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

Research

www. AJOG.org

OBSTETRICS

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 Pedro L. Moro, MD, MPH; Karen Broder, MD; Yenlik Zheteyeva, MD, MPH; Kimp Walton, MS; Patricia Rohan, MD; Andrea Sutherland, MD, MPH, MSc; Alice Guh, MD, MPH; Penina Haber, MPH; Frank DeStefano, MD, MPH; Claudia Vellozzi, MD, MPH OBJECTIVE: 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. STUDY DESIGN: 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. RESULTS: A total of 148 reports after TIV and 27 reports after LAIV

were identified. Twenty TIV (13.5%) and 1 LAIV (4%) reports were clas-

sified 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. CONCLUSION: 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. Key words: pregnancy, seasonal influenza vaccine, surveillance, vaccine safety

Cite this article as: Moro PL, Broder K, Zheteyeva Y, 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.

P

regnant women have a higher risk for serious complications from influenza than nonpregnant women of reproductive age.1-5 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 rec-

ommendation was expanded to cover all trimesters.6 Despite these recommendations, it is estimated that only 12-24% of pregnant women received the influenza vaccine during the 2005-2008 influenza season.7 Patient and health care providers’ concern about the safety of the influenza vaccine during pregnancy may partly explain this low coverage.8,9 Although available data support the safety of seasonal influenza vaccine in pregnant women,7 few studies have assessed the safety of TIV in large populations of

From the Immunization Safety Office, Division of Healthcare Quality Promotion/National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA (Drs Moro, Broder, Zheteyeva, Guh, DeStefano, and Vellozzi, Mr Walton, and Ms Haber), and the Office of Biostatistics and Epidemiology, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD (Drs Rohan and Sutherland). Received June 8, 2010; revised Aug. 13, 2010; accepted Aug. 30, 2010. Reprints: Pedro L. Moro, MD, MPH, Immunization Safety Office, Division Of Healthcare Quality Promotion, Centers for Disease Control and Prevention, 1600 Clifton Rd., MS D26, Atlanta, GA 30333. 0002-9378/$36.00 • Published by Mosby, Inc. • doi: 10.1016/j.ajog.2010.08.050

146.e1

American Journal of Obstetrics & Gynecology FEBRUARY 2011

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 10 and children.11 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.

M ATERIALS AND M ETHODS 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.12 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

Obstetrics

www.AJOG.org

FIGURE

Vaccine Adverse Event Reporting System reports

VAERS reports following influenza vaccine administration in pregnant women, 1990-2009. Moro. Safety of seasonal influenza vaccine in pregnant women. Am J Obstet Gynecol 2011.

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.13 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.13

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).7 Non-US reports were excluded. We used Medical Dictionary for Regulatory Activities (MedDRA),14 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 nonpregnancy-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.

Research

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 GuillainBarré syndrome, we reviewed medical records if available and used the attending physician’s assessment or the Brighton Collaboration definition for these conditions.15 When more than 1 AE was reported for the same person, we selected what we believed to be the primary clinical event of concern.

Analysis 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

FEBRUARY 2011 American Journal of Obstetrics & Gynecology

146.e2

Research

Obstetrics

estimates of the pregnant population in the United States3,16 and influenza vaccination coverage rates for pregnant women for each influenza season.7,17 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.

www.AJOG.org

TABLE 1

Characteristics of the VAERS reports following receipt of TIV in pregnant women, July 1, 1990, through June 30, 2009, United States Characteristic Reports, n

148

..............................................................................................................................................................................................................................................

Serious reports, n (%)

20 (13.5)

Hospitalization

17 (11.5)

.....................................................................................................................................................................................................................................

..............................................................................................................................................................................................................................................

