Trivalent Inactivated Influenza Vaccine and
Spontaneous Abortion
Stephanie A. Irving, MHS, Burney A. Kieke, MS, James G. Donahue, DVM, PhD,
Maria A. Mascola, MD, MPH, James Baggs, PhD, Frank DeStefano, MD, MPH, T. Craig Cheetham, PharmD,
Lisa A. Jackson, MD, MPH, Allison L. Naleway, PhD, Jason M. Glanz, PhD, James D. Nordin, MD, MPH,
and Edward A. Belongia, MD, for the Vaccine Safety Datalink
OBJECTIVE: To estimate the association between spon-
taneous abortion and influenza vaccine receipt with
a case-control study utilizing data from six health care
organizations in the Vaccine Safety Datalink.
METHODS: Women aged 18–44 years with spontaneous
abortion during the autumn of 2005 or 2006 were iden-
tified using International Classification of Diseases, 9th
From the Epidemiology Research Center, Marshfield Clinic Research Foundation,
and Obstetrics and Gynecology, Marshfield Clinic, Marshfield, Wisconsin; the
Immunization Safety Office, Centers for Disease Control and Prevention,
Atlanta, Georgia; Kaiser Permanente of Southern California, Downey,
California; the Group Health Research Institute, Seattle, Washington; Kaiser
Permanente Northwest, Portland, Oregon; Kaiser Permanente Colorado, Denver,
Colorado; and HealthPartners Research Foundation, Minneapolis, Minnesota.
Funded through a subcontract with America’s Health Insurance Plans (AHIP)
under contract 200-2002-00732, from the Centers for Disease Control and
Prevention (CDC).
The authors thank Eric Weintraub, MPH, Centers for Disease Control and
Prevention, for his scientific support and review of the manuscript; Allen Wilcox,
MD, PhD, for consultation on analytic methods; and the following individuals
for their invaluable assistance with data collection: Patti Benson, MPH, and
Anne Zavitkovsky, Group Health Research Institute; Leslie Kuckler, MPH,
HealthPartners Minneapolis; Kate Burniece and Jo Ann Shoup, Kaiser Perma-
nente Colorado; Nick Berger, Vidhu Choudhary, and Deanna Cole, Marshfield
Clinic Research Foundation; Eresha Bluth and Jill Mesa, Kaiser Permanente
Northwest; Zendi Solano and Lina Somsouk Sy, MPH, Kaiser Permanente of
Southern California.
The findings and conclusions in this report are those of the authors and do not
necessarily represent the official position of the funding agency.
Corresponding author: Edward Belongia, MD, Epidemiology Research Center,
Marshfield Clinic Research Foundation, 1000 North Oak Avenue, ML2,
Marshfield, WI 54449; e-mail: belongia.edward@marshfieldclinic.org.
Financial Disclosure
Stephanie A. Irving, Burney A. Kieke, James G. Donahue, and Edward A.
Belongia have received unrelated research support from Medimmune, LLC. T.
Craig Cheetham has received unrelated research support from Merck. Lisa A.
Jackson has received unrelated research support from Sanofi Pasteur, Novartis,
Glaxo Smith Kline, and Pfizer, as well as travel expenses from Pfizer. The other
authors did not report any potential conflicts of interest.
© 2012 by The American College of Obstetricians and Gynecologists. Published
by Lippincott Williams & Wilkins.
ISSN: 0029-7844/13
VOL. 121, NO. 1, JANUARY 2013
Revision, Clinical Modification codes. Cases of spontane-
ous abortion at 5–16 weeks of gestation were confirmed
by medical record review; date of fetal demise was based
on ultrasound information when available. Control group
individuals with a live birth were individually matched to
case group individuals by health care organization and
date of last menstrual period (LMP). The primary expo-
sure of interest was influenza vaccination during the
28 days preceding the date of spontaneous abortion of
the matched pair. Conditional logistic regression models
adjusted for maternal age, health care utilization, mater-
nal diabetes, and parity.
