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The
n e w e ng l a n d j o u r na l
of
m e dic i n e
original article
Risk of Fetal Death after Pandemic
Influenza Virus Infection or Vaccination
Siri E. Håberg, M.D., Ph.D., Lill Trogstad, M.D., Ph.D.,
Nina Gunnes, Ph.D., Allen J. Wilcox, M.D., Ph.D., Håkon K. Gjessing, Ph.D.,
Sven Ove Samuelsen, Ph.D., Anders Skrondal, Ph.D., Inger Cappelen, Ph.D.,
Anders Engeland, Ph.D., Preben Aavitsland, M.D., Steinar Madsen, M.D.,
Ingebjørg Buajordet, Ph.D., Kari Furu, Ph.D., Per Nafstad, M.D., Ph.D.,
Stein Emil Vollset, M.D., Dr.P.H., Berit Feiring, M.Sc.Pharm.,
Hanne Nøkleby, M.D., Per Magnus, M.D., Ph.D.,
and Camilla Stoltenberg, M.D., Ph.D.
A bs t r ac t
Background
During the 2009 influenza A (H1N1) pandemic, pregnant women were at risk for
severe influenza illness. This concern was complicated by questions about vaccine
safety in pregnant women that were raised by anecdotal reports of fetal deaths after
vaccination.
Methods
We explored the safety of influenza vaccination of pregnant women by linking
Norwegian national registries and medical consultation data to determine influenza
diagnosis, vaccination status, birth outcomes, and background information for pregnant women before, during, and after the pandemic. We used Cox regression models
to estimate hazard ratios for fetal death, with the gestational day as the time metric
and vaccination and pandemic exposure as time-dependent exposure variables.
Results
There were 117,347 eligible pregnancies in Norway from 2009 through 2010. Fetal
mortality was 4.9 deaths per 1000 births. During the pandemic, 54% of pregnant
women in their second or third trimester were vaccinated. Vaccination during pregnancy substantially reduced the risk of an influenza diagnosis (adjusted hazard
ratio, 0.30; 95% confidence interval [CI], 0.25 to 0.34). Among pregnant women
with a clinical diagnosis of influenza, the risk of fetal death was increased (adjusted hazard ratio, 1.91; 95% CI, 1.07 to 3.41). The risk of fetal death was reduced
with vaccination during pregnancy, although this reduction was not significant
(adjusted hazard ratio, 0.88; 95% CI, 0.66 to 1.17).
From the Norwegian Institute of Public
Health (S.E.H., L.T., N.G., H.K.G., S.O.S.,
A.S., I.C., A.E., P.A., K.F., P.N., S.E.V., B.F.,
H.N., P.M., C.S.), the University of Oslo
(S.O.S., P.N., P.M.), and the Norwegian
Medicines Agency (S.M., I.B.), Oslo; the
University of Bergen, Bergen (H.K.G., A.E.,
S.E.V.); and the University of Tromsø,
Tromsø (K.F.) — all in Norway; the National Institute of Environmental Health
Sciences, Durham, NC (A.J.W.); and the
London School of Hygiene and Tropical
Medicine, London (A.S.). Address reprint
requests to Dr. Håberg at the Norwegian
Institute of Public Health, P.O. Box 4404,
Nydalen, N-0403 Oslo, Norway, or at
[email protected].
This article was published on January 16,
2013, at NEJM.org.
N Engl J Med 2013;368:333-40.
DOI: 10.1056/NEJMoa1207210
Copyright © 2013 Massachusetts Medical Society.
Conclusions
Pandemic influenza virus infection in pregnancy was associated with an increased
risk of fetal death. Vaccination during pregnancy reduced the risk of an influenza
diagnosis. Vaccination itself was not associated with increased fetal mortality and
may have reduced the risk of influenza-related fetal death during the pandemic.
