In October 2011, in an effort to reduce the burden of pertussis in infants, the Advisory
Committee on Immunization Practices (ACIP) recommended that unvaccinated pregnant
women receive a dose of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis
vaccine (Tdap) (1). Vaccination of women with Tdap during pregnancy is expected to
provide some protection to infants from pertussis until they are old enough to be
vaccinated themselves. Tdap given to pregnant women will stimulate the development
of maternal antipertussis antibodies, which will pass through the placenta, likely
providing the newborn with protection against pertussis in early life, and will protect
the mother from pertussis around the time of delivery, making her less likely to become
infected and transmit pertussis to her infant (1). The 2011 Tdap recommendation did
not call for vaccinating pregnant women previously vaccinated with Tdap. On October
24, 2012, ACIP voted to recommend use of Tdap during every pregnancy. This report
summarizes data considered and conclusions made by ACIP and provides guidance for
implementing its recommendations. These updated recommendations on use of Tdap in
pregnant women aim to optimize strategies for preventing pertussis morbidity and mortality
in infants.
ACIP is chartered as a federal advisory committee to provide expert external advice
and guidance to the Director of the Centers for Disease Control and Prevention (CDC)
on use of vaccines and related agents for the control of vaccine-preventable diseases
in the civilian population of the United States. Recommendations for routine use of
vaccines in children and adolescents are harmonized to the greatest extent possible
with recommendations made by the American Academy of Pediatrics, the American Academy
of Family Physicians (AAFP), and the American College of Obstetricians and Gynecologists.
Recommendations for routine use of vaccines in adults are reviewed and approved by
the American College of Physicians, AAFP, the American College of Obstetricians and
Gynecologists, and the American College of Nurse-Midwives. ACIP recommendations adopted
by the CDC Director become agency guidelines on the date published in the Morbidity
and Mortality Weekly Report (MMWR).
The United States has experienced substantial increases in reported pertussis cases
over the past several years. Provisional case counts for 2012 have surpassed the last
peak year, 2010, with 41,880 pertussis cases and 14 deaths in infants aged <12 months
(2) (CDC, unpublished data, 2012). To reduce this burden, optimizing the current vaccination
program and protecting infants who are at highest risk for death are immediate priorities.
Since the 2011 ACIP vaccination recommendation, uptake of Tdap among pregnant women
has been low; one survey of 1,231 women (August 2011 to April 2012) estimated that
only 2.6% of women received Tdap during their recent pregnancy (3). New data indicate
that maternal antipertussis antibodies are short-lived; therefore, Tdap vaccination
in one pregnancy will not provide high levels of antibodies to protect newborns during
subsequent pregnancies (4).
Methods
In monthly teleconferences during 2012, the ACIP Pertussis Vaccines Work Group considered
published, peer-reviewed literature and unpublished data relevant to vaccinating pregnant
women with Tdap. When data were not available, expert opinion was considered. Summaries
of the data reviewed and work group discussions were presented to ACIP before recommendations
were proposed. The proposed Tdap recommendation for pregnant women was presented at
the October 2012 ACIP meeting and approved by ACIP.
Summary of ACIP Deliberations and Rationale
A dose of Tdap during each pregnancy
Very young infants are dependent solely on maternal antibodies and lack the ability
to mount a cell-mediated response (4). The effectiveness and optimal concentration
of maternal antipertussis antibodies in newborns are not yet known, but high levels
of antibodies in the first weeks after birth likely confer protection and might prevent
pertussis or modify disease severity (5–7). Studies on the persistence of antipertussis
antibodies following a dose of Tdap show antibody levels in healthy, nonpregnant adults
peak during the first month after vaccination, with substantial antibody decay after
1 year (8–10). Antibody kinetics in pregnant women likely would be similar. One study
evaluated persistence of maternal antipertussis antibody concentrations from maternal
delivery and cord blood pairs from women who received Tdap within the prior 2 years
(4). The estimated antipertussis antibody concentrations at birth in most of these
infants were considered unlikely to provide adequate protection. These findings indicate
that maternal antibodies from women immunized before pregnancy waned quickly and the
concentration of maternal antibodies was unlikely to be high enough to provide passive
protection to infants (4). Because antibody levels wane substantially during the first
year after vaccination, ACIP concluded a single dose of Tdap at one pregnancy would
be insufficient to provide protection for subsequent pregnancies.