RESULTS: Our final analysis included 243 women with
spontaneous abortion and 243 matched control group
women; 82% of women with spontaneous abortion had
ultrasound confirmation of fetal demise. Using clinical
diagnosis and ultrasound data, the mean gestational age at
fetal demise was 7.8 weeks. Mean ages at LMP of case
group women and control group women were 31.7 and
29.3 years, respectively (P,.001). Sixteen women with
spontaneous abortion (7%) and 15 (6%) matched control
group women received influenza vaccine within the 28-day
exposure window. There was no association between spon-
taneous abortion and influenza vaccination in the 28-day
exposure window (adjusted matched odds ratio 1.23, 95%
confidence interval 0.53–2.89; P5.63).
CONCLUSION: There was no statistically significant
increase in the risk of pregnancy loss in the 4 weeks
after seasonal inactivated influenza vaccination.
(Obstet Gynecol 2013;121:159–65)
DOI: http://10.1097/AOG.0b013e318279f56f
LEVEL OF EVIDENCE: II
P
regnant women have been considered a high-risk
group for influenza complications since the 1918
and 1957 pandemics.1,2 In 1997, the Centers for Disease
Control and Prevention Advisory Committee on Immu-
nization Practices expanded U.S. recommendations for
OBSTETRICS & GYNECOLOGY 159
pregnant women from only those with an underlying
high-risk medical condition to include healthy preg-
nant women in the second or third trimester of preg-
nancy.3,4 In 2004, the recommendation was further
expanded to include pregnant women in any trimes-
ter.5 Current European guidelines also recommend
the seasonal vaccination of all pregnant women,
regardless of trimester.6,7
Evidence supporting the safety of influenza vacci-
nation in early pregnancy is sparse. Assessment of
spontaneous abortion is difficult because the outcome
is common and not always documented in medical
records. Only three studies have assessed the effects of
first trimester seasonal influenza vaccination on preg-
nancy outcomes, and these studies followed-up a com-
bined total of 65 women who received first trimester
vaccination.8–10 A fourth study included 650 women
who were immunized with seasonal influenza vaccine
in the first trimester, but losses occurring before 20
weeks of gestation were excluded from the analysis.11,12
Several studies have assessed pregnancy outcomes after
seasonal influenza vaccination in the second or third
trimester, and no increased risk of adverse events has
been detected.11,13–16 The safety of several pandemic
influenza A (H1N1) vaccines administered during
pregnancy recently has been evaluated, but these stud-
ies also were limited in their ability to examine first
trimester administration or spontaneous abortion.17,18
We conducted a case-control study to estimate the rela-
tionship between influenza immunization and con-
firmed spontaneous pregnancy loss occurring at or
before 16 weeks of gestational age.
MATERIALS AND METHODS
Participants in this case-control study were enrolled in
one of six Vaccine Safety Datalink health care
organizations: Group Health Cooperative, Seattle,
Washington; HealthPartners, Minneapolis, Minneso-
ta; Kaiser Permanente Colorado, Denver, Colorado;
Marshfield Clinic, Marshfield, Wisconsin; Kaiser
Permanente Northwest, Portland, Oregon; and South-
ern California Kaiser Permanente, Pasadena, Califor-
nia.19 The study was approved by the Institutional
Review Boards of each organization.
July August September October November December
Documented last menstrual periods of cases and controls
Dates of spontaneous abortion identified by ICD-9 code
Documented dates of spontaneous abortion
Documented dates of influenza vaccination
160 Irving et al Influenza Vaccine and Spontaneous Abortion
Ambulatory, urgent care, emergency department,
and inpatient records were searched for relevant
International Classification of Diseases, 9th Revision,
Clinical Modification diagnosis codes (634 [spontane-
ous abortion], 637 [unspecified abortion]) to identify
potential cases of spontaneous abortion. Codes
assigned from October 25, 2005 to February 4,
2006, and from October 22, 2006 to February 3,
2007, were included to maximize the potential for
influenza vaccine exposure in early pregnancy. These
dates maximized inclusion of women who conceived
in the autumn, when influenza vaccine is commonly
administered in the United States (Fig. 1).
