Wiesen AR, Littell CT. Relationship Between Prepregnancy Anthrax Vaccination and Pregnancy
and Birth Outcomes Among US Army Women. JAMA. 2002;287(12):1556-1560. doi:10.1001/jama.287.12.1556
Author Affiliation: Department of Preventive Medicine, Madigan Army Medical Center, Tacoma, Wash.
Context Substantial concern surrounds the potential health effects of the anthrax
vaccine, particularly the potential adverse effects on reproductive processes.
Objective To determine whether receipt of anthrax vaccination by reproductive-aged
women has an effect on pregnancy rates.
Design, Setting, and Patients Cohort study, based on information from a computer database, of women
aged 17 to 44 years who were stationed at Fort Stewart, Ga, or Hunter Army
Airfield, Ga, from January 1999 through March 2000.
Main Outcome Measures Pregnancy and birth rates and adverse birth outcomes.
Results Of a total of 4092 women, 3136 received at least 1 dose of the anthrax
vaccine. There was a total of 513 pregnancies, with 385 following at least
1 dose of anthrax vaccine. The pregnancy rate ratio (before and after adjustment
for marital status, race, and age) comparing vaccinated with unvaccinated
women was 0.94 (95% confidence interval [CI], 0.8-1.2; P = .60). There were 353 live births and 25 pregnancies lost to follow-up.
The birth odds ratio after anthrax vaccination (before and after adjustment
for marital status and age) was 0.9 (95% CI, 0.5-1.4; P = .55). After adjusting for age, the odds ratio for adverse birth
outcome after receiving at least 1 dose of anthrax vaccination was 0.9 (95%
CI, 0.4-2.4; P = .88). However, this study did not
have sufficient power to detect adverse birth outcomes.
Conclusion Anthrax vaccination had no effect on pregnancy and birth rates or adverse
In 1970, the anthrax vaccine was licensed by the US Food and Drug Administration
for human use.1 Independent civilian panels
have repeatedly affirmed the safety and efficacy of the anthrax vaccine.1- 5
Until 1990, the primary recipients of this vaccine were individuals occupationally
exposed to anthrax (textile mill workers, selected veterinarians, certain
laboratory workers). With the advent of the Persian Gulf War, the US Department
of Defense determined there was a credible threat of anthrax exposure to its
troops from biological weapons and a large-scale vaccination program with
anthrax vaccine was started.
Due to the persistent threat of biological weapons use, the US Department
of Defense directed in 1998 that all military services begin an anthrax vaccination
The US military has given more than 2 million anthrax vaccinations to more
than 500 000 individuals since beginning the vaccination program. Military
personnel at Fort Stewart, Ga, and Hunter Army Airfield, Ga, began a program
of anthrax vaccinations in the fall of 1998. Medical exemptions to vaccination
were granted as clinically appropriate, the most common being deferral of
vaccination during pregnancy. The program continued until March 2000, when
it was curtailed because of a shortage of vaccine. After March 2000, new vaccine
starts were limited to persons assigned to "high-threat" areas.
Anthrax vaccine adsorbed, distributed by BioPort Corp (Lansing, Mich),
consists of aluminum hydroxide–adsorbed supernatant material, principally
protective antigen, from an avirulent, nonencapsulated strain of Bacillus anthracis.1,10
There is no live material in this vaccine. The vaccine series consists of
6 doses over 18 months, followed by an annual booster. Injection-site reactions
(principally due to the aluminum hydroxide) have been well described.1,4,10- 13
Limited studies of long-term effects found no evidence of adverse consequences.13,14 Although no biologically plausible
mechanism for a reproductive effect has ever been proposed, this vaccine is
administered to large numbers of women in their early reproductive years.
Questions relating to reproductive effects are the most common concerns among
callers to the US Department of Defense's anthrax toll-free information line
(LTC J. D. Grabenstein, RPh, PhD, USA, written communication, 2001). Because
of this concern, we wished to assess whether anthrax vaccination would result
in a measurable decrease in pregnancy rates. Secondary objectives were to
measure effects on fetal loss and adverse birth outcomes.
The study population was US Army women aged 17 to 44 years assigned
to Fort Stewart, Ga, or Hunter Army Airfield, Ga, at any time during January
1999 through March 2000. Demographic information, period of assignment, and
anthrax immunization dates were obtained from local administrative and clinical
databases. All outcome information (pregnancy, birth, and adverse birth outcome)
was obtained from the Fort Stewart Hospital's computerized database. The study
design was reviewed and approved by the institutional review board at Dwight
David Eisenhower Army Medical Center, Augusta, Ga.
The primary outcome measure was pregnancy. Additional outcomes were
birth following pregnancy and adverse birth outcomes. A woman was considered
pregnant if a qualitative serum or urine β-human chorionic gonadotropin
(hCG) test result was positive or a quantitative serum test was more than
5 IU/mL, or if she was hospitalized and discharged with an International Classification of Diseases, 9th Revision (ICD-9) diagnosis that included live birth and was assigned to Fort
Stewart for at least 270 days prior to the birth. Live births included all ICD-9 diagnosis codes of 640 to 679, but excluded those
codes whose fifth digit was a 3 or 4 (admitted either for a prepartum complication
without delivery or for postpartum complication without delivery, respectively).