Reports with no AEs, n (%)

30 (20.3)

Mean (median) age, y

28.2 (29.0)

Mean (median) onset interval, d

35.4 (8.0)

Mean (median) gestational age at time of AE, wks

18.5 (18.0)

.............................................................................................................................................................................................................................................. a

R ESULTS 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. The 148 reports to VAERS resulted in a total of 230 MedDRA terms, indicating that multiple symptoms, signs, or conditions were recorded in some reports. The 5 most common MedDRA terms other than drug exposure during pregnancy were unintended pregnancy, incorrect dose administered, spontaneous abortion, fetal disorder, and injection site erythema. Selected reported outcomes in pregnant women who received TIV are presented in Table 2. The most frequent pregnancy-specific AE reported following TIV administration was spontaneous abortion in 17 (11.5%) followed by stillbirth in 6 (4.0%), oligohydramnios in 3 (2.0%), and polyhydramnios in 2 (1.4%) reports. The mean gestational age at the time of symptom presentation for spontaneous 146.e3

.............................................................................................................................................................................................................................................. b .............................................................................................................................................................................................................................................. c ..............................................................................................................................................................................................................................................

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 (ⱖ28 wks)

22 (24.2)

..................................................................................................................................................................................................................................... ..............................................................................................................................................................................................................................................

TIV given alone (%)

119 (80.4)

MedDRA terms coded for all reports, n

230

.............................................................................................................................................................................................................................................. d ..............................................................................................................................................................................................................................................

Mean number of codes per report

3.4

..............................................................................................................................................................................................................................................

AE, adverse event; MedDRA, Medical Dictionary for Regulatory Activities; TIV, trivalent inactivated influenza vaccine; VAERS, Vaccine Adverse Event Reporting System. a

Maternal age unknown for 20 reports; age of neonates in 2 reports not included; b Onset interval unknown for 30 reports. In 20 reports onset was less than 1 day; onset interval is the difference between date of onset and vaccination date; c Duration of pregnancy unknown for 57 reports; d The MedDRA was used to code symptoms and/or conditions described in each report.

Moro. Safety of seasonal influenza vaccine in pregnant women. Am J Obstet Gynecol 2011.

abortions was 10.0 weeks (range, 5–18 weeks). A total of 7 congenital malformations (4.7%) were reported as the main diagnosis. Two of these were malformations detected by ultrasound examination of the fetus during the second or third trimester, and 3 were detected in newborn infants whose mothers received TIV during pregnancy. Local injection site reactions were described in 31 reports (20.9%). Systemic or generalized reactions (eg, fever, malaise, fatigue) were described in 12 reports (8.1%). Three reports described pregnant women with the Guillain-Barré syndrome; medical records allowed verification of this clinical diagnosis in 2 cases. These 2 cases met the provisional Brighton Collaboration levels 1 and 3 criteria for Guillain-Barré syndrome18; insufficient information was available to verify the Guillain-Barré syndrome diagnosis in the third case. Anaphylactic reaction following influenza vaccine administration was reported in 1 case: a 24 year old pregnant woman who experienced urticaria, pru-

American Journal of Obstetrics & Gynecology FEBRUARY 2011

ritus, and dyspnea within seconds following administration of TIV. She was managed with epinephrine, diphenhydramine, and steroids. She was admitted overnight at a hospital for fetal monitoring and was discharged home following recovery. The case met the Brighton collaboration anaphylaxis level 1 criteria.19 We also identified 3 reports of Bell’s palsy, but sufficient information was not available to confirm this diagnosis.

Reported AEs following LAIV administration in pregnant women From July 1, 2003, through June 30, 2009, VAERS received 27 reports of pregnant women who received LAIV. One of these reports (4%) was classified as serious. No AEs were reported in 16 reports (59%). Reports occurred after the vaccine was licensed in 2003, with most reports received in 2007 and 2008 (Figure). Characteristics of the reported cases are shown in Table 3. Among reported cases, LAIV had been administered mostly during the first trimester of pregnancy (63%). In 21 reports (77.8%),

Obstetrics

www.AJOG.org

TABLE 2

Adverse events in pregnant women following trivalent inactivated influenza vaccine, VAERS, July 1, 1990, through June 30, 2009a Event

n ⴝ 148b

%c

Pregnancy-specific AEs and outcomes (n ⫽ 35)

.....................................................................................................................................................................................................................................