All potential cases of spontaneous abortion iden-
tified through electronic diagnosis codes were manu-
ally reviewed by trained abstractors. Confirmation of
spontaneous abortion required medical record docu-
mentation of intrauterine pregnancy and evidence of
natural or spontaneous fetal demise; cases of thera-
peutic abortion were excluded. Women were eligible
for the study if they were aged 18–44 years at the time
of pregnancy loss, had documentation of last men-
strual period (LMP) in the medical record, and had
continuous enrollment in the health care organization
for the 12 months preceding the spontaneous abortion
diagnosis. The latter was applied to ensure that pre-
vious influenza vaccinations and chronic medical con-
ditions would be captured in the medical record. The
requirement for LMP documentation was included to
allow individual matching of case group and control
group participants by LMP (and thus approximate date
of conception). Pregnancy losses through 16 weeks of
gestation were included to capture potential events
occurring after exposure to influenza vaccine during
the first trimester.
Control patients were eligible for inclusion in the
study if they were aged 18–44 years at the time of
delivery, had continuous enrollment in the health care
organization for the 12 months preceding delivery,
and had documentation of LMP in the medical
record. Potential control group participants were ran-
domly identified using International Classification of
Diseases, 9th Revision, Clinical Modification codes
specifying delivery assigned to encounters occurring
January February
Fig. 1. Timeline illustrating date ranges
for last menstrual periods, influenza
vaccination, and spontaneous abortion.
Irving. Influenza Vaccine and Spontaneous
Abortion. Obstet Gynecol 2013.
OBSTETRICS & GYNECOLOGY
from May 7, 2006 to September 2, 2006, and from
May 6, 2007 to September 1, 2007. These periods
allowed for conception within a similar timeframe as
case group individuals and facilitated matching on
LMP. Medical records were then abstracted for all
potential control group participants, and only those
with confirmation of intrauterine pregnancy and
delivery beyond 20 weeks of gestation were eligible
for inclusion in the analysis.
Control group participants were initially fre-
quency-matched to case group participants based on
LMP strata (2-week intervals) and health care organi-
zation. Within each LMP interval, the case group and
control group participants were individually matched
based on closest LMP. Matching on LMP and
organization was performed to ensure that case group
and control group participants had similar opportu-
nity for influenza vaccine exposure in early
pregnancy.
The exposures of interest were the 2005–2006
and 2006–2007 seasonal trivalent inactivated influ-
enza vaccines, with receipt documented in the medical
record. The primary exposure window for case group
and control group participants within each matched
pair was the 28-day period preceding the date of spon-
taneous abortion within the matched pair. The 28-day
window was chosen based on the known immuno-
logic effects of influenza vaccine that occur within
2–4 weeks after vaccination.20
Case group participants were defined by the
natural or spontaneous loss of an embryo or fetus.
Date of spontaneous abortion was determined using
ultrasound data when available. For those case group
participants in whom ultrasound dating was unavail-
able, date of loss was based on clinical diagnosis.
Ultrasound dating provides a more precise determi-
nation of date of pregnancy loss than clinical diagno-
sis, which is dependent on presentation of symptoms
of loss, changes in blood test results over time, and
health-seeking behavior of the mother. All cases of
spontaneous abortion with an ultrasound scan dis-
playing a gestational sac were adjudicated by an
obstetrician (M.A.M.) who was blinded to the patient’s
vaccination status to determine exact gestational age.
For this group, date of spontaneous abortion was cal-
culated as date of LMP plus gestational age (in days) at
demise. Date of spontaneous abortion within each
matched case-control pair was used as the reference
date for analysis. Cases of spontaneous abortion
occurring before 5 weeks of gestation were excluded
from the final analyses because of increased difficulty
in ascertaining accurate date of fetal demise and ges-
tational age.