(Funded by the Norwegian Institute of Public Health.)
n engl j med 368;4 nejm.org january 24, 2013
The New England Journal of Medicine
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333
The
D
uring the 2009 influenza A (H1N1)
pandemic, pregnant women were particularly vulnerable to severe influenza illness, with a heightened risk of adverse pregnancy
outcomes and maternal death.1-4 The susceptibility of pregnant women to influenza has also
been observed in the past.5-12
The World Health Organization’s recommendation for the administration of seasonal influenza
vaccine, which included vaccination of pregnant
women, did not change during the H1N1 pandemic.13 In addition, it was recommended that
pregnant women receive a pandemic vaccine.14
Before 2009, pregnant women in Norway were not
routinely advised to be vaccinated against seasonal
influenza. During the pandemic, a trivalent seasonal influenza vaccine and an H1N1 vaccine with
an AS03 adjuvant were recommended for high-risk
groups, although it was recommended that pregnant women receive the pandemic vaccine only, in
the second or third trimester. Studies in animals
and results provided by the vaccine manufacturer
indicated no excess risk of miscarriage or stillbirth after vaccination.15 Still, anecdotal reports of
fetal deaths occurring shortly after vaccination
raised public concern about vaccine safety.15
After the 2009 pandemic, we used the national
health registries and data regarding reimbursement of primary care physicians in Norway to
assess the effectiveness of the pandemic vaccine in
pregnant women and the effect of vaccination or
influenza on fetal survival.
Me thods
Data Sources and Study Population
We linked information on women of reproductive
age in Norway to various national health registries
and to national data regarding reimbursement of
primary care physicians. We obtained the data
from the National Population Register,16 the Norwegian Immunization Register,17 the Surveillance
System for Communicable Diseases,18 the Medical
Birth Registry of Norway,19 and the Directorate of
Health (for reimbursement data). The Norwegian
Patient Registry provided the number of hospitalized pregnant women during the pandemic. Of
1,153,738 girls and women (hereafter referred to as
women) living in Norway in 2009 who were between the ages of 13 and 49 years, 117,026 gave
birth in 2009 or 2010. We restricted our sample to
women who became pregnant 43 weeks before
334
of
m e dic i n e
December 31, 2010, so as not to oversample short
pregnancies during the latter part of 2010. We
excluded from the main analysis children who
were part of a multiple birth, women with invalid
vaccination dates, and the few women who received only a vaccine without adjuvant (Celvapan,
Baxter), leaving 113,331 women in the analyses.
Details on the numbers and type of information
from each data source and a flow chart showing
eligibility are provided in the Methods section and
Figure S1 in the Supplementary Appendix, available with the full text of this article at NEJM.org.
The study was approved by the Regional Committee for Medical and Health Research Ethics and
the Norwegian Data Protection Authority. All authors vouch for the integrity of the data and accuracy of the analysis. The makers of the vaccines
that were analyzed had no role in the study.
Outcome and Exposure Information
We defined fetal death as any recorded miscarriage or stillbirth after 12 completed weeks of
pregnancy. On the basis of both laboratory-confirmed cases of pandemic influenza and physician
visits for influenza that were reported to the Norwegian Institute of Public Health,20 the main pandemic wave in Norway occurred between October
1, 2009, and December 31, 2009. For women who
were already pregnant on October 1, exposure to
the pandemic was defined as the period from
October 1 to the day of delivery. Women whose
first day of pregnancy fell between October 1 and
December 31 were considered to have been exposed to the pandemic from the first day of pregnancy until delivery.
Exposure to influenza was defined as a contact
with a primary care physician that led to a diagnosis of influenza (code R80 in the International
Classification of Primary Care; criteria are listed
in the Supplementary Appendix). Pregnant women were considered to have been exposed to influenza from the day of diagnosis until delivery.
If there were multiple consultation dates during
the main pandemic wave, the first visit was used.
The immunization registry provided information on two types of pandemic influenza vaccine
against the A(H1N1)pdm09 strain: a vaccine with
adjuvant (Pandemrix, GlaxoSmithKline) and one
without adjuvant (Celvapan). Pregnant women
were considered to be unexposed to the vaccine
from the first day of pregnancy until the day of
vaccination and to be exposed to the vaccine
Fetal Death after Influenza Virus Infection or Vaccination
from the day of vaccination until delivery. The
Norwegian Institute of Public Health recommended one dose of Pandemrix. For the 266
pregnant women who received two doses, exposure was defined as starting with the first dose.
Fetuses of mothers who were unvaccinated, vaccinated before pregnancy, or vaccinated on the
day of delivery or thereafter were classified as
unexposed to the vaccine.
Statistical Analysis
The analysis required methods that handle timedependent exposures and data censoring.21 We
used a Cox proportional-hazards model22 with the
gestational day as the underlying time metric.
