The content on this page is being archived for historic and reference purposes only. The content, links, and pdfs are no longer maintained and might be outdated.
Prevention of Pertussis, Tetanus, and Diphtheria Among
Pregnant and Postpartum Women and Their Infants
Recommendations of the Advisory Committee on Immunization
Trudy V. Murphy, MD1
Barbara A. Slade, MD1
Karen R. Broder, MD1,2
Katrina Kretsinger, MD1,2
Tejpratap Tiwari, MD1
M. Patricia Joyce, MD1
John K. Iskander, MD2,3
Kristin Brown, MPH1
John S. Moran, MD1,2
1Division of Bacterial Diseases, National Center for Immunization and Respiratory Diseases
2United States Public Health Service
3Office of the Chief of Science, Office of the Director
The material in this report originated in the National Center for Immunization and Respiratory Diseases, Anne Schuchat, MD, Director; the
Division of Bacterial Diseases, Rana Hajjeh, MD, Director; and the Office of the Chief of Science,
Tanja Popovic, PhD, Director.
Corresponding preparer: Trudy V. Murphy, MD, Division of Bacterial Diseases, National Center for Immunization and Respiratory Diseases,
CDC, 1600 Clifton Road, NE, MS C-25, Atlanta, GA 30333. Telephone: 404-639-8845; Fax: 404-639-8616; E-mail: firstname.lastname@example.org.
In 2005, two tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccines were licensed
and recommended for use in adults and adolescents in the United States:
ADACEL® (sanofi pasteur, Swiftwater,
Pennsylvania), which is licensed for use in persons aged 11--64 years, and
BOOSTRIX® (GlaxoSmithKline Biologicals, Rixensart,
Belgium), which is licensed for use in persons aged 10--18 years. Both Tdap vaccines are licensed for single-dose use to add
protection against pertussis and to replace the next dose of tetanus and diphtheria toxoids vaccine (Td). Available evidence does
not address the safety of Tdap for pregnant women, their fetuses, or pregnancy outcomes sufficiently. Available data also do
not indicate whether Tdap-induced transplacental maternal antibodies provide early protection against pertussis to infants
or interfere with an infant's immune responses to routinely administered pediatric vaccines. Until additional information
is available, CDC's Advisory Committee on Immunization Practices recommends that pregnant women who were not
vaccinated previously with Tdap: 1) receive Tdap in the immediate postpartum period before discharge from hospital or birthing
center, 2) may receive Tdap at an interval as short as 2 years since the most recent Td vaccine, 3) receive Td during pregnancy
for tetanus and diphtheria protection when indicated, or 4) defer the Td vaccine indicated during pregnancy to substitute
Tdap vaccine in the immediate postpartum period if the woman is likely to have sufficient protection against tetanus
and diphtheria. Although pregnancy is not a contraindication for receiving Tdap vaccine, health-care providers should weigh
the theoretical risks and benefits before choosing to administer Tdap vaccine to a pregnant woman. This report 1) describes
the clinical features of pertussis, tetanus, and diphtheria among pregnant and postpartum women and their infants, 2)
reviews available evidence of pertussis vaccination during pregnancy as a strategy to prevent infant pertussis, 3) summarizes
Tdap vaccination policy in the United States, and 4) presents recommendations for use of Td and Tdap vaccines among
pregnant and postpartum women.
Pertussis is an acute and prolonged infectious cough illness caused by
Bordetella pertussis, a fastidious
gram-negative coccobacillus. Pertussis results in substantial morbidity among adults and adolescents whose immunity to past
childhood vaccination or B. pertussis infection might have waned and who have not received booster immunization for pertussis
adult tetanus, reduced diphtheria, and acellular pertussis (Tdap) vaccine
(1,2). In 2004, women aged 15--39
years accounted for 97% of all live births in the United States
(3). During 2000--2006, a total of 103,940 cases of pertussis
were reported to CDC's National Notifiable Diseases Surveillance System (NNDSS); 27,759 (27%) of these cases occurred
among persons aged 15--39 years (CDC, unpublished data, 2007). Parents with pertussis, including new mothers, are the
identified source of B. pertussis infection in
>25% of pertussis cases in early infancy, when rates for complications and fatalities
are highest (4--8). Infants aged <12 months accounted for 145 (93%) of 156 pertussis-related deaths reported to CDC for
2000--2006 (CDC, unpublished data, 2007). Decennial booster vaccination with adult tetanus toxoid and reduced diphtheria
toxoid (Td) vaccine has been largely responsible for reducing the average annual number of tetanus and respiratory diphtheria
cases reported during 2000--2006 to 31 and less than one, respectively. In contrast, the average annual
number of pertussis cases was 14,849 during the same period
(9--15; CDC, unpublished data, 2007).
In 2005, two Tdap vaccines were licensed in the United States:
ADACEL® (sanofi pasteur, Swiftwater, Pennsylvania) for
use in persons aged 11--64 years (16) and
BOOSTRIX® (GlaxoSmithKline Biologicals, Rixensart, Belgium) for persons aged
10--18 years (17) (Table 1). Both vaccines are
licensed for single-dose administration. Acellular pertussis vaccines formulated
with tetanus and diphtheria toxoids also are available for adults and adolescents in other countries, including an increasing
number of European countries (e.g., France, Austria, and Germany), Canada, and Australia
(18--20). No vaccine containing acellular pertussis antigens without tetanus and diphtheria toxoids is available in the United States.
Vaccinating adults and adolescents using Tdap reduces the burden of pertussis among vaccine recipients and might
prevent transmission of B. pertussis to infants
(1,2). Statements and recommendations by CDC's Advisory Committee
for Immunization Practices (ACIP) regarding use of Tdap by adults, including health-care personnel, and adolescents
(Table 2) provide background information on pertussis and extensive discussion regarding the safety and immunogenicity of Tdap
in prelicensure trials. These recommendations encourage
adult and adolescent women of childbearing age to receive Tdap at
a routine health assessment before conception to prevent the morbidity of pertussis that could occur during pregnancy
and encourage use of Tdap among adults and adolescents who anticipate contact with an infant aged <12 months both
for personal protection and to reduce the risk for transmitting
B. pertussis to the infants
In 2006, ACIP recommended routine administration of Tdap for postpartum women who were not vaccinated
previously with Tdap to provide personal protection and reduce the risk for transmitting pertussis to their infants
(1,2) . After careful consideration, in June 2006, ACIP voted to reaffirm its recommendation for use of Td in pregnant women who have
urgent indication for tetanus toxoid or diphtheria toxoid vaccination to prevent maternal or neonatal tetanus, or to
prevent diphtheria. Pregnant women not vaccinated previously with Tdap will receive a measure of protection against pertussis
by ensuring that children in the household are up-to-date with recommended doses of pediatric diphtheria and tetanus
toxoids and acellular pertussis vaccine (DTaP)*
(21--23) and that adult and adolescent household contacts have received a dose
of Tdap (Table 2) (1,2). Health-care providers can monitor pregnant women who have not received a dose of Tdap for
exposures to pertussis or to respiratory illness consistent with pertussis, and they can administer antimicrobials for
postexposure prophylaxis or treatment of pertussis, if needed, to reduce the risk for transmitting pertussis to their infants.
This report provides the background and rationale for routine administration of Tdap in postpartum women who were
not vaccinated previously with Tdap and for maintaining the previous recommendation for use of Td in pregnant women
if indicated. The safety and efficacy of using Tdap in pregnant women has not been demonstrated, and Tdap is
not recommended for use in pregnant women in any country. No evidence exists of excess morbidity or any fatality
among pregnant women ascribed to pertussis. No evidence exists demonstrating whether
Tdap in pregnant women harms the fetus or increases risk for adverse pregnancy outcomes,
transplacental antibody induced by Tdap administered during pregnancy will protect infants against pertussis, or
Tdap-induced transplacental maternal antibody will have a negative impact on an infant's protective immune
response to later-administered routine pediatric DTaP or to conjugate vaccines containing tetanus toxoid or diphtheria toxoid.