Potential Impact of Tdap During Pregnancy
For the 2011 ACIP recommendation, ACIP reviewed a decision analysis model developed
to assess the impact and cost effectiveness of Tdap vaccination during pregnancy compared
with immediately postpartum vaccination (1). The model showed that Tdap vaccination
during pregnancy would prevent more infant cases, hospitalizations, and deaths compared
with the postpartum dose (11).
For this updated recommendation, the model was rereviewed and the analysis updated.
To estimate the potential impact of Tdap given either during pregnancy or postpartum,
percent mean reductions were applied to the annual mean number of reported pertussis
cases in infants aged <12 months during 2000–2011 (CDC, unpublished data, 2011). During
2000–2011, the annual mean of pertussis cases in infants aged <12 months was 2,746
(range: 1,803–4,298), hospitalizations was 1,217 (range: 687–1,938), and deaths was
18 (range: 8–35) (CDC, unpublished data, 2011). Based on the model, Tdap vaccination
during pregnancy might prevent 906 (range: 595–1,418) infant cases, 462 (range: 261–736)
hospitalizations, and nine (range: 4–17) deaths; a postpartum dose might prevent 549
(range: 361–860) infant cases, 219 (range: 124–349) hospitalizations, and three (range:
1–6) deaths (CDC, unpublished data, 2012).
Birth Statistics in the United States
To address the likelihood that women might receive Tdap during consecutive pregnancies
in a short period, and therefore theoretically be at greater risk for adverse reactions,
ACIP reviewed available data on birth statistics. In the United States, approximately
4 million births are reported each year, and an average of 2.06 children are born
per woman in a lifetime (12,13). Among women with more than one pregnancy, only 2.5%
have an interval ≤12 months between births (14). The majority of women, who have two
pregnancies, have an interval of ≥13 months between births (14). For women of lower
socioeconomic status, the interval between pregnancies generally is ≥18 months (15).
Approximately 5% of women have four or more babies (16). ACIP concluded that the interval
between subsequent pregnancies is likely longer than the persistence of maternal antipertussis
antibodies, and were reassured that most women would receive only 2 Tdap doses and
a small proportion of women would receive ≥4 doses of Tdap.
Safety of Repeat Tdap Administration to Pregnant Women
In 2011, ACIP concluded that available data did not suggest any elevated frequency
or unusual patterns of adverse events in pregnant women who received Tdap and that
the few serious adverse events reported were unlikely to have been caused by the vaccine;
at that time, a dose of Tdap for every pregnancy was not considered (9). Published
data on receipt of 2 doses of Tdap and multiple doses of tetanus toxoid–containing
vaccines were reviewed. Receipt of a second dose of Tdap at a 5- or 10-year interval
in healthy nonpregnant adolescents and adults was well tolerated; injection site pain
was the most commonly reported adverse event (9,17–20). The frequency of reported
adverse events for the second dose was similar to the first dose in these same subjects
and in naïve controls receiving Tdap for the first time. Of the few serious adverse
events reported, none were attributed to the vaccine. Fever was reported in 2.4%–6.5%
of recipients of a Tdap booster; the frequency of fever was similar to that in the
same subjects after their first Tdap dose and in naïve controls (9,17–19). Studies
on short intervals (i.e., within 21 days or ≤2 years) between receipt of tetanus and
diphtheria toxoids (Td) and Tdap or Tdap-inactivated polio vaccine in healthy, nonpregnant
adolescents and adults found no serious adverse events (21–23). Fever was reported
in 1.7%–6.8% of subjects who received Tdap ≤2 years after Td; rates were comparable
to the control group and to cohorts that received Tdap longer after receipt of Td
(21,22). The number of subjects in these studies was small, and therefore, the findings
do not rule out the possibility of rare but serious adverse events.
A theoretical risk exists for severe local reactions (e.g., Arthus reactions, whole
limb swelling) for pregnant women who have multiple closely spaced pregnancies. Arthus
reactions and whole limb swelling are hypersensitivity reactions that have been associated
with vaccines containing tetanus toxoid, tetanus and diphtheria toxoids, and/or pertussis
antigens. Historical data on multiple doses of Td and tetanus toxoid vaccines (TT)
indicate that hypersensitivity was associated with higher levels of preexisting antibody
(24–26). The frequency of side effects depended on antigen content, product formulation,
preexisting antibody levels related to the interval since last dose, and the number
of doses (24–26). Challenges to reviewing historical data on multiple doses of TT
and Td include differences in adjuvant and toxoid amounts in vaccines over time and
severity of adverse events by number of vaccines received (24–26). Most of the data
are historical, and the risk for severe adverse events likely has been reduced with
current formulations that contain lower doses of TT.
