Oct. 1, 2009, through Feb. 28, 2010, from the National 2009 H1N1 Flu Survey (NHFS) (unpublished data from the CDC).
To estimate the number of pregnant women during the period of this review, we used the most recent vital statistics data available on fertility, fetal loss, and induced abortions. The 2009 population of women of reproductive age (61,948,144) was determined from US Census estimates. We calculated reporting rates of AEs in pregnant women by dividing the number of AEs by the estimated number of inactivated 2009 H1N1 vaccine doses administered to pregnant women during the time period covered in this review. A supplementary technical appendix shows in detail the calculations used to determine the number of pregnant women vaccinated with inactivated 2009 H1N1 vaccine.
Analysis
We calculated frequencies of the most common MedDRA coding terms, demographic and medical history information, and selected pregnancy and fetal outcomes and reporting rates for selected outcomes using SAS version 9.2 (SAS Institute Inc, Cary, NC).
Results
From Oct. 1, 2009, through Feb. 28, 2010, VAERS received a total of 10,186 reports after H1N1 vaccination; 422 of these reports involved pregnant women. We excluded 128 pregnancy reports in which no AE was reported after the administration of inactivated or live 2009 H1N1 vaccine. These pregnant women are being followed up prospectively as part of a separate CDC study that seeks to assess delivery and infant outcomes.
Of the remaining 294 reports, 288 followed inactivated and 6 followed live vaccines. Medical records were obtained for 240 reports (81.6%). Sixty reports (20.4%) were coded as serious, including 2 maternal deaths. Serious reports corresponded to 59 pregnant women who were hospitalized for any reason and 1 to an infant born with a congenital anomaly. The 2009 H1N1 vaccine was reported as administered mostly during the first (133; 53.8%) and second trimester of pregnancy (67; 27.1%). In 31 reports (10.5%), the 2009 H1N1 vaccine was administered on the same date as the seasonal influenza vaccine ( Table 1 ).