This report discusses certain situations in which health-care providers might choose to administer Tdap to a
pregnant woman. Health-care providers should weigh the theoretical risks and benefits before choosing to administer Tdap vaccine to
a pregnant woman.
During June 2006, ACIP evaluated the limited evidence available concerning safety, immunogenicity, and
pregnancy outcomes after administration of Tdap; evidence from historic use of pertussis, tetanus, and diphtheria vaccines in
pregnant women; and the potential effects of transplacental maternal antibody on the infant's immune response to active
immunization with pediatric diphtheria and tetanus toxoids and whole-cell pertussis (DTP) or DTaP vaccines, or to conjugate
vaccines containing tetanus toxoid or diphtheria toxoid. The evaluation included a synthesis of information from scientific
literature published in English, unpublished sources of information, consultations, analyses, and extensive discussion by an
ACIP working group during 2005--2006. The working group comprised persons with expertise in pertussis, tetanus,
and diphtheria; obstetrics and gynecology; pediatrics, family practice, internal medicine, immunology, public health, and
vaccine regulation; and liaison members from partner
The workgroup considered multiple diverse views on the adequacy of evidence needed to form a recommendation for use
of Tdap in pregnant and postpartum women. A minority view held that available data from nonpregnant women and men,
and experience with the use of Td in pregnant women to prevent neonatal and maternal tetanus, were sufficient to support
a recommendation for the safe use of Tdap in pregnant women for individual protection from pertussis. The
majority view, while acknowledging the desirability of preventing pertussis in pregnant women and the substantial body of
information demonstrating the usefulness of Td to prevent maternal and neonatal tetanus, held that the evidence was
insufficient at this time to support a recommendation for
routine administration of Tdap in pregnant women. The specific issues for
pertussis differ from those for tetanus and diphtheria. Important among these is the limited understanding of immunity and
correlates of protection for pertussis. In
addition, data supporting the safety of vaccinating pregnant women with Tdap to
prevent pertussis are scarce for women, their fetuses, and pregnancy outcomes. Whether transplacental maternal antibody exerts
an inhibitory or other effect on the infant-protective immune response to active immunization with pediatric DTaP or
conjugate vaccines containing tetanus toxoid or diphtheria toxoid has not been studied. Protection against infant pertussis
through Tdap-induced transplacental maternal antibody has not been demonstrated. Until additional information is available,
the majority view of the working group held that Tdap administered to women in the immediate postpartum period, in
addition to ensuring pertussis vaccination of close contacts, would likely provide a measure of protection for mother and infant.
B. pertussis, the organism that causes
pertussis,elaborates multiple toxins, including tracheal cytotoxin, which damages
the respiratory epithelial tissue in vitro
(24), and pertussis toxin, which has systemic effects (e.g., promoting lymphocytosis)
(25). Illnesses caused by other species of Bordetella are not considered preventable by available pertussis vaccines
B. pertussis infections and reinfections among adults and adolescents can be asymptomatic or range from a mild
cough illness to the severe, prolonged cough illness of classic pertussis
(28). The clinical presentation of pertussis can be similar
to that for respiratory illness caused by B. parapertussis,
B. bronchiseptica, B. holmseii, Mycoplasma
pneumoniae, Chlamydia (Chlamydophila) pneumoniae, and multiple viral agents (e.g., adenovirus, parainfluenza virus,
human metapneumovirus, influenza virus, rhinovirus, and coronavirus). The incubation period for pertussis typically is 7--10
days (range: 5--21 days) (29,30).
Classic pertussis is characterized by three phases: catarrhal, paroxysmal, and convalescent
(28,29). The catarrhal phase lasts 1--2 weeks and consists of a watery nasal discharge and frequent cough, frequent sneezing, and injection of the
conjunctiva, often with lacrimation. The cough typically suggests tracheal irritation (e.g., a tickle in the throat) and is short, sharp,
hacking, and isolated (as distinguished from paroxysmal). The cough is equally persistent during day and night and rarely croupy
or hoarse. Fever is uncommon during any phase unless the illness is complicated by secondary infection or coinfection
(28). The paroxysmal phase lasts 2--6 weeks. The patient has intermittent periods of intense coughing (paroxysms) alternating
with periods of appearing relatively well with a normal respiratory rate. The paroxysms are characterized by spasms of
coughing, choking, posttussive vomiting, and inspiratory whoop
(29,31). Adults experience greater severity
of illness than adolescents, including cough-related incontinence in 28% of cases in women; in up to 5% of cases, adults and adolescents experience
or more rib fracture, syncope, or pneumonia, or they require hospitalizations
(1,2,31,32). Approximately one third of
adults and adolescents lose weight during the illness
(31,33). Anecdotal reports of pneumothorax, seizures, stroke, and
other complications have been summarized previously
(1,34). The convalescent phase of pertussis typically lasts 2--6 weeks
(35). Symptoms can persist for >6 months
(1,2). Factors that can lessen the severity of
B. pertussis infection include
residual immunity from previous infection or vaccination and use of macrolide antimicrobials in the catarrhal (early) phase of
the illness (36).
Adults and adolescents with pertussis make repeated medical visits and miss work and school. During 1998--2000
in Massachusetts, among 936 adults and 1,679 adolescents
reported with confirmed pertussis, the median number of
medical visits was two (range: 0--15) (31). Among 203 adults and 314 adolescents with confirmed pertussis who
were interviewed during 2001--2003, 158 (78%) adults were
employed. Of these employed adults, 123 (78%) missed work
(mean: 9.8 days; range: 0.1--180 days); 261 of the 314 (83%) adolescents missed school (mean: 5.5 days; range: 0.4--32
days). Among primary caregivers for adolescents, 136 of
314(43%) missed work (mean: 2.4 days; range: 0.1--25 days); a
second caregiver in 53 families also missed work (mean: 1.8 days; range: 0.1--11 days)
Pertussis is transmitted from person to person via large respiratory droplets generated by coughing or sneezing;
early reports suggested that B. pertussis can be recovered from dried mucus for up to 3 days
(28,30). Pertussis is highly
infectious, with attack rates among exposed, nonimmune household contacts as high as 80%--90%
(29,37,38). The most infectious periods are the catarrhal and early paroxysmal phases
(28). Untreated patients, particularly infants, remain infectious for
6 weeks or longer (29). Among older children and adults with previous vaccination or infection, the infectious period typically
is <21 days (29).
In a Canadian study conducted in 1999, a source was identified in 60%--70% of adults and adolescents with
pertussis. Among adults aged 18--39 years, the source was a person in the household in 25%--44% of cases or at work or school
in 17%--25% of cases. Among adolescents aged 12--17 years, the source was a person in the household in 9% of cases and
a friend or person at school or work in 51% of cases
Pertussis During Pregnancy
Case reports suggest that the morbidity of pertussis is not increased among pregnant women compared with
nonpregnant women. In a general medical practice during 1979--1980, four pregnant women had onset of cough during the 12th,
14th, 14th, and 36th week of gestation and cough that lasted 36, 6, 8, and 6 weeks, respectively; two women had vomiting
after coughing and worsening cough paroxysms at night; and one woman developed hemoptysis and subconjunctival
hemorrhage after repeated and forceful coughing paroxysms
(40). A 1993 case report described a pregnant woman who was hospitalized
6 days before delivery for severe paroxysms and posttussive emesis
(41). In a series of 32 women who had pertussis
during pregnancy or at term, the illness was characterized as "a very tiresome disease"; no obstetric complication was reported, and
no infant was premature (42). No pertussis-related deaths have been reported in pregnant women. The source of pertussis
in infected pregnant women has not been examined systematically.
Reports of fetal morbidity among pregnant women with pertussis are rare, and no causal relationship with abnormal
fetal development, fetal morbidity, or adverse outcome of pregnancy has been confirmed. One fetus of a mother who had
severe paroxysmal coughing early in pregnancy had an extradural hematoma that was identified by ultrasonography and
magnetic resonance at 31 weeks' gestation; studies had been normal at 12 and 22 weeks' gestation
(43). Another fetus of a mother who had pertussis during the first trimester had prenatal diagnosis of laryngotracheal obstruction
Infants aged <12 months typically have the most severe pertussis, often requiring hospitalization for respiratory or
other complications (Table 3) (8,45--49). The risk for pertussis death or severe pertussis is highest among infants in the first
6 months of life and remains elevated until infants have received
1--2 doses of pediatric DTaP
(8,50,51). During 2000--2006, the average annual incidence of pertussis among infants aged
<6 months was 111 cases per 100,000 population; for
infants aged 6--11 months, incidence was 19 cases per 100,000 population (CDC, unpublished data, 2007).