Abortion spontaneous (less than 20 wks’ gestation)

17

11.5

Stillbirth (ⱖ20 wks’ gestation)

6

4.0

Oligohydramnios

3

2.0

Polyhydramnios

2

1.4

..................................................................................................................................................................................................................................... ..................................................................................................................................................................................................................................... ..................................................................................................................................................................................................................................... d .....................................................................................................................................................................................................................................

Gestational diabetes

1

0.7

Menorrhagia

1

0.7

Placenta previa

1

0.7

Pregnancy-induced hypertension

1

0.7

Intrauterine fetal death

1

0.7

..................................................................................................................................................................................................................................... ..................................................................................................................................................................................................................................... ..................................................................................................................................................................................................................................... ..................................................................................................................................................................................................................................... ..............................................................................................................................................................................................................................................

Birth defects/fetal adverse events (n ⫽ 8)

.....................................................................................................................................................................................................................................

Upper-limb reduction

1

0.7

Multiple malformations

1

0.7

Agenesis of the corpus callosum

1

0.7

Cystic adenomatoid malformation

1

0.7

Fetal arrhythmia

1

0.7

Patent foramen ovale and peripheral pulmonic stenosis

1

0.7

Spina bifida

1

0.7

Pyloric stenosis, pneumonia

1

0.7

..................................................................................................................................................................................................................................... e ..................................................................................................................................................................................................................................... ..................................................................................................................................................................................................................................... ..................................................................................................................................................................................................................................... ..................................................................................................................................................................................................................................... ..................................................................................................................................................................................................................................... ..................................................................................................................................................................................................................................... ..............................................................................................................................................................................................................................................

Adverse neonatal outcomes (n ⫽ 4)

.....................................................................................................................................................................................................................................

Meningitis

1

0.7

.....................................................................................................................................................................................................................................

Developmental disability

1

0.7

Jaundice

1

0.7

Autism

1

0.7

..................................................................................................................................................................................................................................... ..................................................................................................................................................................................................................................... ..............................................................................................................................................................................................................................................

Non–pregnancy-related maternal outcomes (n ⫽ 73)

.....................................................................................................................................................................................................................................

Local reactions

31

20.9

Systemic or generalized reactions

12

8.1

Allergic reactions (other than anaphylaxis)

10

6.8

Guillain-Barré syndrome

3

2.0

Bell’s palsy

3

2.0

..................................................................................................................................................................................................................................... ..................................................................................................................................................................................................................................... ..................................................................................................................................................................................................................................... ..................................................................................................................................................................................................................................... .....................................................................................................................................................................................................................................

Anaphylaxis

1

0.7

13

8.8

30

20.3

..................................................................................................................................................................................................................................... f

Other

..............................................................................................................................................................................................................................................

No AEs

..............................................................................................................................................................................................................................................

AE, adverse event; VAERS, Vaccine Adverse Event Reporting System. a

Based on main diagnosis; b A total of 146 reports was reviewed, but 1 report described 3 stillbirths in 3 pregnant women; Percentages shown correspond to those of the AEs and not the incidents of these AEs in vaccinated pregnant women; d Congenital anomaly in fetus: bilateral hydronephrosis in both; e Multicystic renal dysplasia, atrial and ventricular septal defect, single umbilical artery; f Other AEs include 2 each of abnormal laboratory tests and visual alterations and 1 each of abdominal pain, arrhythmia, anxiety, autoimmune hemolytic anemia, asthma exacerbation, influenza-like illness, viral meningitis, kidney failure, and multiple sclerosis. c

Moro. Safety of seasonal influenza vaccine in pregnant women. Am J Obstet Gynecol 2011.