Hazard ratios with 95% confidence intervals were
estimated. Pregnancies were included in the risk
set on day 84 (after pregnancy week 12) and were
followed until delivery; the end point was fetal
death, and data were censored at the time of a live
birth. Pregnancies longer than 84 days as of January 1, 2009, were included at the gestational age
as of that date. Pregnancy days before January 1,
2009, were not included in the risk set. Figure 1
illustrates the study design, eligible pregnancies,
observed pregnancy days, and exposure to the
pandemic wave.
The study had three specific aims: to investigate the risk of fetal death after exposure to the
pandemic, the risk after clinical diagnosis of
influenza, and the risk after vaccination in pregnancy. In the first model, we used a binary timedependent variable for exposure to the pandemic
during pregnancy. In the second model, we treated
a clinical diagnosis of influenza during pregnancy
as a time-dependent variable, using the following
categories: no exposure to the pandemic (reference), exposure without a clinical diagnosis, and
exposure with a clinical diagnosis. Exposure to
vaccination during pregnancy was a binary timedependent variable.
A separate model was used to examine the risk
of an influenza diagnosis after vaccination during
the pandemic. In this model, only pregnancy days
during the main pandemic wave (October 1, 2009,
to December 31, 2009) were included, and the end
point was physician consultation for influenza.
For this outcome, the vaccine was regarded as
effective from 1 week after vaccination. The time
metric was the gestational day, and pregnancies
were included in the risk set on October 1, 2009,
or on the first day of pregnancy if this date was
within the pandemic window. Follow-up ended on
the day of an influenza diagnosis, the day of delivery, or December 31, whichever occurred first.
There were 3208 women who had two pregnancies during the study period. We used a sandwich estimator to obtain confidence intervals that
accounted for dependence between the pregnancies. We conducted sensitivity analyses that included multiple births and that excluded women
who were vaccinated during the first trimester of
pregnancy. We also performed analyses in which
women who had been vaccinated before pregnancy were classified as having been vaccinated
on the first pregnancy day. The body-mass index
was available for only 39% of the women and was
therefore analyzed in a separate model. The remaining confounder data were complete for 98%
of women and were included in the fully adjusted
models. The assumption of proportional hazards
was assessed with the use of Schoenfeld residuals
and found to be valid. Analyses were performed
with the use of SPSS software, version 19 (SPSS),
and Stata software, version 11 (StataCorp).
R e sult s
Fetal Death and Vaccination
There were 117,347 births in Norway in 2009 and
2010 among women who became pregnant during the eligible time window, including 570 fetal
deaths (4.9 per 1000 births). There were 113,331
eligible singleton pregnancies, of which 492 ended
in fetal death (4.3 deaths per 1000 births). Among
the 99,539 women who delivered outside the pandemic window, there were 410 fetal deaths (4.1
deaths per 1000 births).
Pandemic influenza vaccinations were offered
starting October 19, 2009, and nearly all vaccinations (97%) were administered by December 31,
2009. A total of 25,976 children were born after
their mothers were vaccinated during pregnancy,
with almost all vaccinations occurring during
the second or third trimester. Among the vaccinated women, there were 78 fetal deaths. Among
the 87,335 women who were pregnant during the
pandemic but unvaccinated, there were 414 fetal
deaths. The vaccination status of eligible women
and the distribution of gestational age at vaccination are shown in Table S1 and Figure S2 in the
Supplementary Appendix.
Of the 46,491 women in the second or third
trimester during the pandemic wave (October 1,
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The
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The main wave of the pandemic
Oct. 1–Dec. 31, 2009
Eligible dates of pregnancy onset
43 wk
12 wk
Jan. 1,
2009
Oct. 1,
2009
Unobserved pregnancy
days (not in risk set)
Jan. 1,
2010
Observed pregnancy days
as exposed to influenza
Jan. 1,
2011
Observed pregnancy days
as unexposed to influenza
Figure 1. Eligible Pregnancies, Observed Pregnancy Days, and Exposure to the Main Pandemic Wave.
Births in Norway that occurred in 2009 and 2010 were eligible for the study if women had become pregnant at least
43 weeks before December 31, 2010. Eligible pregnancies were classified as involving maternal exposure to the influenza pandemic if any day of pregnancy occurred between October 1, 2009, and December 31, 2009. For a given pregnancy, days at risk were defined as pregnancy days after week 12 that occurred starting on January 1, 2009, and exposure days were defined as all pregnancy days from the first day of exposure until delivery. For simplicity, the figure
shows all pregnancies as lasting 9 months. The study included all registered pregnancies lasting at least 12 weeks.