Complications and deaths from infant pertussis have been characterized by necrotizing bronchiolitis
(52) and high rates of primary or secondary pneumonia and/or coinfection with bacterial and viral pathogens
(8,28,47,53). Since 1993, pulmonary
hypertension has been increasingly recognized among fatal infant cases
(47,52,54--58). The majority of all infant deaths
have occurred among unvaccinated infants
(47,53,58; CDC, unpublished data, 2007). Hispanic infants and infants born
at estimated gestational age <37 weeks or with low birth weight have comprised a larger proportion of pertussis deaths
than would have been expected on the basis of population estimates
(47,53,58). Compared with the prevaccine era, during
2000--2006, the proportion of reported pertussis deaths among infants aged <3 months increased from 37% to 83%
(Figure 1) (38,47; CDC, unpublished data, 2007).
Since the 1970s, parents, especially mothers, have been identified as the most important source of infant pertussis;
however, a source has been identified in only 30%--60% of cases investigated
(5--7,34,38,42,48,59--68). One or more
household contact with pertussis is the source of pertussis in
approximately 75% of cases among infants aged <6 months for whom the source is identified. A parent is implicated in approximately 25% of cases in infants, including the mother in 16%--19%
of cases. A sibling is implicated as the source of transmission in <10% of cases
Mathematical modeling evaluating different vaccine strategies for the United States has suggested that pertussis
vaccination of 90% of household contacts (children, adolescents, and adults) of newborns, in addition to pertussis vaccination of 75%
of adolescents generally in the population, might prevent approximately 75% of pertussis cases among infants aged 0--23
months (69). Another model estimated vaccination of
both parents of an infant before discharge from the hospital could prevent 38%
of infant cases and deaths (70). However, the efficacy of these strategies in practice has not been evaluated.
Although pertussis is a nationally notifiable disease in the United States
(71), data on the pregnancy status of women
with pertussis have not been collected. However, the burden of pertussis among pregnant women is likely to be similar to
the burden among other adults in the population. Pertussis reports typically demonstrate increases in
activity every 3--4 years (72); aside from these cycles of activity, the number of reported cases of pertussis in the United States has increased gradually
since 1976. During 2004--2005, more than 25,000 cases were reported per year
(Figure 2). During 2006, a total of 15,632 pertussis cases were reported, including 2,029 (13%) cases among infants, 5,045 (32%) cases among children aged
1--14 years, 5,148 (33%) cases among persons aged 15--39 years, and 3,331 (21%) cases among adults aged
>40 years. A total of 40 pertussis-related deaths were reported in 2005 and 16 in 2006; 39 (98%) of these deaths occurred among infants in 2005
and 14 (88%) in 2006 (CDC unpublished data, 2007). Prospective and serologic studies suggest that pertussis infection
and reinfection are underrecognized among adults and adolescents
(29,73--75). The pertussis burden is believed to be
substantially more than the number of reported cases; approximately 600,000 cases are estimated to occur annually just among
Transmission in Obstetric and Neonatal Health-Care Settings
Health-care personnel can transmit B.
pertussis in health-care settings if pertussis has not been considered by hospital
staff (1,77,78). Outbreaks have been documented in prenatal and postnatal clinics
(79,80), maternity wards
(51,62,81--83), neonatal nurseries, and neonatal intensive-care services
(62,81,84--90). Ongoing transmission is facilitated by delay
in isolation and treatment of patients and in prophylaxis of contacts and by inconsistent use of face or nose and
mouth protection (1,85,87,91). Unprotected exposures to pertussis in health-care settings can result in labor-intensive,
disruptive, and costly investigations and control measures, particularly when the number of contacts is substantial
(80,92). Pertussis transmitted to health-care personnel or patients can result in substantial morbidity (and on rare occasions in fatal
disease) among hospitalized infants
Health-care personnel who have not been vaccinated with Tdap (Table 2) can be an important source of pertussis
and pertussis outbreaks in obstetric and neonatal settings. A wide range of health-care disciplines have been implicated,
including physicians, resident physicians, and students
(80,82, 85,95); nurses and nurse midwives
(51,81,85,87,96--98); and aides, medical assistants, and educators
(1,51,78,79,81,82, 85,87). Pregnant and postpartum women with unrecognized
pertussis and visitors to prenatal, obstetric, and neonatal units, including fathers and other close relatives, pose a substantial risk
for transmission to infants, pregnant women, and health-care personnel and have been associated with outbreaks in these
settings (6,41,62,80,81,84--86,93,98). Early recognition and treatment of pertussis in pregnant and postpartum women
and prophylaxis of household contacts who visit health-care settings is critical to prevent continuing transmission.
treatment for women who have pertussis near term or at delivery and prophylaxis for their newborns and household contacts
are effective in preventing further transmission
The diagnosis of pertussis is complicated by the limitations of currently available diagnostic tests. The only
pertussis diagnostic tests that are accepted to confirm a case for purposes of national reporting are culture and polymerase
chain reaction (PCR) (when the clinical case definition also is met)
(100; Box 1). Multiple factors affect the sensitivity,
specificity, and interpretation of diagnostic tests for pertussis
Culture to isolate B. pertussis is essential for identifying the organism early in the course of disease
(103) and for antimicrobial susceptibility testing, if indicated. Isolation of
B. pertussis by culture is 100% specific; for optimal yield,
culture requires specimens that contain nasopharyngeal cells obtained by aspirate or nasopharyngeal swab and special medium
for growth. The sensitivity of culture early in pertussis varies (range: 30%--60%)
(103--105). Outside of infancy, the yield
of B. pertussis declines to 1%--3% in specimens taken in the third week of cough illness or later, after starting
antimicrobial treatment, or in a patient who was vaccinated previously
(106,107). B. pertussis can be isolated in culture as early as 72 hours
after plating but requires 1--2 weeks before a result can
definitively be called negative (108).
Polymerase Chain Reaction
DNA amplification (e.g., PCR) to detect B. pertussis has increased sensitivity and more rapid turnaround time
(109--111). When symptoms of classic pertussis are present (e.g., >2 weeks of paroxysmal cough), PCR can be two to three times
more likely than culture to detect B. pertussis in a known positive sample
(101,103,112,113). As with culture, the PCR result
is affected by the technique used to collect the specimen; a poorly taken nasopharyngeal swab is more likely to be negative
by both culture and PCR. PCR is less affected than culture by antimicrobial therapy because the organism does not need to
be viable for the test to be positive. Adults and adolescents who have specimens taken later in the course of illness, who
have started antibiotic treatment, or who were vaccinated previously tend to have PCR-positive, culture-negative test
Although PCR testing for pertussis has been available for nearly 20 years
(115), no U.S. Food and Drug Administration (FDA)--licensed PCR test kit is available. The analytical sensitivity, accuracy, and quality control of PCR-based
B. pertussis tests vary widely among laboratories. PCR assays used by the majority of laboratories amplify a single gene
sequence, typically within the insertion sequence IS481. Both false-positive and false-negative results have been reported with these
assays; reported outbreaks of respiratory illness mistakenly attributed to pertussis have resulted in unnecessary
investigation and treatment, and unnecessary chemoprophylaxis of contacts
(112,116--119). Using more than one genetic
target and consensus interpretation criteria for PCR diagnosis of pertussis
(120,121) has been suggested as a way to provide increased assurance
of specificity (122) and to allow discrimination between Bordetella species.