VOL. 121, NO. 1, JANUARY 2013 Irving et al
We performed conditional logistic regression to
estimate the association between spontaneous abor-
tion and receipt of influenza vaccine in the 28-day
exposure window, adjusting for the following poten-
tial confounders: maternal age; parity; maternal
diabetes; and previous health care utilization. Age
was included in the model as an unrestricted quadratic
spline.21 Dichotomous variables were created for par-
ity (none compared with one or more live births) and
maternal diabetes (history of type 1 or 2 diabetes com-
pared with no history). Health care utilization was
defined as the number of days with an outpatient or
inpatient encounter in the year before the LMP, and
was included in the model as an unrestricted quadratic
spline. Smoking status during pregnancy was exam-
ined in a preliminary model and determined not to be
a confounder with vaccine exposure in our study pop-
ulation. Additionally, because smoking status was
unavailable for at least one member of 31 (13%)
matched pairs, we excluded smoking status from the
final model to maximize sample size and power.
Febrile illness in the first trimester, asthma, and hyper-
tension also were evaluated as potential confounders
but were not included in final adjusted models after
also being ruled out as confounders.
Our primary analysis included a three-level cate-
gorical variable for influenza vaccine exposure relative
to the reference date of the matched pair (ie, the date
of spontaneous abortion within the matched pair): 1)
exposure 1–28 days before the reference date, 2) same-
season exposure more than 28 days before the refer-
ence date, and 3) unexposed as of the reference date.
The unexposed category served as the referent group
for both categories 1 and 2.
A secondary analysis was performed examining
the association between spontaneous abortion and
influenza vaccine receipt relative to pregnancy status
(preconception and postconception). This analysis
also included a three-level categorical variable for
influenza vaccine exposure: 1) exposure after concep-
tion and before reference date, 2) same-season expo-
sure before conception, and 3) unexposed as of the
reference date. The unexposed category served as the
referent group for both categories 1 and 2. For this
analysis, date of conception was estimated as LMP
plus 14 days, and vaccine receipt before conception
included influenza vaccine administered on or before
the estimated date of conception. Conditional logistic
regression models for this analysis adjusted for
maternal age, parity, maternal diabetes, and health
care utilization.
When planning the study, we estimated that
inclusion of 233 case group and 233 control group
Influenza Vaccine and Spontaneous Abortion 161
individuals in the analysis would provide 80% power Table 1. Demographic and Medical Characteristics
to detect an odds ratio (OR) of 2.0 or more, assuming of Case and Control Group Participants
12.8% vaccine exposure among control group partic- Case Group Control Group
ipants overall and a50.05. It was difficult to estimate Participants Participants
vaccination rates within the exposure window; there- (n5243) (n5243) P*
fore, seasonal estimates of influenza vaccine uptake
Age at LMP (y) 31.766.0 29.365.4 ,.001
among pregnant women were used. The proportion No. of physician 3 (1–5) 2 (1–6) .30
of control group participants receiving influenza vac- visits in the 12 mo
cine was estimated based on data from the Centers for before LMP
Disease Control and Prevention.22 Parity
Univariate P values represent findings from 0 84 (35) 88 (36) .86
1 or more 156 (64) 154 (64)
paired t tests and Wilcoxon rank-sum tests for contin- Unknown 3 (1) 1 (0)
uous variables or McNemar tests for dichotomous Previous
variables. All reported P values were based on two- spontaneous
sided tests for significance, and P,.05 was considered abortion
statistically significant; SAS 9.2 was used for analyses. Yes 80 (33) 66 (27) .15
No 153 (63) 176 (72)
A temporal scan statistic was used to objectively eval- Unknown 10 (4) 1 (0)
uate whether vaccinations were clustered within any Multiple gestations 4 (2) 2 (1) .38
segment of the 8-week preconception period among Febrile illness in first 5 (2) 4 (2) 1.00
women with spontaneous abortion.23,24 trimester
Smoked during
pregnancy
Yes 24 (10) 25 (10) 1.00
RESULTS No 195 (80) 212 (87)
Three hundred eighty-six potential cases of spontane- Unknown 24 (10) 6 (2)
ous abortion were identified electronically; 255 cases Diabetes 10 (4) 1 (0) .01
were confirmed by medical record review and Asthma 24 (10) 26 (11) .88
Hypertension 10 (4) 9 (4) .81
matched to control group participants. After exclud-
ing six pairs with unknown vaccination status, one LMP, last menstrual period.