The period of the main wave of the influenza pandemic is shaded.
2009, to December 31, 2009), 54% were vaccinated. Characteristics of these pregnancies are
provided in Table 1, with an extended list in
Table S2 in the Supplementary Appendix. Vaccination coverage of pregnant women was higher in
those with chronic diseases and lower in daily
smokers and younger women.
A clinical diagnosis of influenza during the
pandemic wave was recorded for 2278 eligible
pregnant women, among whom there were 16
fetal deaths. There were 516 women with positive laboratory results for the A(H1N1)pdm09
strain; among these women, there were 5 fetal
deaths (too few to estimate risk). The temporal
distribution of vaccinations and positive laboratory tests in pregnant women is shown in Fig
ure 2. Vaccination during pregnancy reduced the
risk of receiving a clinical diagnosis of influenza
(adjusted hazard ratio, 0.30; 95% confidence interval [CI], 0.25 to 0.34).
In an analysis in which women who were pregnant outside the pandemic window were the ref336
erence group, women who were exposed to the
pandemic had an increased risk of fetal death
(adjusted hazard ratio, 1.26; 95% CI, 1.02 to 1.55)
(Table 2). The risk of fetal death was increased
among women with a clinical diagnosis of influenza (adjusted hazard ratio, 1.91; 95% CI, 1.07 to
3.41). Pregnant women who were vaccinated had
a slightly lower risk of fetal death, as compared
with unvaccinated women, a difference that was
not significant (hazard ratio, 0.88; 95% CI, 0.66
to 1.17). Since nearly all vaccinations occurred
during the main pandemic wave, the estimated
hazard ratio in effect compares vaccinated and
unvaccinated women who were pregnant during
the pandemic period. Unvaccinated women had
a higher risk of fetal death during the pandemic
(hazard ratio, 1.25; 95% CI, 1.02 to 1.55) (Table 3).
Adjustment for covariates did not substantially
influence the estimates, which were likewise similar in models in which multiple births were included, women who received first-trimester vaccinations were excluded, adjustment was made for
Table 1. Vaccination Coverage and Characteristics
of Women Who Were Pregnant during the 2009
Influenza Pandemic.*
No. of
Women Vaccinated†
percent
All women
46,491
54
<20 yr
1,008
42
20–24 yr
6,723
48
25–29 yr
14,373
54
30–34 yr
15,191
57
35–39 yr
7,661
55
≥40 yr
1,535
54
0
19,640
52
1
16,719
55
2
7,171
56
≥3
2,961
50
32,148
55
Occasionally
1,266
57
Daily
6,291
50
Declined to give information
6,397
52
389
46
No
41,146
53
Yes
5,345
57
Age
No. of previous pregnancies
Confirmed H1N1 (no.)
Characteristic
1500
20
Vaccinations
15
1000
10
500
5
0
July
2009
Confirmed H1N1
Aug.
2009
Sept.
2009
Oct.
2009
Nov.
2009
Dec.
2009
Jan.
2010
Vaccinations during Pregnancy (no.)
0
Figure 2. Temporal Distribution of Vaccination and Laboratory-Confirmed
Pandemic Influenza.
Shown are the number of pregnant women in Norway with a laboratoryconfirmed diagnosis of pandemic influenza and the number of vaccinations
that were administered from October 19, 2009, through February 2010. The
numbers were smoothed by kernel estimation.
Smoking during pregnancy
No
Missing data
Chronic illness
*Listed are data for women with at least 1 day in the second or third trimester that occurred between October 1,
2009, and December 31, 2009 (the main wave of the
2009 influenza pandemic).
†Listed are the proportions of women who received the 2009
pandemic influenza vaccine at any time during pregnancy.
body-mass index, or women who were vaccinated before pregnancy were reclassified as having
been exposed to the vaccine on the first pregnancy day.
The Norwegian Patient Registry reported that
40 pregnant women were hospitalized with influenza during the pandemic wave; of these hospitalizations, only one was associated with a fetal
death. We also considered nonfatal birth outcomes
(preterm delivery, low birth weight at term, and
low Apgar score at term) and found no evidence of
an association between vaccination and these outcomes (Table S3 in the Supplementary Appendix).