Other Diagnostic Tests
Direct fluorescent antibody (DFA) tests provide rapid
results (within hours), but sensitivity (10%--50%) is less than
with culture (123). With use of monoclonal reagents, the specificity of DFA should be >90%. However, interpretation of the test
is subjective, and, when interpreted by an inexperienced microbiologist, the specificity can be lower
(110). Diagnosis of pertussis by serology requires a substantial change in titer for pertussis antigens (typically fourfold) from acute (<2 weeks after
cough onset) to convalescent sera (>4 weeks after the acute sample). The results typically become available too late in the course
of the illness to be useful clinically. Single-sample serologic tests for antipertussis toxin (anti-PT) IgG have been developed
for research purposes; sera must be collected at least 2 weeks after the onset of symptoms
(124). Pertussis serology assays using commercial reagents are available, but these assays are not validated clinically and do not differentiate between recent
and remote infection and vaccination
(125,126). No serologic assay is licensed by FDA for routine diagnostic use in the
Postexposure Prophylaxis and Treatment
A macrolide (erythromycin, azithromycin, or clarithromycin)
is the preferred antimicrobial for postexposure prophylaxis
and treatment of pertussis (127). Antimicrobial treatment administered in the early (catarrhal) phase of the illness can modify
the severity of the symptoms (36,128,129). An antimicrobial generally does not modify the severity or the course of the
illness after paroxysmal cough is established but is used to eliminate
B. pertussis and halt transmission
(36,127--129). Without use of an effective antimicrobial,
B. pertussis can be recovered for 6 weeks or longer from infant patients and for 21 days or
longer from adult and adolescent patients. Detailed
recommendations, indications, and schedules for postexposure
antimicrobial prophylaxis and treatment of pertussis have been published previously
Pregnant women with pertussis near term and other household contacts with pertussis are an important source of
pertussis for newborn infants
(6,41,42,62,64,99). Antimicrobial treatment and prophylaxis are effective in preventing transmission
of pertussis to neonates. A macrolide is administered to a woman with pertussis that is acquired late in pregnancy or
shortly before delivery, her household contacts, and the neonate. Early recognition of pertussis in a pregnant woman is necessary
to ensure the effectiveness of this approach
Pregnancy is not a contraindication for use of erythromycin, azithromycin, or clarithromycin. Erythromycin
and azithromycin are listed as FDA Category B drugs, and clarithromycin is listed as a Category C drug
(130--132). Macrolides can interact with a variety of other therapeutic agents, precluding concurrent use. Although macrolides can
have gastrointestional side effects (e.g., nausea and vomiting),
seriousside effects (e.g., hepatic dysfunction or
pseudomembranous colitis) are rare (127). Infants aged <1 month who receive erythromycin are at increased risk for infantile hypertrophic
pyloric stenosis (83,133--136). For this reason, and because azithromycin is associated with fewer adverse effects than
erythromycin, azithromycin is the preferred antimicrobial for prophylaxis of neonates exposed to pertussis
(127). Infantile hypertrophic pyloric stenosis has been reported in two preterm infants who received azithromycin for postexposure prophylaxis
(137); however, a causal association between infantile hypertrophic pyloric stenosis and azithromycin has not been established.
Immunity to Pertussis
The mechanisms of protection against pertussis are incompletely understood. On the basis of studies in animals
and humans, both humoral and cellular immunity are believed to play a complementary role
(138--143). The protection that results from
B. pertussis infection or pertussis vaccines persists for an estimated 5--10 years or more. Protection wanes
over time, leaving persons susceptible to infection or reinfection
Humoral Immunity to Pertussis Vaccine Antigens
Immune responses to B. pertussis can be directed variably against a range of pertussis toxins and antigens. No level
of antibody, presence of specific antibodies, or antibody profile has been accepted universally as a quantifiable serologic
measure of protection (139,141,151--158). Studies of parenterally administered immune globulins for postexposure
prophylaxis (159,160) or for treatment of pertussis
(28,161--165) report mixed results and do not clarify the role of passive antibodies
in prevention or treatment of pertussis. By extrapolation, these results do not help predict the role of transplacental
maternal antibodies in infant protection.
Pertussis toxin (PT), previously called lymphocytosis promoting factor (LPF), is considered one of the most important of
a range of clinically relevant toxins and virulence factors of B. pertussis (including pertactin or 69-kDa protein [PRN],
fimbriae types 2 and 3 [FIM], filamentous hemagglutinin [FHA])
(140,142,152,157,166--169). Detoxified PT is a component of
all pertussis vaccines. The preventive efficacy of a pediatric DTaP vaccine containing detoxified PT as the only
immunizing antigen was 71% (95% confidence interval [CI] = 63%--78%) against classical pertussis
(170). However, the contribution to protection by anti-PT varied in analyses of the humoral immune responses to specific vaccine antigens when evaluated in
two household studies. Elevated concentrations of anti-PRN and anti-FIM were associated most closely with protection in
these (152,157) and other studies
(171). Evidence of added protection from anti-FHA has been mixed
Cellular Immunity to Pertussis Vaccine Antigens
Cell-mediated immune mechanisms clear
B. pertussis from within macrophages and other cells
(52,139,174--177). In addition to humoral immune responses, B. pertussis antigens in acellular pertussis vaccines induce cell-mediated
immune responses (178) after primary immunization with pediatric DTaP among infants
(158,179), after booster vaccination among
children (140,141,149), and after booster vaccination with reduced pertussis antigen content vaccines among
adolescents (178,180--183) and adults
(183,184). Protection is maintained among children whose antibody levels drop
below the level of detection over time (185) suggesting that cell-mediated immunity is an important component of protection.
Cell-mediated immune responses remain measurable substantially longer than antibodies to the same antigens, particularly PT, and the
cell-mediated immune responses to initial doses of pertussis vaccines are believed to correlate better with long-term immunity
than antibody responses
Prevalence of Pertussis-Specific Antibodies: Pregnant Women and their Infants
Although the importance of antipertussis activity in sera relative to protection remains uncertain, studies conducted
since the 1930s have determined the prevalence of antipertussis activity in sera from mothers and infants using
multiple assays (Tables 4--8)
(37,154,186--199). Detectable pertussis-specific antibodies have been identified in unvaccinated
women without a history of pertussis
(28,187,190,192), women with a past history of pertussis
(28,187,190,192), women who likely received whole-cell pertussis vaccine during childhood
(195,196,198--200), and women with a recent history of
pertussis (99). With the exception of women with recent pertussis, the majority of pregnant women have low geometric
mean concentrations (GMCs) of anti-PT and antibodies to other pertussis antigens (Tables 4--8)
(159), consistent with generally low concentrations of antipertussis antibodies among adults surveyed in the general population
(147,201--205). GMCs of pertussis-specific antibodies among pregnant women typically have been low regardless of age, as demonstrated in
a predominantly (80%) African-American population reported in 2005
(199). A 2006 study of pregnant Hispanics found
lower GMCs among adolescents than among women aged >20 years (198).
The efficiency of maternal-fetal transfer of IgG antibodies to pertussis-specific antigens varies; the majority of
investigators report similar antigen-specific concentrations in cord or neonatal infant sera and in maternal sera measured late in
pregnancy or at delivery (195--200), but higher concentrations in cord or neonatal sera than in maternal sera have been reported,
which might indicate active transport in certain settings (Tables 7 and
(195,197,199). In a 2005 survey of mothers and
their infants, anti-PT, anti-FHA, and anti-PRN were detected in maternal sera from 35%, 95%, and 80% of women,
respectively, and in cord sera from 45%, 93%, and 81% of infants, respectively
(199). Among 17 infants studied in 1990, the half-life
of transplacental maternal antibody was 36.3 days for anti-PT, 40.3 days for anti-FHA, and 55.0 days for pertussis
agglutinins (195). Transplacental maternal antibody was not detectable or was negligible in the majority of infants by age 6--8
weeks (195,197) or by age 4 months
(195), consistent with the results of early studies
(186). By contrast, in a study of 23 unvaccinated Swedish infants whose mothers had pertussis late in pregnancy, five infants had neutralizing antibody
detectable as long as 14 months and detectable anti-PT for 5 months or longer
Kinetics of Pertussis Booster Vaccination in Nonpregnant
Adults and Adolescents
The majority of adults and adolescents have had exposure to
B. pertussis, pertussis antigen--containing vaccines, or both,
and they will have a booster response to vaccination with pertussis antigens
(184,206). A rise in antibodies is measurable by 7
days after vaccination (207), and GMCs reach near-peak levels by 2 weeks after booster vaccination
(207--210). Antibody concentrations decline rapidly in the first few months following vaccination, after which the rate of decline
slows (157,181,209,211). Anti-PT levels decline more rapidly than anti-PRN or anti-FHA levels. Among adults who received
a booster dose of an acellular pertussis vaccine without tetanus or diphtheria toxoids, concentrations of IgG anti-PT and
anti-PRN declined 58% and 39%, respectively, after 6 months. By 18 months after vaccination, concentrations declined 73%
and 56%, respectively (209).