Data are mean6standard deviation, median (interquartile range),
pair with an invalid LMP, and five pairs with fetal or n (%) unless otherwise specified.
demise at less than 5 weeks of gestation, 243 pairs * P calculated using paired t test, Wilcoxon signed rank test, and
were included in the final analysis. The number of McNemar test.
cases identified at each health care organization
ranged from 21 to 62. Two hundred (82%) case group Sixteen percent of case group participants and
participants had one or more ultrasound examina- 13% of control group participants received the same-
tions; 153 of 200 ultrasound reports provided addi- season influenza vaccine before the pair-specific
tional information to confirm the date of fetal demise. reference date (Table 2); all vaccinations in our
Case group and control group participants were
similar in terms of health care utilization, previous
spontaneous abortion, history of asthma, hypertension, 90
and parity (Table 1). Women with spontaneous abor- 80
tion were older than control group participants (mean 70
age at LMP 31.7 years compared with 29.3 years; 60
Cases (n)

P,.001) and more likely to have insulin-dependent 50

diabetes mellitus or noninsulin-dependent diabetes 40
mellitus diagnosed (10 case group participants com- 30
pared with one control group participant; P5.01). 20
The mean pair-wise difference in LMP between case 10
group participants and matched control group partici- 0
pants was 20.41 days (median 0 days, range 212 to 5 6 7 8 9 10 11 12 13 14 15 16
14 days). The mean gestational age at fetal demise was Gestational age (weeks)
7.8 weeks (range 5.0–16.6 weeks, median 7.1 weeks) Fig. 2. Histogram of gestational age at spontaneous abortion.
based on ultrasound dating (if available) or date of Irving. Influenza Vaccine and Spontaneous Abortion. Obstet Gyne-
clinical diagnosis (Fig. 2). col 2013.

162 Irving et al Influenza Vaccine and Spontaneous Abortion OBSTETRICS & GYNECOLOGY
Table 2. Seasonal Influenza Vaccination Status of
Case and Control Group Participants
Case Group Control Group
Participants Participants
(n5243) (n5243) P*
Vaccinated before 38 (16) 31 (13) .42
reference date†
Vaccinated 16 (7) 15 (6) 1.00
1–28 d before
reference date
Vaccinated before 22 (9) 11 (5) .04
conception‡
Data are n (% of case and control group participants) unless
otherwise specified.
* P calculated using McNemar test.
†
Reference date is the date of pregnancy loss within the case–
control matched pair; all same-season vaccinations before this
date were included.
‡
Conception defined as last menstrual period plus 14 days; all
same-season vaccinations before this date were included.
analysis occurred before conception or in the first tri-
mester. In unadjusted matched analyses, case group
participants and matched control group participants
did not differ in exposure during the 28-day exposure
window (unadjusted matched OR 1.10, 95% confi-
dence interval [CI] 0.53–2.29) or in overall exposure
to same-season influenza vaccine (vaccination at any
time before pair-specific reference date) (unadjusted
matched OR 1.29, 95% CI 0.76–2.20).
In the adjusted conditional logistic regression
model, the matched OR for vaccine receipt in the
primary 28-day exposure window was 1.23 (95% CI
0.53–2.89; P5.63). The OR for exposure more than
28 days before the reference date also was not statis-
tically significantly increased (Table 3). This analysis
was repeated using the subset of pairs in which the
date of fetal demise was confirmed by ultrasonogra-
phy (153 of 243 pairs; 63%). The adjusted matched
OR for vaccination in the 28-day exposure window
for this subset was 1.29 (95% CI 0.41–4.02).