Research

LAIV was the only vaccine administered on the day of vaccination. A total of 44 MedDRA terms were used to code these 27 reports. The 5 most common MedDRA terms other than drug exposure during pregnancy were pyrexia (fever), unintended pregnancy, medication error, pharyngolaryngeal pain, and vomiting. Some selected outcomes in pregnant women who received LAIV are presented in Table 4. The only serious report involved a 26 year old female who received LAIV when she was 12 weeks pregnant. Approximately 4 weeks later she presented with oligohydramnios secondary to rupture of membranes for which she was hospitalized. The woman experienced a miscarriage at 16 weeks. She was discharged from the hospital in good condition.

Reporting rates of spontaneous abortion During the time period 1996 through 2009, the average influenza vaccination coverage rate for pregnant women was 13.3%. Applying this vaccination coverage to the population of 89.05 million pregnant women16 for those same years gives an estimated 11.8 million pregnant women immunized with the influenza vaccine. The overall VAERS adverse event reporting rate in pregnant women was 12.5 per 1 million pregnant women vaccinated. The reporting rate of spontaneous abortion varied across the influenza seasons with the highest peak during the 2008-2009 season, with 5.5 reported cases per 1 million vaccinations in pregnant women. The overall reporting rate of spontaneous abortion was 1.9 cases per 1 million vaccinations in pregnant women.

C OMMENT In our review of 19 years of VAERS reports of pregnant women after the administration of seasonal influenza vaccine, we did not find any new, unusual, or unexpected pattern of adverse pregnancy events or fetal outcomes. Spontaneous abortion was the most frequent outcome reported, but even during the season with the highest reporting rate of spontaneous abortions in pregnant

FEBRUARY 2011 American Journal of Obstetrics & Gynecology

146.e4

Research

Obstetrics

women following influenza vaccination (5.5 per 1 million vaccinations for the 2008-2009 season), this reporting rate was lower than published rates of miscarriage in the general pregnant population. Rates of spontaneous abortion vary according to age group, country, and surveillance period. In the United States during the period 1980-1990, a rate of 10.4% was observed for pregnant women younger than 25 years, whereas, for women older than 34 years, the rate of spontaneous abortion was 22.4%.20 Because our reporting rate for spontaneous abortions is significantly lower than the background rate for spontaneous abortion that would be expected in the population, we cannot make any inferences regarding the rate of this event following vaccination. However, this potentially indicates that there was no cause for concern regarding the numbers of spontaneous abortions following vaccination. Our low reporting rate for spontaneous abortion is likely due to underreporting of this event in VAERS. Many of the local and systemic reactions observed were consistent with the published literature regarding AEs following influenza vaccine administration in the general population.21,22 One serious AE, an anaphylactic reaction following influenza vaccine administration, is also consistent with similar reports in the literature, which describe allergic reactions following influenza vaccine.19 Bell’s palsy, a mononeuropathy of the VII (facial) cranial nerve, has been reported to occur 3 times more frequently in pregnant women than in nonpregnant women of child-bearing age.23 Therefore, we would also expect more cases of Bell’s palsy to be reported following receipt of vaccine in pregnant women as compared to nonpregnant women. However, in our study we found only 3 reports of pregnant women with this condition following influenza vaccination. Although a previous study in VAERS found a signal of possible association between influenza vaccine and Bell’s palsy,24 a review conducted by the Institute of Medicine found the evidence to be limited for a possible role of influenza vaccines in the etiology of neurological complications.25 A large population-based 146.e5

www.AJOG.org

TABLE 3

Characteristics of VAERS reports following administration of LAIV to pregnant women, July 1 2003, through June 30, 2009, United Statesa Characteristic

n

Reports, n

27

..............................................................................................................................................................................................................................................

Serious reports, n (%)

1 (4)

..............................................................................................................................................................................................................................................

Reports with no adverse events, n (%)

16 (59.3)

Mean (median) age, y

24.3 (24)

Mean (median) onset interval, d

22.0 (13)

Mean (median) gestational age at time of vaccination, wksd

14.3 (10.0)

Gestational age at time of vaccination (n ⫽ 16)

No (%)

.............................................................................................................................................................................................................................................. b .............................................................................................................................................................................................................................................. c ..............................................................................................................................................................................................................................................