Vaccinating Pregnant Women against Pertussis
No prelicensure studies were conducted with Tdap in pregnant women. In 2005, to increase understanding of the safety
of Tdap in relationship to pregnancy, both Tdap manufacturers established registries to solicit voluntary reports of
pregnant women who received Tdap during pregnancy or who received Tdap and were determined subsequently to be
pregnant (212,213). The main utility of the registries is to signal the possibility and nature of any risk
(214). All women who are vaccinated with Tdap at any time during pregnancy should be reported to the registry as early as possible during
the pregnancy. Information from pregnancy registries differs from surveillance reports, which are used to evaluate
among women when an adverse outcome of pregnancy already might have occurred (e.g., an infant born with a birth
As of December 31, 2007, GlaxoSmithKline had received five reports of pregnancy exposure to
BOOSTRIX® within 28 days before conception or during any trimester of pregnancy, including two in the first trimester, one in the second
trimester, and two during an unknown trimester. Among the two first-trimester exposures, one subject delivered a normal infant at
33 weeks' gestation, and one subject was lost to
follow-up. Of the remaining exposures, information on the outcome of
two pregnancies was not yet available, and one subject was lost to follow-up (GlaxoSmithKline, unreported data, 2008).
As of November 23, 2007, sanofi pasteur had received 107 spontaneous reports and 47 reports from
postlicensing surveillance studies of exposure to
ADACEL® during pregnancy. For these 154 reports, pregnancy outcomes were 68
live infants (including 64 term deliveries [one with a congenital anomaly] and four preterm deliveries [one at 28 weeks
after complications of pregnancy, labor, and delivery; two at 35 weeks for preeclampsia; and one at 35 weeks for
breech presentation]); three spontaneous abortions (at 9, 51, and 99 days postvaccination); three induced abortions; and one
fetal demise (at 35 days postvaccination). For 32 reports, either the outcome of pregnancy was unknown or the patient was lost
to follow-up, and for 47 reports, information on outcome of pregnancy was not yet available (sanofi pasteur,
unreported data, 2008).
A retrospective survey of 4,524 health-care personnel vaccinated in a mass vaccination campaign conducted in
2006 provides additional information regarding adverse reactions in pregnant women within 14 days of receiving
Tdap (ADACEL®) (215,216). Pregnancy was not an exclusion criterion for Tdap; 24 health-care personnel who received
Tdap identified themselves as pregnant at the time of vaccination. Among 2,676 (59%) survey respondents, 1,792
(67%) received Tdap at an interval of >2 years after their most recent dose of Td; 17 of these respondents identified themselves
as pregnant. Adverse reactions reported by the 17 pregnant women were compared with reactions reported by 472
nonpregnant female personnel aged 18--44 years. The frequencies of injection-site pain, redness, and swelling of moderate to
severe intensity were not greater among the pregnant women than among the nonpregnant women. Three of the
pregnant women reported feeling "feverish" after receiving Tdap. None of the 17 pregnant women reported seeking nonroutine medical
attention for the adverse reaction (215,216). Among the pregnant women vaccinated with Tdap, results of the outcome of pregnancy
were known for 10 women; no pregnancy resulted in premature birth or abnormality in the infant when assessed shortly after
birth (Elizabeth A. Talbot, Dartmouth College, Lebanon, New Hampshire, personal communication, 2007).
Whole-Cell Pertussis Vaccine
Five clinical trials conducted during the 1930s and 1940s evaluated vaccinating pregnant women with whole-cell
pertussis vaccine as a strategy to increase the levels of maternal pertussis-specific antibodies transferred to their infants via the
placenta (Table 9) (186,189,190,192,193,217). The protective efficacy of the vaccine against pertussis in the women was not
a consideration. Whole-cell pertussis vaccine was prepared from sterile extracts of killed
B. pertussis. To maximize the passive transfer of maternal antibody, pregnant women were vaccinated with 2--6 doses at 1- to 2-week intervals during the
Local reactions to vaccination in the pregnant women were common, some of which were severe. Systemic reactions
were uncommon, adverse pregnancy outcomes were not reported (Table 9)
The majority of women had substantial rise in titer to
B. pertussis antigens in postvaccination sera compared with
prevaccine titers (Tables 4--6)
(186,189,190,192,193,217). Neither history of pertussis
(190,192) nor preexisting titers of antibodies
in the women correlated with maternal titers after vaccination
(193). The majority of infant antibody titers were lower
than (186) or similar to maternal titers
(37,150,186,187,189--193). Infant titers exceeded maternal titers in certain cases
although higher titers might have been within the range of assay variation
In subsets of infants in two studies, the duration of detectable transplacental pertussis antibodies was followed
among unvaccinated infants (186,217). The mothers in both studies had received 3 doses of whole-cell pertussis vaccine during
the third trimester. The mean of the agglutinin titers among 13 infants in one study dropped
from 1:160§ at birth to 1:80 at age
2 months; titers no longer were measurable at "a few months of age"
(186). Of 36 infants with high agglutinin titers
at birth in the other study, 16 (44%) had titers of
>1:300 at age 3 months. None of 9 infants followed to age 6 months had a titer
of 1:300 (217).
Infant Protection by Transplacental Maternal Antibody
The role of transplacental maternal antibody in infant protection against pertussis remains uncertain. Prevaccine
era observations concluded that infants have no "congenital
immunity" and are susceptible to pertussis from the "day of
birth," with the possible exception of an infant whose mother had pertussis during pregnancy
). Transplacental maternal antibodies might explain the smaller proportion of infant pertussis deaths observed in the first
month of life compared with the second and third months of life (Figure 1)
(35,45). An alternative explanation might be that
parents avoid exposing newborn infants to ill contacts
Two retrospective surveys were conducted after early vaccine trials in pregnant women to assess infant protection
(217,220). In one survey conducted during the 1940s, a subset of 100 (59%) of 170 women who received 6 doses of whole-cell
pertussis vaccine during the third trimester and 100 women who were not vaccinated were questioned regarding pertussis in
their infants during the first year of life. During the first 6 months of life, eight exposures (three of which were "close
exposures") and no cases of pertussis were reported among
infants whose mothers had been vaccinated, and six exposures and three
cases of infant pertussis were reported among infants whose mothers had not been vaccinated. From age
6--11 months, two cases of infant pertussis were reported in each group
(220). In a second survey by the same investigators, a subset of 66 (62%) of
106 women who received 3 doses of whole-cell pertussis vaccine during the third trimester
reported two exposures and no case of pertussis among their infants during the first 6 months of life
(217). The results of these surveys suggested that
high concentration of transplacental pertussis antibodies might provide a degree of infant protection against pertussis in the first
6 months of life (217,220).