Discussion
Although safety data for use of the Pandemrix
vaccine in pregnant women were lacking at the
time of the pandemic, studies in animals showed
no reproductive toxicity, and it was considered safe
for use during pregnancy.15 Nevertheless, early
reports of fetal losses after vaccination, including
30 reports in Norway,23 raised public concern
about the safety of vaccination during pregnancy.
Using national registries and records of health care
reimbursement in Norway, we found no evidence
that influenza vaccination of pregnant women increased the risk of fetal death. However, influenza
virus infection itself posed a major risk; among
pregnant women who received a clinical diagnosis
of influenza, the risk of fetal death nearly doubled.
Vaccination appeared to provide some protection
against excess fetal mortality during the pandemic.
A strength of this study was the use of nationwide registries with mandatory reporting of dates
of events, combined with relatively high vaccination coverage. Because of the organization of
health care in Norway, nearly all consultations for
influenza symptoms are in primary care or emergency outpatient settings, for which physicians
are reimbursed by the government. Pregnant
women in Norway receive free prenatal care and
give birth free of charge in hospitals. During the
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Table 2. Hazard Ratios for Fetal Death, According to Status Regarding Vaccination, Pregnancy during the Pandemic
Wave, and a Clinical Diagnosis of Influenza.*
No. of PregnancyDays at Risk†
Variable
Hazard Ratio (95% CI)
Without
Adjustment
Total no. of days
With Initial
Adjustment‡
With Further
Adjustment§
18,970,404
Vaccinated during pregnancy
No
15,942,252
Yes
3,028,152
1.00
1.00
1.00
0.95 (0.74–1.21)
0.84 (0.64–1.10)
0.88 (0.66–1.17)
Pregnant during the pandemic
No
10,422,035
Yes
8,548,369
Without an influenza diagnosis
With an influenza diagnosis
1.00
1.00
1.00
1.15 (0.96–1.37)
1.21 (1.00–1.48)
1.26 (1.02–1.55)
8,221,514
1.11 (0.93–1.33)
1.18 (0.96–1.44)
1.23 (0.99–1.52)
326,855
2.00 (1.20–3.32)
2.10 (1.27–3.49)
1.91 (1.07–3.41)
*Shown are hazard ratios based on the 492 fetal deaths among 113,331 women who gave birth to or miscarried a singleton
in Norway in 2009 or 2010. Hazard ratios were estimated with the gestational day as the time metric. Fetal death was
defined as a recorded miscarriage or stillbirth after 12 completed weeks of pregnancy. A pregnancy during the pandemic
included at least 1 day between October 1, 2009, and December 31, 2009.
†Each woman could have contributed both exposed and unexposed days at risk.
‡Vaccination status was adjusted for pregnancy during the main pandemic wave (yes or no) but not for other covariates.
Influenza exposure was adjusted for vaccination status but not for other covariates.
§ In addition to adjustment for influenza exposure and vaccination status, hazard ratios were also adjusted for age, parity,
marital status, and status with respect to use of nutritional supplements during pregnancy, smoking during pregnancy,
previous fetal death, and eight chronic medical conditions (asthma, hypertension, heart disease, kidney disease, rheumatoid arthritis, epilepsy, thyroid disease, and diabetes).
pandemic, vaccines were offered to all Norwegian residents either free of charge or with a
small administration fee. It is therefore unlikely
that cost or availability influenced vaccination
status in pregnant women.
The birth-registry data have been found to
have adequate validity,24,25 and it is unlikely that
they would be influenced by vaccination status.
However, if awareness of potential risks after
vaccination triggered more reporting of early
losses in vaccinated women than in unvaccinated
women, the adverse effects of the vaccine might
have been overestimated, and the potential protective effects underestimated. Registration of
vaccination was mandatory, although around
10% of the 2.43 million doses distributed in
Norway were not registered. If some women who
were classified in our analysis as unvaccinated had
been vaccinated without registration, the benefits
of vaccination might be greater than we estimate.
Our estimates could be confounded if women
with known risk factors for fetal death (e.g., diabetes or a history of previous fetal death) were
either more or less likely to accept vaccination.
338
The vaccination coverage was higher among women with chronic conditions and those who were
obese (high-risk groups for influenza) and lower
among women who were smokers, indicating
that lifestyle factors may have confounded associations. However, adjustment for known potential confounding factors had little effect on
the associations.
The main pandemic wave and the vaccination
period had substantial overlap (Fig. 2), and women could have been exposed to influenza before
being vaccinated (or before the vaccine became
effective), which could have attenuated the protective effects of the vaccine. We used three approaches to assess exposure to influenza virus.