.............................................................................................................................................................................................................................................. .....................................................................................................................................................................................................................................

First trimester (0-13 wks)

10 (62.5)

.....................................................................................................................................................................................................................................

Second trimester (14-27 wks)

3 (18.8)

Third trimester (ⱖ28 wks)

3 (18.8)

..................................................................................................................................................................................................................................... .............................................................................................................................................................................................................................................. e

LAIV given alone (%)

21 (77.8)

MedDRA coded events, n

44

.............................................................................................................................................................................................................................................. a ..............................................................................................................................................................................................................................................

Mean number of coded events per report

2.9

..............................................................................................................................................................................................................................................

LAIV, live attenuated influenza vaccine; MedDRA, Medical Dictionary for Regulatory Activities; VAERS, Vaccine Adverse Event Reporting System. a

The MedDRA was used to code symptoms and/or conditions described in each report; b Age unknown for 2 reports; c Onset interval unknown for 7 reports; onset interval is the difference between date of onset and vaccination date; d Duration of pregnancy unknown for 11 reports; e LAIV first licensed in June 17, 2003.

Moro. Safety of seasonal influenza vaccine in pregnant women. Am J Obstet Gynecol 2011.

study using the General Practice Research Database in the United Kingdom failed to show evidence for an increased risk of Bell’s palsy following parenteral inactivated influenza vaccine. 26 Live attenuated influenza vaccine is not recommended in pregnant women.

However, because the mechanism for stimulating a systemic immune response involves the replication of the attenuated virus in the nose, without systemic viral replication, the inadvertent use of LAIV in pregnant women would likely have a similar risk profile as use in healthy non-

TABLE 4

Adverse events in pregnant women following LAIV, VAERS, July 1, 2003, through June 30, 2009, United Statesa Outcome

n ⴝ 27

Adverse pregnancy outcomes (n ⫽ 4)

..................................................................................................................................................................................................................................... b

Abortion spontaneous

3

Abortion threatened

1

..................................................................................................................................................................................................................................... ..............................................................................................................................................................................................................................................

Systemic or generalized reactions (n ⫽ 7)

.....................................................................................................................................................................................................................................

Fever, vomiting, headache

3

Pharyngeal pain

2

Influenza

1

Malaise

1

..................................................................................................................................................................................................................................... ..................................................................................................................................................................................................................................... ..................................................................................................................................................................................................................................... ..............................................................................................................................................................................................................................................

No AEs

16

..............................................................................................................................................................................................................................................

AE, adverse event; LAIV, live attenuated influenza vaccine; VAERS, Vaccine Adverse Event Reporting System. a

Based on main diagnosis; b One serious case was hospitalized, experienced oligohydramnios secondary to rupture of membranes, which lead to intrauterine death at 16 weeks’ gestation.

Moro. Safety of seasonal influenza vaccine in pregnant women. Am J Obstet Gynecol 2011.

American Journal of Obstetrics & Gynecology FEBRUARY 2011

Obstetrics

www.AJOG.org pregnant persons.7 In approximately half of the reports we reviewed in which LAIV was administered to pregnant women, vaccinees were either not aware of their pregnancy status or did not inform the vaccine administrator of their pregnancy when they received the vaccine. In 1 report, the vaccine administrator was not aware that this vaccine was not indicated in pregnant women, which highlights the need to educate vaccine administrators about the proper indications for use of LAIV. Despite concerns regarding exposure to a live influenza virus, there were relatively few reported AEs and only 1 serious report. Nearly 60% of the reports did not mention any adverse events following LAIV. The safety of inactivated influenza vaccine has been studied in approximately 10,000 pregnant women, and all studies have found influenza vaccine to be safe when given during pregnancy.27 A large prospective study of 2291 pregnant women who received TIV did not find any fetal malformations, malignancies, or increased childhood mortality during 7 years of follow-up that could be associated with exposure to the vaccine in pregnancy.28 A retrospective study of 252 TIV vaccinated pregnant women matched to a control group of 826 healthy pregnant unvaccinated women found no serious adverse events within 42 days of vaccination. No differences in pregnancy outcomes and infant conditions up to 6 months after birth were found.29 An advantage of VAERS is that it is a national surveillance system that may be used to detect signals of potential adverse events following vaccination, which can be further explored in carefully designed epidemiological studies. Any finding in VAERS needs to be interpreted with caution, given the inherent limitations of passive surveillance systems such as over- or underreporting, biased reporting, and inconsistency in quality and completeness of reports. VAERS also generally cannot determine whether a vaccine caused an adverse event.12 In our study we noted that a substantial number of VAERS reports (50% of serious reports) did not have any medical follow-up; therefore, it was not pos-