Inhibitory Effect of Transplacental Maternal Antibody on Infant Immunization
Transplacental maternal antibodies to pertussis antigens can interfere with the infant's response to active immunization
with the pertussis components of pediatric DTP and pediatric DTaP
(221). A proposed mechanism for the interference
with pertussis and other vaccine antigens is maternal antibody binding to vaccine antigens, masking the vaccine antigens from
the infant's B cells. Infant antigen-presenting cells also might take up maternal antibody-vaccine antigen complexes
stimulating selective T-cell responses without humoral immune responses to the vaccine antigens
(221--223). The concentrations and specificities of the maternal antibodies for vaccine-antigen epitopes contributes to the degree of interference
(221,223--225). The inhibitory effect of transplacental maternal antibody can be detectable for a few weeks or for more
than 1 year (221,222,224--228). As transplacental
maternal antibody declines over time, a threshold is reached when the
infant's immune system responds to vaccine antigens in subsequent doses. In theory, the threshold concentration of
residual maternal antibody could be lower than the concentration of antibody needed for infant protection, but this concentration
is not known for pertussis. In this setting, a theoretical window of "relative
susceptibility"exists for the infant until the
infant mounts a humoral immune response to a subsequent dose of vaccine
Interference with Pertussis Responses to Pediatric DTP
Substantially lower concentrations of infant IgG anti-PT result after 3 doses of pediatric DTP among infants with
"high" (variably defined) prevaccination levels of maternal IgG anti-PT, than among infants with "low" or no
measurable prevaccination level of maternal IgG anti-PT
(195, 230--233). The post-dose 3 concentrations of infant anti-PT in one
study were 28% or 56% lower with each doubling of the concentration of transplacental maternal anti-PT, respectively, for the
two DTP products studied (p <0.05)
(233). The reductions in post--dose 3 concentrations also were significant for
anti-FIM (18% lower) and agglutinins (15% lower) for one DTP product, and for anti-FHA (16% lower) for the other DTP
product, with each doubling of the concentration of the specific transplacental maternal antibodies (p
Interference with Pertussis Responses to Pediatric DTaP
Transplacental maternal IgG anti-PT might interfere less with infant responses after 3 doses of pediatric DTaP than
after pediatric DTP (195,196,230,233). The percentage
decrease in post--dose 3 infant antibody response with each doubling
of the concentration of maternal antibodies was 3% for anti-PT (not statistically significant), but was 13% for anti-PRN,
17% for anti-FIM, 10% for agglutinins, and 8% for anti-FHA (all statistically significant; p
<0.05) when results from several DTaP products were combined in one study
(233). The difference between interference by maternal antibody with infant
responses to DTP and DTaP might result from the higher content of pertussis-specific antigens in pediatric DTaP than in
DTP relative to the concentration of transplacental maternal antibody
(159,222). In addition, the maternal
antibodies induced by the mothers' childhood DTP vaccinations might have less specificity for the pertussis vaccine antigens in
acellular pertussis vaccines (222,234--236).
Noninterference with Pertussis Cellular Immune Responses to Pediatric DTP or DTaP
Infants who have relatively poor humoral immune responses to active immunization with whole-cell or acellular
pertussis vaccine in the presence of inhibitory concentrations of transplacental maternal antibody have evidence of T-cell priming
for booster (anamestic) responses (158,237). Protection against pertussis in T-cell primed infants in the absence of
specific humoral antibodies has not been established
Existing data do not provide evidence that human colostral pertussis antibodies contribute to infant protection,
although pertussis-specific antibodies present in the mother are found in colostral milk
(186,190,242). Protection studies in animal models suggest human and animal colostral-derived pertussis antibodies can protect animals when the antibodies
are absorbed or injected parenterally
(243--245); however, the relevance of these studies for human infants is
uncertain (190,246,247). Human breast milk antibodies do not enter the human neonatal circulation from the intestine in
substantial amounts. In contrast, infant pigs, horses, ruminants, dogs, and cats acquire the majority of neonatal protection
through intestinal uptake of colostral antibodies
(245,248--250). Maternal antibodies in human milk do not interfere with the
infant immune response to pediatric vaccines
Tetanus is caused by Clostridium tetani spores, which are ubiquitous in the environment. Spores enter the body
through disrupted skin or mucus membranes. When inoculated into oxygen-poor sites (e.g., necrotic tissue or wounds),
C. tetani spores germinate to vegetative bacilli that elaborate tetanospasmin, a potent neurotoxin. More than 80% of cases of tetanus
are of the generalized syndrome; the remaining cases are localized or cephalic. Persons with generalized cases typically have
trismus (lockjaw), followed by rigidity and painful contractions of the skeletal muscles that can impair respiratory function.
Glottic spasm, respiratory failure, and autonomic instability can result in death. The onset of tetanus typically is within 7 days of
the injury (range: 0--112 days) The course of tetanus is up to 4 weeks or longer, followed by a prolonged period of
Obstetric and Neonatal Tetanus
Obstetric tetanus is defined as tetanus during pregnancy or with onset within 6 weeks after the termination of
pregnancy (253). Obstetric tetanus occurs after contamination of wounds or abrasions during pregnancy or after unclean deliveries
or abortions. In a review covering 1941--1990, an estimated 65%--80% of cases of obstetric tetanus occurred in the puerperal
or postpartum period; the majority of the other cases occurred after surgical or spontaneous abortions
Obstetric tetanus has the highest mortality when the incubation period is short and respiratory complications are
present (255). Cases can be complicated by gram-negative sepsis
(256). Case-fatality rates vary (range: 16%-->50%); higher
fatality rates are reported from places where access to medical intensive care is limited
(255,257,258). Case-fatality rates
historically have been higher for postabortal than for postpartum obstetric tetanus
Neonatal tetanus (tetanus neonatorum) is associated with contamination of the umbilical stump. In nearly all cases of
infant tetanus, onset occurs in the first month of life. Symptoms commonly begin at 3--14 days of life and are characterized
by increasing irritability and difficulty feeding. Signs of neonatal tetanus are similar to tetanus in older age groups.
Case-fatality rates vary (range: 10%--100%)
(252,259). Infants who survive can have residual neurologic injury (e.g., cerebral palsy
and psychomotor retardation) (252).
Tetanus is a nationally notifiable disease in the United States
(260). In 2006, a total of 41 cases were reported. No
cases occurred among women aged 15--19 years or those aged
30--39 years. One case occurred among women aged 20--29
years, and three cases occurred among women aged 40--49 years. None of the women died. During 1972--2006,
case reporting forms did not collect information regarding pregnancy; however, no case of obstetric tetanus was identified
among more than 1,000 reports to NNDSS (CDC, unpublished data, 2006). In 1999, tetanus-specific coding became available
in CDC's mortality database; no case of tetanus-associated
obstetric death was reported through 2005, the most recent year
for which data are available (CDC, unpublished data, 2008).
During the 1950s, approximately 100 neonatal tetanus deaths were reported annually in the United States, and
neonates comprised more than one third of tetanus deaths in all age groups
(261,262). During 1972--2006, the cumulative number
of reported neonatal tetanus cases decreased to 32; the most recent cases were reported in 1989, 1995, 1998, and 2001
(263). Among these 32 neonatal cases, 27 (84%) births occurred in a nonhospital setting; 30 of 31 mothers with available
history reported never having received a dose of tetanus toxoid vaccine
(264--266; CDC, unpublished data, 2006).
Diagnosis and Treatment
The diagnosis of tetanus is clinical and is supported by a compatible setting, immunization history, and exclusion of
other possible diseases. Anaerobic cultures of tissues or aspirates for
C. tetani typically are not positive. Low or undetectable levels
of serum antitoxin at the time of onset are compatible with the diagnosis of tetanus, but higher levels of antitoxin do not
exclude the diagnosis (252,267). Electromyography might aid in the diagnosis of certain cases
(268). Postpartum eclampsia, which typically occurs within the first few days after delivery, was the most important disease in the differential diagnosis
in community-based studies (254).
Treatment of tetanus is directed at neutralizing unbound toxin with administration of human tetanus immune
globulin, removing the source of infection through debridement, and use of an antimicrobial (e.g., metronidazole). The control
of rigidity and spasms, attendant respiratory and autonomic dysfunction and their complications, and maintaining
nutrition require careful and sustained attention that is best provided in intensive-care settings with specialty
Immunity to Tetanus
The level of antitoxin that protects against obstetric and neonatal tetanus can vary with the wound characteristics, the
degree of contamination, the specificity of the antitoxin, and the type of assay employed to measure the antitoxin level
(270). The minimum level of antitoxin correlating with protection is 0.01 IU/mL as measured by in vivo neutralization assay.