First, we accessed all reported cases of laboratory-confirmed pandemic influenza. The Norwegian Institute of Public Health issued recommendations for laboratory testing during the
pandemic. Until July 20, 2009, physicians were
encouraged to sample widely. After this date, for
reasons of limited capacity, the recommendations
were revised to restrict testing to prioritized
groups, including pregnant women. However, too
Table 3. Hazard Ratios for Fetal Death, According to Pregnancy during the Pandemic Wave and Vaccination Status.*
Pregnancy and Vaccination Status
during Pandemic
No. of PregnancyDays at Risk†
Hazard Ratio (95% CI)
Unadjusted
Adjusted‡
10,414,633
1.00
1.00
7,402
NA
NA
Not pregnant during the pandemic
Not vaccinated during pregnancy
Pregnant during the pandemic
Not vaccinated during pregnancy
5,527,619
1.21 (1.00–1.48)
1.25 (1.02–1.55)
3,020,750
1.02 (0.79–1.32)
1.10 (0.84–1.45)
*Shown are hazard ratios for the 492 fetal deaths among 113,331 women who gave birth to or miscarried a singleton in
Norway in 2009 or 2010. Hazard ratios were estimated with the gestational day as the time metric. Fetal death was defined as a recorded miscarriage or stillbirth after 12 completed weeks of pregnancy. A pregnancy during the pandemic
included at least 1 day between October 1, 2009, and December 31, 2009. NA denotes not available because there were
too few days at risk to estimate the hazard ratio.
†Each woman could have contributed both exposed and unexposed days at risk.
‡In addition to adjustment for influenza exposure and vaccination status, hazard ratios were adjusted for age, parity, marital
status, and status with respect to use of nutritional supplements during pregnancy, smoking during pregnancy, previous
fetal death, and eight chronic medical conditions (asthma, hypertension, heart disease, kidney disease, rheumatoid arthritis, epilepsy, thyroid disease, and diabetes).
few women were tested during pregnancy to make
analyses of fetal death meaningful.
Second, we obtained data on physician contacts
leading to a diagnosis of influenza. Approximately
20 to 30% of the Norwegian population had clinical influenza during the pandemic.26 In our study
of women who gave birth in 2009 or 2010, a
total of 8.9% received a diagnosis of influenza by
a physician. It is likely that a greater proportion
of women with more severe symptoms contacted
a physician than did those with mild symptoms,
so our results may reflect risks related to infection with more severe clinical symptoms. However, only one woman who was hospitalized
with influenza had a fetal death during the pandemic, so our fetal-loss data represent almost
entirely nonhospitalized women. Among women
with a clinical diagnosis of influenza, the risk of
subsequent fetal death was nearly doubled.
Third, we used the time period of the main
pandemic wave as a proxy for exposure to the
pandemic influenza virus. Pregnant women who
were exposed to the main pandemic wave had an
elevated risk of fetal death (Table 2). The risk of
fetal death was slightly lower among vaccinated
women than among those who were not vaccinated (Table 3). Taken together, these results are
consistent in suggesting a harmful effect of pandemic influenza virus on fetal survival.
Recent, smaller studies in Denmark and Can-
ada have likewise shown no evidence that influenza vaccination during the 2009 pandemic increased the risk of stillbirth27,28 or other adverse
birth outcomes.29 Unlike these earlier studies, our
study showed an increased risk of fetal death
after maternal infection with influenza virus, especially among women with a clinical diagnosis
of influenza. This consequence of infection was
suggested by data from the influenza pandemic
of 19185,7,8 and was reported in women hospitalized during the 2009 pandemic.4 However, maternal infection with influenza virus had not generally been recognized as a risk to fetal survival in
the absence of hospitalized maternal illness.
Given the danger posed by maternal influenza
virus infection for fetal survival, our study adds
to growing evidence that vaccination of pregnant
women during an influenza pandemic does not
harm — and may benefit — the fetus. We found
no basis for withholding influenza vaccination
from pregnant women in their second or third
trimester — an important group, given that these
women can be particularly vulnerable to the severe effects of influenza virus infection.
Supported by the Norwegian Institute of Public Health. Dr.
Wilcox was supported by the Intramural Research Program of
the National Institute of Environmental Health Sciences, National Institutes of Health.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
339
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