The ICD-9 codes were used to define low birth weights
(764-765) and congenital structural abnormalities (740-759). Low birth weight
was defined as infants weighing less than 2500 g at birth. Structural abnormalities
were defined as those abnormalities with medical or cosmetic significance.
Births for women who departed Fort Stewart within 260 days of their pregnancy
date without giving birth were tracked using the Defense Eligibility Enrollment
System (DEERS). The only information available through DEERS was whether a
birth occurred. Nonpregnant women who left Fort Stewart or Hunter Army Airfield
were not tracked for pregnancy status.
Anthrax vaccination status was considered positive if the woman received
at least 1 anthrax immunization before the date of her positive pregnancy
test result. Anthrax vaccination dates were obtained from the US Department
of Army immunizations tracking database (Military Occupational Data System
[MODS]). Other vaccinations required for military readiness or that were medically
indicated were administered simultaneously. Age, marital status, and race,
which are associated with pregnancy and birth rates (A.R.W., unpublished data,
2001),15,16 were examined as possible
confounding factors. Age and marital status were assessed at the beginning
of the study period. Race was subdivided into categories of black, white,
and all other, which included Hispanic, American Indian, Pacific Islander,
A general log-linear model, using the Poisson distribution, was used
to estimate rates and rate ratios for predictor variables. Model building
and goodness-of-fit testing were performed using standard methods.17 Unconditional logistic regression was used to estimate
odds ratios (ORs) for birth outcome following pregnancy. Univariate comparisons
were made between pregnancy occurrence and major demographic variables. Statistical
analyses were performed using SPSS software, version 10.0 (SPSS Inc, Chicago,
Ill). For 90% power to detect a 25% decline in pregnancy rates, assuming the
fraction exposed to anthrax vaccine was 75%, the pregnancy rate was 160 pregnancies
per 1000 women per year and the type 1 error held at 5% (2-sided), a total
sample size of 4000 women was required. Power estimates were based on known
prestudy anthrax vaccine exposure rate (47%), expected rate of rise, and previous
estimates of pregnancy rates in military women (A.R.W., unpublished data,
2001). All confidence intervals (CIs) were 2-sided.
During the 15-month study period, 4098 women were assigned to Fort Stewart
or Hunter Army Airfield. Six women were excluded because of incomplete data,
leaving 4092 women eligible for data analysis; 3136 women received at least
1 dose of anthrax vaccine. There were no important demographic differences
between those vaccinated and not vaccinated, except for a slight difference
in racial distribution (Table 1).
The most common reason for not being vaccinated was departure from Fort Stewart
before the vaccine could be given. Persons already at Fort Stewart or Hunter
Army Airfield were vaccinated as rapidly as time, training, vaccine supply,
and medical resources allowed. Vaccine was administered to all persons newly
arrived at Fort Stewart or Hunter Army Airfield. Women were present for a
median of 12 months (interquartile range, 6-15 months) and 1518 (37%) women
were present for the entire 15-month period. There were 1276 new arrivals
and 1387 departures prior to the end of the study period. Those who left had
a lower likelihood of receiving vaccine (OR, 0.17; 95% CI, 0.15-0.20; P<.001) but were similar in age, race, and marital status
to those remaining. There were 7464 anthrax vaccinations given during the
study period. The majority of women received 2 to 3 doses during the study
period (median, 2; interquartile range, 2-3; range, 1-6). The percentage vaccinated
with 1 or more doses increased from 47% in January 1999 to 89% by March 2000.
Persons were not allowed to defer or refuse vaccine for reasons other than
bona fide medical indications (pregnancy or immune compromising disease).
Pregnant women were required to be vaccinated after they gave birth or their
pregnancy ended. Women who were vaccinated and then became pregnant were deferred
from receiving further vaccine until they were no longer pregnant.
There were 385 pregnancies following at least 1 anthrax vaccination
during 28 815 person-months of follow-up time, for an annualized pregnancy
rate of 159.5 per 1000 person-years. In the unvaccinated group, 130 pregnancies
occurred during 9734 person-months of follow-up, for a pregnancy rate of 160.0
per 1000 person-years. The pregnancy rate ratio was 0.94 (95% CI, 0.8-1.2; P = .60). A general log-linear model, using a Poisson distribution,
showed that age, marital status, and race were independently associated with
pregnancy rates (Table 2). The
model with the 3 predictors (age, race, marital status) was not statistically
significantly different from the fully saturated model (χ262 = 74.2; P = .14). Addition of the immunization
term did not improve the fit of the model (χ261
= 74.0; P = .12).
Women who received the anthrax vaccination were 1.2 times as likely
to give birth as unvaccinated women (95% CI, 0.8-1.8; P = .52). The OR after adjustment for marital status, race, and age
was unchanged (OR, 1.2; 95% CI, 0.7-1.8; P = .53).
Eighty-five women left Fort Stewart within 260 days of their positive pregnancy
test but 54 women remained eligible for medical care in the military system.
Six had laboratory evidence of fetal loss prior to departing Fort Stewart.