An antitoxin concentration at >0.1 IU/mL is the preferred correlate of protection based on the results of other assays
(e.g., enzyme-linked immunoabsorbant assay [ELISA]), and
because higher concentrations of antitoxin might be necessary
to protect in certain circumstances
(252,270). The serum level of tetanus antitoxin achieved in response to vaccination
is determined by the number of doses of tetanus toxoid, the type of tetanus toxoid administered (adjuvanted toxoid, which
is more immunogenic, has replaced fluid toxoid), the interval since the most recent dose, and individual variation in
the response to vaccination (270).
Deferring Td During Pregnancy to Substitute Tdap in the Immediate
Ensuring maternal and neonatal tetanus protection as part of prenatal care is a priority for women who are due for
a recommended decennial tetanus and diphtheria toxoids booster dose. For women who have not received a dose of
Tdap previously, administering Td during pregnancy, followed in a few months by Tdap postpartum, theoretically
could increase the risk or severity of adverse reaction, which typically is local. Moderate to severe local reactions have
been associated with high levels of tetanus and diphtheria antitoxin (see Interval Between Td and Tdap). In these women,
deferring the Td booster during pregnancy to substitute Tdap in the immediate postpartum period may be considered to
boost protection against pertussis as well as tetanus and diphtheria. The majority of women of childbearing age who have lived
the United States since infancy or childhood have received
4--5 infant and childhood doses of tetanus toxoid with
pediatric DTP or DTaP and >1 booster dose of Td (or tetanus toxoid without diphtheria toxoid [TT]) in accordance with
national recommendations (1,2,271). The recommended schedule of vaccination to prevent tetanus is intended to maintain levels
of antitoxin considerably higher than the minimum level required for protection against the majority of cases of
tetanus, including protection among persons with intrinsically lower responses to vaccination
In 2004, women aged 15--39 years accounted for 97% of all births in the United States
(3). Data from a population-based serosurvey conducted nationwide in the United States during 1988--1994 documented tetanus antitoxin concentrations
at >0.15 IU/mL among >80% of women aged 12--39 years
(274,275). The proportion of women with antitoxin at
>0.15 IU/mL declined with increasing age to 62% among women aged 40--49 years
(274,275). Slightly lower prevalence of this
titer was found among women aged 20--59 years who were not born in the United States
(276). A 1999--2000 study evaluated 2,134 adult patients in an emergency department for wound management and measurement of their antitoxin titer
(277). Antitoxin concentrations of
>0.15 IU/mL were present among 1,051 (95%) of 1,106 adults aged 18--39 years. Among
adults of all ages studied, approximately 95% of those with up-to-date vaccination histories and approximately 86% of those
whose vaccinations were not up-to-date had antitoxin titers >0.15 IU/mL. The rates of a protective titer were lower for
immigrants, persons with less education, and persons aged >70 years
(277). Limitations of these studies are that one study did not
report any connection between vaccination histories and antitoxin concentrations
(274--276), and the other study included
subjects who might not be representative of the U.S. population
(277). However, when combined with the small number of
tetanus cases among women of childbearing age in the United States, these studies suggest that when pregnant women have
previously received the recommended schedule of tetanus and diphtheria toxoids vaccinations, a routine decennial Td booster
during pregnancy typically can be deferred so Tdap can be substituted at delivery or before discharge from the hospital or
Vaccinating to Prevent Obstetric and Neonatal
Success in preventing obstetric and neonatal tetanus relies on antitoxin being present at delivery
(254). In countries where access to childhood vaccines is limited, neonatal tetanus constitutes a major cause of infant mortality; during 1978--1985,
an estimated 800,000 neonatal tetanus deaths occurred
annually worldwide (278). In 1974, worldwide elimination of
neonatal tetanus (less than one case per 1,000 live births) through vaccine initiatives became a major focus of the
Expanded Program of Immunization of the World Health
Organization (WHO) (259,279). The initiative promoted clean deliveries and
tetanus toxoid vaccination for pregnant women. Nonpregnant women of childbearing age also were targeted for at least 3 doses
of tetanus toxoid vaccine in supplemental immunization activities.
The strategy of targeting pregnant women for vaccination to prevent neonatal tetanus was based on reports published in
the 1960s concerning two vaccine trials that demonstrated that
>2 doses of tetanus toxoid administered during pregnancy
were >95% effective in preventing neonatal tetanus
(Table 10) (280,281). Subsequent studies confirmed that 3 doses of
aluminum phosphate-adjuvanted tetanus toxoid (rather than fluid toxoid) administered during pregnancy induced antitoxin levels
that would protect the mother and prevent neonatal tetanus for >10 years. Adjuvanted vaccine also lowered the rates of
local reactions in pregnant women (282--284).
Although the burden of obstetric tetanus has not been characterized as well as the burden of neonatal tetanus, the
annual worldwide burden of obstetric tetanus deaths has been estimated at 15,000--30,000, accounting for approximately 5% of
all maternal deaths in the 1990s
(254,259). In April 2006, WHO's Strategic Advisory Group of Experts (SAGE) reported on
the success of the maternal and neonatal tetanus elimination initiatives and the plan to transition from vaccination goals
for women of childbearing age to universal tetanus control, to be achieved through sustained high coverage with
pediatric DTP starting in infancy and childhood and booster doses to prevent tetanus throughout life
Safety of Tetanus Vaccination During Pregnancy
No evidence suggests that adverse outcomes for a mother or fetus increase after tetanus toxoid is administered to a
pregnant woman (1,2,23). Tetanus toxoid administered during any trimester of pregnancy was evaluated for association with
congenital abnormalities at birth during 1980--1994 in Budapest, Hungary. The rate of tetanus toxoid vaccination among
21,563 mothers of infants with congenital abnormalities was not significantly different than the rate of tetanus toxoid
vaccination among 35,727 mothers of infants who were normal (0.12% and 0.09%, respectively; p = 0.39)
(287). In a similar study
conducted in nine countries in South America starting in 1977, approximately one half of the women had received
tetanus toxoid during the first trimester of pregnancy. The rate of early tetanus toxoid vaccination among the mothers of
34,293 newborns with congenital malformations (9.2 [CI = 8.2--10.3] per 1,000 mothers) was not substantially different than the
rate among the mothers of 34,477 newborns who were normal (7.6 [CI = 6.6--8.5] per 1,000 mothers)
Infant Protection by Transplacental Maternal Antibody
Tetanus toxoid is one of the most immunogenic protein antigens in any vaccine. Administration of 2 doses of tetanus
toxoid to pregnant women at least 4--6 weeks before delivery stimulates antitoxin that protects the mother and readily crosses
the placenta, thereby protecting the newborn against tetanus when the risk is highest
(289). Pregnant women who receive a booster dose of tetanus toxoid have a measurable immune response within 5 days and a peak response in <2 weeks.
The response to vaccination might be slower after a first (primary) dose or when the interval after the most recent booster dose
is long (252,272). Placental transport of maternal IgG antitoxin is efficient; cord blood levels generally are similar to
maternal levels (290,291). After the neonatal period, the infant is at little risk for tetanus until becoming self-mobile, typically at an
age when sustained protection has been induced by 3
infant doses of pediatric DTP or DTaP (252).
Inhibitory Effect of Transplacental Maternal Antibody on Infant Immunization
Transplacental maternal tetanus antitoxin can interfere with the infant response to active immunization after up to 3
doses of tetanus toxoid (e.g., in pediatric DTP, DTaP, or DT)
(222,230,292--297). Certain studies
(296,297), but not all (298), indicate that antitoxin inhibits the response to tetanus toxoid after vaccination with
Haemophilus influenzae type b polysaccharide conjugated to tetanus toxoid. An
age-accelerated schedule results in further decrease in infant
responses in the presence of maternal antitoxin
(295). When levels of transplacental maternal antitoxin wane sufficiently, infants respond
to subsequent doses of vaccine
(229,293,294,299--301). T-cell priming for a booster response is not substantially affected
by maternal antitoxin (222,302, 303). Typically, infants respond to the second dose of tetanus toxoid--containing vaccine with
a protective level of antitoxin, even when the initial levels of maternal antitoxin are high;
3 doses of tetanus toxoid are required to achieve antitoxin concentrations that persist above protective levels
No substantial difference in the infant immune response to tetanus toxoid (in DTP) has been identified with consumption
of human milk compared with consumption of cow milk
Respiratory diphtheria is an acute, severe infection caused by strains of
Corynebacterium diphtheriae that produce
diphtheria toxin. Rarely, toxin-producing strains of
C. ulcerans cause a diphtheria-like illness
(306). Respiratory diphtheria is characterized by a grayish-colored adherent membrane on the pharynx, palate, or nasal mucosa that can obstruct the
airway with fatal outcome. The disease can be complicated by toxin-mediated cardiac, neurologic, or renal dysfunction.