Secondary post hoc analyses were performed to
examine the association between spontaneous abor-
tion and the timing of influenza vaccination relative to
estimated date of conception. Twenty-two case group
participants and 11 control group participants
received the influenza vaccine before conception.
There were 24 discordant pairs for this analysis,
including 17 pairs in which the case group participant
was vaccinated before conception and the matched
control group participant was not (unadjusted
matched OR 2.55, 95% CI 1.06–6.11) (Table 3).
In a logistic regression model that adjusted for
age, health care utilization, maternal diabetes, and
parity, the association between vaccine receipt before
conception and spontaneous abortion was not signifi-
cant (matched OR 2.34, 95% CI 0.86–6.33; P5.10).
Among all case group participants, vaccination dates
tended to cluster in the week before conception; seven
women with spontaneous abortion received the influ-
enza vaccine in this period compared with two control
group participants (Fig. 3).
We used a scan statistic to formally evaluate the
distribution of vaccination in the preconception
period. This analysis included 39 vaccinated women
with spontaneous abortion (exposed case group par-
ticipants). The null hypothesis was that the interval
from vaccine receipt to date of conception was
randomly distributed, ie, not clustered anywhere
within the range of observed intervals. The observed
range was vaccination 56 days before conception to
55 days after conception. The scan statistic identified
the cluster least likely due to chance as a 3-day
window from 2 to 4 days before conception when 6
of the 39 (15.4%) vaccinations occurred (P5.12).
DISCUSSION
The analysis reported here adds evidence to support
the safety of influenza vaccination when administered
during the first trimester. We found no statistically

Table 3. Odds of Influenza Vaccination in Cases of Early Pregnancy Loss in Varying Exposure Windows as
Compared With Control Group Participants
No. of Crude Adjusted 95% Confidence
Discordant Pairs Odds Ratio Odds Ratio* Interval P

Primary analysis
Exposed 1–28 d before reference date 27 1.10 1.23 0.53–2.89 .63
Exposed more than 28 d before reference date 28 1.51 1.24 0.54–2.86 .61
Secondary analysis
Exposed while pregnant† 31 0.80 0.80 0.36–1.78 .58
Exposed before pregnant‡ 24 2.55 2.34 0.86–6.33 .10
* Adjusted for maternal age (spline), maternal diabetes, parity, and health care utilization (spline).
†
Exposed after date of conception, defined as last menstrual period plus 14 days.
‡
Exposed to same-season influenza vaccine before conception, including date of conception (last menstrual period plus 14 days).

VOL. 121, NO. 1, JANUARY 2013 Irving et al Influenza Vaccine and Spontaneous Abortion 163
 8 conception (LMP plus 14 days). Although the point
7 Cases estimate was increased, there was no statistically
Controls significant association between spontaneous abortion
Women vaccinated (n)

6
Last menstrual period
5 all 243 pairs were included in the analysis. Temporal
4 clustering was greatest in the window 2–4 days before
3
2
1 because humoral and cell-mediated immune response
0 occurs 7–14 days after vaccination; however, the
8 7 6 5 4 3 2 1
Weeks before conception (n) Conception
Fig. 3. Receipt of influenza vaccine in case and control
patients before conception. Date of conception was esti-
mated as date of last menstrual period plus 14 days.
Irving. Influenza Vaccine and Spontaneous Abortion. Obstet Gyne-
col 2013.
significant association between pregnancy loss occur-
ring between 5 and 16 weeks of gestation and
influenza vaccination in a 28-day exposure window,
predefined based on the period of maximum immune
response to the vaccine.