sible to confirm the reported events. Because no denominator data are collected, it is not possible to directly calculate rates of adverse events. Furthermore, the sources of data used to estimate the number of pregnant women who received influenza vaccine contain their own inherent source of errors that need to be taken into consideration. Therefore, our estimated reporting rates of spontaneous abortion may be underestimating the true rates of miscarriage in pregnant women who received influenza vaccine. It is also important to recognize that in approximately 20% of pregnancy reports submitted to VAERS influenza vaccines were administered with other vaccines. Data from our 19 year review of VAERS add to an existing body of evidence for safety of TIV use in pregnant women.27 Although LAIV is not indicated during pregnancy, it is reassuring to know that the inadvertent administration of this vaccine to pregnant women did not result in reported unexpected reactions. Until additional safety data on the use of LAIV in pregnant women become available, providers and patients need be reminded that LAIV should not be administered to pregnant women.7 In October 2009 the federal government, in collaboration with state and other partners, implemented a vaccination program to reduce morbidity and mortality from pandemic 2009 (H1N1) influenza A. Vaccine safety monitoring is an important component of this program.30 The VAERS data were collected for pregnant women during this response and are under review. Health care providers are encouraged to promptly and accurately report any clinically significant AE that occurs following vaccination to the VAERS (http://vaers.hhs.gov/index). f ACKNOWLEDGMENT We would like to thank Dr Naomi Tepper and Dr Dmitry Kissin for their helpful support and advice during the development of this article.

REFERENCES 1. Naleway AL, Smith WJ, Mullooly JP. Delivering influenza vaccine to pregnant women. Epidemiol Rev 2006;28:47-53.

Research

2. Rasmussen SA, Jamieson DJ, Bresee JS. Pandemic influenza and pregnant women. Emerg Infect Diseases 2008;14:95-100. 3. Jamieson DJ, Honein MA, Rasmussen SA, et al. H1N1 2009 influenza virus infection during pregnancy in the USA. Lancet 2009;374:451-8. 4. Dodds L, McNeil SA, Fell DB, 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. 5. 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. 6. Skoronski DM, De Serres G. Is routine influenza immunization warranted in early pregnancy? Vaccine 2009;27:4754-70. 7. Fiore AE, Shay DK, Broder K, et al. Prevention and control of seasonal influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2009. MMWR Recomm Rep 2009;58:1-52. 8. Yudin MH, Salaripour M, Sgro MD. Pregnant women’s knowledge of influenza and the use and safety of the influenza vaccine during pregnancy. J Obstet Gynaecol Can 2009;31:120-5. 9. Broughton DE, Beigi RH, Switzer GE, Raker CA, Anderson BL. Obstetric health care workers’ attitudes and beliefs regarding influenza vaccination in pregnancy. Obstet Gynecol 2009;114:981-7. 10. Vellozzi C, Burwen DR, Dobardzic A, Ball R, Walton K, Haber P. Safety of trivalent inactivated influenza vaccines in adults: background for pandemic influenza vaccine safety monitoring. Vaccine 2009;27:2114-20. 11. Rosenberg M, Sparks R, McMahon A, Iskander J, Campbell JD, Edwards KM. Serious adverse events rarely reported after trivalent inactivated influenza vaccine (TIV) in children 6-23 months of age. Vaccine 2009;27:4278-83. 12. Varricchio F, Iskander J, Destefano F, Ball R, Pless R, Braun MM. Understanding vaccine safety information from the Vaccine Adverse Event Reporting System. Pediatr Infect Dis J 2004;23:287-94. 13. Food and Drug Administration. 21 CFR Part 600.80. Postmarketing reporting of adverse experiences. Federal Register; 1997;62:52252-3. 14. Medical Dictionary for Regulatory Activities. Available at: www.meddramsso.com/MSSO Web/index.htm. Accessed Aug. 24, 2009. 15. Kohl KS, Gidudu J, Bonhoeffer J, et al. The development of standardized case definitions and guidelines for adverse events following immunization. Vaccine 2007;25:5671-4. 16. Ventura SJ, Abma JC, Mosher WD. Estimated pregnancy rates by outcome for the United States, 1990 –2004. Natl Vital Stat Rep 2008;56:1-28. Available at: www.cdc.gov/ nchs/data/nvsr/nvsr56/nvsr56_15.pdf. Accessed Aug. 24, 2009. 17. Lu P, Bridges CB, Euler GL, Singleton JA. Influenza vaccination of recommended adult populations, United States, 1989-2005. Vaccine 2008;26:1786-93.