Of the 25 pregnancies lost to follow-up, 12 of the women received the anthrax
vaccine and 13 did not. These women were younger, significantly less likely
to have been vaccinated, and more likely to be single and white (Table 3). If the 488 women with at least
260 days of follow-up are considered (Table
4), the OR for birth and anthrax vaccination was 0.9 (95% CI, 0.5-1.4; P = .55). The OR after adjustment for marital status, race,
and age was unchanged (OR, 0.9; 95% CI, 0.5-1.4).
Complete ICD-9 coding data for 327 births were
available for birth outcome analysis. Eleven (3.3%) of the births were of
low birth weight (<2500 g). The OR for anthrax vaccination and low birth
weight, after adjusting for age, was 1.3 (95% CI, 0.2-6.4; P = .72). There were 15 structural abnormalities of cosmetic and/or
medical significance (ICD-9 codes 740-759). No unusual
patterns or clusters were noted. The only abnormality with multiple occurrences
was polydactyly of the fingers (3 cases: 2 in the anthrax immunized group
and 1 in the nonimmunized group). The OR for anthrax vaccination and structural
abnormality, after adjusting for age, was 0.7 (95% CI, 0.2-2.3; P = .71). The overall OR for anthrax vaccination and any adverse birth
outcome, after adjusting for age, was 0.9 (95% CI, 0.4-2.4; P = .88).
When the US Department of Defense began immunizing military personnel
with the anthrax vaccine, its use was questioned by many receiving the vaccine,
for only those exposed to an anthrax biological weapon would benefit. Because
most would not be exposed, the attention of many service members turned to
This is the first study to our knowledge to examine the effects on reproduction
among a large group of women given the anthrax vaccine. In a previous study
on pregnancy in Army women (A.R.W., unpublished data, 2001), we found a pregnancy
rate of 161 per 1000 person-years in 5500 women followed up for more than
66 000 person-months. When this cohort was standardized for age and race
to the 1995 US population, the pregnancy rate ratio was 1.05 (95% CI, 0.96-1.04).
Furthermore, the pregnancy rate at Fort Stewart and Hunter Army Airfield during
the 32 months prior to the study period was not statistically significantly
different from the rate during the study (rate ratio = 1.0; 95% CI, 0.9-1.1; P = .90). These results do not support the hypothesis of
a decrease in pregnancy rates nor an increase in fetal loss rates or adverse
fetal outcome among those receiving anthrax vaccination prior to pregnancy.
Although the number of adverse outcomes was small, the percentage of low-birth-weight
infants was about half the expected 7.5% of low-birth-weight infants seen
This may be due to the young age of women in our cohort. The structural abnormality
rate was comparable with national rates.22,23
This is not surprising, given the lack of a biologically plausible mechanism
for any reproductive effect.
In addition, there is no evidence of infertility, miscarriages, or other
reproductive problems with the use of any inactivated vaccine.24,25
For example, tetanus, meningococcal, hepatitis B, poliovirus, and influenza
vaccines are specifically recommended for susceptible women during their pregnancy.26
This study has several strengths. First, there is the nonbiased nature
of the exposure to vaccine. This military post had a blanket policy for immunization.
Hence, potentially important independent risk factors, such as intent to become
pregnant, use of contraceptives, marital status, age, race, and smoking status,
were not related to vaccine exposure and therefore could not confound the
results. There are no known medical conditions related to fertility and pregnancy
that would have exempted a woman from receiving the anthrax vaccine. Second,
another strength is the objectivity and completeness of the outcomes. Personnel
on active military service have little opportunity to receive health care
outside the military system; health care is free and testing to document pregnancy
is required. Therefore, we are confident that we captured the vast majority
of all pregnancies. All the medical testing at Fort Stewart is done at the
installation's hospital and the results are maintained in a single computerized
database. Finally, the study size provides confidence that the hypothesis
regarding rate of pregnancy was not inappropriately rejected due to lack of
There are several potential limitations to this study. First, there
is our reliance on the accuracy of ICD-9 coding.
This is unlikely to introduce a significant bias as any miscodings would be
expected to be equally distributed over both the vaccinated and unvaccinated
groups. Second, we were unable to adjust for other potentially important confounders
such as intent to become pregnant and smoking status. However, these were
not related to the exposure to anthrax vaccine and should not confound the
results. Third, it was not possible to test for dose response. The vaccine
schedule calls for the first 3 immunizations to be given in the first month,
then the next 3 to be given at 6-month intervals. This led to most participants
receiving either 3 or 4 immunizations with insufficient numbers receiving
less or more vaccine to permit a meaningful analysis of dose response. However,
given the lack of overall effect, it is unlikely that a significant dose response
effect is present. Fourth, there was no way to evaluate the effect of the
vaccine given during pregnancy; only prepregnancy vaccine exposure was evaluated.
Finally, the study does not have adequate statistical power to rule out a
small effect of vaccination on adverse birth outcome, given the low incidence
of adverse outcomes. A post hoc power analysis showed the study only had a
12% power to detect a 20% increase in adverse birth outcomes, based on potential
effects on likelihood of pregnancy.