The risk of spontaneous abortion after receiving
a seasonal influenza vaccine has not been thoroughly
examined in existing literature. Previous studies did not
detect an increased risk of spontaneous abortion, but
were limited in size or timing of vaccine administration,
or excluded spontaneous abortion as an outcome
measure.8–12 Pasternak et al25 recently evaluated fetal
loss after receipt of pandemic influenza vaccine in a large
register-based cohort study. Although this study exam-
ined a novel, adjuvanted vaccine, it also found no asso-
ciation between vaccination and spontaneous abortion.
The availability and use of seasonal influenza
vaccine vary greatly by season and month, and time is
a potential source of confounding in any observa-
tional study of influenza vaccine safety in pregnancy.
In this analysis, pregnant women were tightly
matched based on date of LMP as reported in the
medical record. The median pair-wise difference in
date of LMP was less than 0.5 days. This limited the
potential for differential access to influenza vaccina-
tion based on calendar time. Other strengths of the
study include the use of geographically diverse
populations via six health care organizations across
the United States, medical confirmation of pregnancy
for all study participants, medical confirmation of
spontaneous abortion, and examination and inclusion
of potential confounders in the analysis.
We performed a post hoc analysis using an
exposure window defined by estimated date of
and influenza vaccine receipt before conception when
estimated date of conception, but this also was not
statistically significant. An increased risk after precon-
ception vaccination could be biologically plausible,
actual mechanism by which the immune response
would result in fetal demise is unknown.26–28 This
study was not designed to examine vaccine exposure
before conception, and further research could address
this question in greater detail.
There are several limitations of this study that
should be considered. It is important to note that this
study was powered to exclude only a minimum of
twofold increase in risk. A smaller increase may not
have been identified. We examined only the associa-
tion between influenza vaccination and spontaneous
abortion; therefore, no conclusions can be drawn
regarding other adverse pregnancy outcomes. Because
we examined exposure within an exposure window,
precisely defining the window was critically important.
This required accurate determination of the date of
spontaneous abortion, which was used to define the
28-day exposure window. Although spontaneous abor-
tion was confirmed by medical record review, deter-
mining the exact date of loss can be difficult, because
clinical presentation and diagnosis do not always align
with timing of fetal demise. Ultrasound reports allowed
calculation of gestational age at demise to the day, but
these were unavailable for 18% of case group partic-
ipants and did not provide useful information for
another 19% (eg, report of empty uterus on date of
clinical diagnosis). However, as noted, results from the
primary analysis were similar when restricted to
women with ultrasound confirmation.
Misclassification of vaccine exposure is possible if
women received influenza vaccines outside the health
plans. We could not assess this, but it is likely that
most insured pregnant women receive influenza
vaccines from health care providers rather than retail
outlets or public health clinics. Any vaccines admin-
istered outside the health plan would be captured in
this study if they were reported to the provider and
captured in the medical record. Given the universal
recommendation for vaccination, providers either
should have administered the vaccine or should have
asked about previous same-season receipt, which then
would have been documented in the medical record.

164 Irving et al Influenza Vaccine and Spontaneous Abortion OBSTETRICS & GYNECOLOGY
 Other limitations include the inability to assess
differences by vaccine manufacturer, race or ethnicity,
and the insufficient power to assess risk in women
with chronic medical conditions. As is the case with all
observational studies, unmeasured confounding may
have occurred; we were unable to examine body mass
index and potential exposures such as prescription or
recreational drug use or alcohol intake, for example.
Finally, this study examined spontaneous abortion
identified in the medical setting. Our results may not
be representative of loss never brought to medical
attention, if those pregnancies differ systematically.
We found no statistically significant increase in
the risk of pregnancy loss in the 4 weeks after seasonal
inactivated influenza vaccination. However, our sam-
ple size was not large enough to rule out any increase
in risk. Although the results of this study support the
current Advisory Committee on Immunization Prac-
tices recommendations for influenza vaccination dur-
ing all trimesters of pregnancy, further research on the
safety of influenza vaccine in pregnant women and
other high-risk groups should remain a priority,
including further assessment of pregnancy outcomes.
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