TT and Td have been used extensively in pregnant women worldwide to prevent neonatal
tetanus; large studies on use of TT during pregnancy have not reported clinically
significant severe adverse events (27–30). Safety data on use of Td during multiple
pregnancies have not been published. ACIP believes the potential benefit of preventing
pertussis morbidity and mortality in infants outweighs the theoretical concerns of
possible severe adverse events.
ACIP concluded that experience with tetanus-toxoid containing vaccines suggests no
excess risk for severe adverse events for women receiving Tdap with every pregnancy.
ACIP stated the need for safety studies of severe adverse events when Tdap is given
during subsequent pregnancies. Plans for safety monitoring in pregnant women following
Tdap administration include enhanced monitoring in Vaccine Adverse Event Reporting
System (VAERS) and utilizing the Vaccine Safety Datalink (VSD) to assess acute adverse
events, adverse pregnancy outcomes affecting the mother, and birth outcomes; assessing
risks for rare adverse events in pregnant women after Tdap will require data collection
for several years (31).
Vaccination During the Third Trimester
Tdap may be administered any time during pregnancy, but vaccination during the third
trimester would provide the highest concentration of maternal antibodies to be transferred
closer to birth (4). After receipt of Tdap, a minimum of 2 weeks is required to mount
a maximal immune response to the vaccine antigens (32,33). Active transport of maternal
immunoglobulin G does not substantially take place before 30 weeks of gestation (34).
One study of pregnant women who received Tdap within the prior 2 years noted that
maternal antibodies waned quickly; even women immunized during the first or second
trimester had low levels of antibodies at term (4). Therefore, to optimize the concentration
of vaccine-specific antipertussis antibodies transported from mother to infant, ACIP
concluded that pregnant women should be vaccinated with Tdap during the third trimester.
ACIP Recommendations for Pregnant Women
ACIP recommends that providers of prenatal care implement a Tdap immunization program
for all pregnant women. Health-care personnel should administer a dose of Tdap during
each pregnancy, irrespective of the patient’s prior history of receiving Tdap.
Guidance for Use
To maximize the maternal antibody response and passive antibody transfer to the infant,
optimal timing for Tdap administration is between 27 and 36 weeks gestation although
Tdap may be given at any time during pregnancy. For women not previously vaccinated
with Tdap, if Tdap is not administered during pregnancy, Tdap should be administered
immediately postpartum.
Special Situations
Pregnant women due for tetanus booster
If a tetanus and diphtheria booster vaccination is indicated during pregnancy (i.e.,
>10 years since previous Td), then Tdap should be administered. Optimal timing is
between 27 and 36 weeks gestation to maximize the maternal antibody response and passive
antibody transfer to the infant.
Wound management for pregnant women
As part of standard wound management to prevent tetanus, a tetanus toxoid–containing
vaccine might be recommended for wound management in a pregnant woman if ≥5 years
have elapsed since the previous Td booster. If a Td booster is recommended for a pregnant
woman, health-care providers should administer Tdap.
Pregnant women with unknown or incomplete tetanus vaccination
To ensure protection against maternal and neonatal tetanus, pregnant women who never
have been vaccinated against tetanus should receive three vaccinations containing
tetanus and reduced diphtheria toxoids. The recommended schedule is 0, 4 weeks, and
6 through 12 months. Tdap should replace 1 dose of Td, preferably between 27 and 36
weeks gestation to maximize the maternal antibody response and passive antibody transfer
to the infant.
Cocooning
ACIP recommends that adolescents and adults (e.g., parents, siblings, grandparents,
child-care providers, and health-care personnel) who have or anticipate having close
contact with an infant aged <12 months should receive a single dose of Tdap to protect
against pertussis if they have not received Tdap previously. Guidance will be forthcoming
on revaccination of persons who anticipate close contact with an infant, including
postpartum women who previously have received Tdap.
Research Needs
Future research needs will address the effectiveness of Tdap vaccination of pregnant
women to prevent infant pertussis morbidity and mortality, the impact of timing of
Tdap during pregnancy on infant pertussis, and safety of multiple doses of Tdap in
pregnant women. CDC will monitor and assess the safety of Tdap use during pregnancy.
Results from these studies and monitoring systems will inform future considerations
made by ACIP on use of Tdap in preventing infant pertussis morbidity and mortality.