FEBRUARY 2011 American Journal of Obstetrics & Gynecology

146.e6

Research

Obstetrics

18. The Brighton Collaboration: definitions and guidelines. Available at: www.brighton collaboration.org/internet/en/index/definition_ guidelines.html. Accessed June 1, 2010. 19. Ruggeberg JU, Gold MS, Bayas JM, et al. Anaphylaxis: case definition and guidelines for data collection, analysis, and presentation of immunization safety data. Vaccine 2007;25:5675-84. 20. Black S, Eskola J, Siegrist CA, et al. Importance of background rates of disease in assessment of vaccine safety during mass immunization with pandemic H1N1 influenza vaccines. Lancet 2009;374:2115-22. 21. Yeager DP, Toy EC, Baker B 3rd. Influenza vaccination in pregnancy. Am J Perinatol 1999;16:283-6. 22. 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.

146.e7

www.AJOG.org 23. Shapiro JL, Yudin MH, Ray JG. Bell’s palsy and tinnitus during pregnancy: predictors of preeclampsia: three cases and a detailed review of the literature. Acta Otolaryngologica 1999;119:647-51. 24. Zhou W, Pool V, Destefano F, et al. A potential signal of Bell’s palsy after parenteral inactivated influenza vaccines: reports to the Vaccine Adverse Event Reporting System (VAERS)—United States, 1991-2001. Pharmacoepidemiol Drug Saf 2004;13:505-10. 25. Stratton K, Alamario D, Wizeman T, McCormick M, eds. Immunization safety review: influenza vaccines and neurological complications. National Academy Press, Washington, DC; 2004. 26. Stowe J, Andrews N, Wise L, Miller E. Bell’s palsy and parenteral inactivated influenza vaccine. Hum Vaccine 2006;2:110-2.

American Journal of Obstetrics & Gynecology FEBRUARY 2011

27. Tamma PD, Ault KA, Del Rio C, Steinhoff MC, Halsey NA, Omer SB. Safety of influenza vaccination during pregnancy. Am J Obstet Gynecol 2009;201:547-52. 28. Heinonen OP, Shapiro S, Monson RR, et al. Immunization during pregnancy against poliomyelitis and influenza in relation to childhood malignancy. Int J Epidemiol 1973;2:229-35. 29. Munoz FM, Greisinger AJ, Wehmanen OA, et al. Safety of influenza vaccination during pregnancy. Am J Obstet Gynecol 2005; 192:1098-106. 30. Centers for Disease Control and Prevention. Safety of influenza A (H1N1) 2009 monovalent vaccines—United States, October 1-November 24, 2009. MMWR Morb Mortal Wkly Rep 2009;58:1-6.