Case-fatality rates are >10%
Obstetric and Neonatal Diphtheria
Respiratory diphtheria (309--312) or vulvovaginal infection
(313,314) can occur during any trimester of pregnancy, at
term, or in the postpartum period. The mortality rate of
obstetric respiratory diphtheria is high (estimated at 50%) without
infusion of diphtheria antitoxin, even with tracheostomy or intubation, and is accompanied by fetal loss or premature birth
in approximately one third of survivors. Early treatment with serum diphtheria antitoxin improves survival and
pregnancy outcomes, although complications of the disease might require prolonged supportive care
(309--312). Postpartum women with respiratory diphtheria can transmit
C. diphtheriae to their neonates
Respiratory diphtheria is a nationally notifiable disease in the United States. Rare cases occur in the United States
after infection with diphtheria toxin--producing strains of C. diphtheriae or other corynebacteria
(315,316). During 1998--2006, seven cases of respiratory diphtheria were reported to CDC. The most recent culture-confirmed adult case of
respiratory diphtheria caused by C.
diphtheriae was reported in 2000, and an adult case of respiratory diphtheria caused by
C. ulcerans was reported in 2005
(306). The risk for diphtheria can be increased during travel to areas in which diphtheria is endemic; a list
of these areas is available at http://www.cdc.gov/travel/default.aspx. Diphtheria also can be acquired from persons with
imported cases or from carriers (i.e., asymptomatic persons who are colonized with toxin-producing
C. diphtheriae) (315,316).
Diagnosis and Treatment
The diagnosis of diphtheria is confirmed by isolation of
C. diphtheriae in culture of the adherent membrane and by
testing the isolate for toxin production
(317). The mainstay of treatment in respiratory diphtheria is early administration
of diphtheria antitoxin (equine), which is available to physicians in the United States from CDC through an
FDA-Investigational New Drug protocol (24-hour telephone, 770-488-7100). Additional information is available
at http://www.cdc.gov/vaccines/vpd-vac/diphtheria/dat/dat-main.htm. No human-derived serum diphtheria antitoxin is
available. Antibiotics are administered to limit transmission and to prevent continuing production of diphtheria toxin
(318). Prompt reporting of suspect cases, investigation, culture, and antimicrobial prophylaxis of contacts and immunization of the
affected community (317,318) is of critical importance.
Because respiratory diphtheria does not always confer protection against
future illness, patients should complete active immunization
with diphtheria toxoid after recovery (286).
Protection against respiratory diphtheria is predominantly from IgG antibody to diphtheria toxin (antitoxin) induced
after infection with toxin-producing C.
diphtheriae or after vaccination with diphtheria toxoid. In areas with little or no
endemic exposure to toxin-producing C.
diphtheriae, periodic vaccination is required to maintain immunity
(237,286,307, 319--321). Although the immune responses to infection and vaccination vary, antitoxin concentrations of
>0.1 IU/mL typically are considered protective. Concentrations of 0.01 IU/mL--0.1 IU/mL might provide protection against severe
disease; concentrations <0.01 IU/mL do not protect against diphtheria
Td Booster During Pregnancy for Diphtheria Protection
Data from a national population-based serosurvey conducted during 1988--1994 that evaluated the prevalence of
immunity to diphtheria (defined as a diphtheria antitoxin concentration of >0.1 IU/mL) among women in the United States
determined immunity to diphtheria to be lower than immunity to tetanus (see Tetanus: Deferring Td During Pregnancy to
Substitute Tdap in the Immediate Postpartum Period). The prevalence of immunity to diphtheria decreased with increasing age
(77% among women aged 12--19 years, 74% among women aged 20--29 years, 65% among women aged 30--39 years, and
<45% among women aged >40 years) and with birth outside the United States or less formal education
Vaccinating Pregnant Women, Infant Protection by Transplacental Antibody
Diphtheria toxoid vaccine trials conducted among pregnant women in the 1940s demonstrated quantitative increases
in diphtheria antitoxin after the women were vaccinated.
Maternal antitoxin was transferred efficiently to the
fetus (217,226,320,323,324). Several studies indicate transplacental maternal antitoxin provides newborn infants with
protection against diphtheria at birth if their mother
The safety of diphtheria toxoid (without tetanus toxoid) vaccination in pregnant women was examined during the
1970s (326). After diphtheria toxoid was administered during the first 4 months of pregnancy, 75 mother-child pairs were
followed for malformations until the child reached age 7 years. Although the number of vaccinated pregnant women studied was
small, the risk for malformations in their children was lower than the risk among children in a much larger group of
pairs in which the women were not vaccinated with diphtheria toxoid during pregnancy (survival- and
race-standardized relative risk: 0.88) (327).
Inhibitory Effect of Transplacental Maternal Antibody on Infant Immunization
Transplacental maternal diphtheria antitoxin concentrations of <0.1 IU/mL can interfere with primary diphtheria
toxoid immunization in infancy
(237,292,321,328--331). The duration of interference is affected by the concentration of
maternal antitoxin, the formulation and toxoid content of the infant vaccine (e.g., the limit of flocculation [Lf] units of
diphtheria toxoid, aluminum hydroxide-adsorbed, or fluid preparation), and the length of the interval between
299,321,328--331). Infants typically respond with increases in antitoxin after 2 doses of
high-content diphtheria toxoid vaccine when maternal antitoxin concentrations are 0.1 IU/mL in cord sera but not until after
>3 infant doses of high-content diphtheria toxoid vaccine when maternal antitoxin concentrations are
>1.0 IU/mL in cord sera
(225,229,292,299,321,329,331,332). When infants
receive subsequent doses of diphtheria toxoid, the responses are
rapid, often within 2 weeks (330), suggesting that T-cell priming occurs in the absence of an infant antibody response to
previous doses of vaccine
Consumption of human milk does not affect the infant
immune response to diphtheria toxoid--containing
vaccines (292,332). Ingestion of colostrum from an immune mother does not result in an increase in the concentration of
diphtheria antitoxin in infant sera (250).
Adult and Adolescent Acellular Pertussis Combined with Tetanus
and Reduced Diphtheria Toxoids (Tdap) Vaccines and Tetanus and
Reduced Diphtheria Toxoids (Td) Vaccines
Both Tdap vaccines used in the United States
BOOSTRIX®) were licensed on the basis of clinical trials
in the United States demonstrating immunogenicity not inferior to that of U.S.-licensed Td
(333,334) and the pertussis components of pediatric DTaP made by the same manufacturer and an acceptable safety profile
(212,213). Adsorbed Td products for adults and adolescents have been licensed in the United States since the 1950s
(335). Components of these and other diphtheria and tetanus
toxoids--containing vaccines have been listed (Table 1) and are available at
In prelicensure trials, data on local and systemic adverse events were collected using standard diaries for the day
of vaccination and the next 14 consecutive days
(212,213,336--338). The efficacies of the tetanus toxoid and the
diphtheria toxoid components of Tdap were inferred from the immunogenicity of the antigens in Tdap compared with Td
using established serologic correlates of protection in sera obtained before and approximately 1 month after vaccination. Because
no well-accepted serologic or laboratory correlate of protection is available for pertussis, the efficacy of the pertussis
components of Tdap was inferred using a serologic bridge (comparison) to the immune response to vaccine antigens among infants
who received 3 doses of pediatric DTaP (made by the same manufacturer) during clinical efficacy trials for pertussis during
the 1990s (339). The efficacy against pertussis of an acellular pertussis vaccine without tetanus and diphtheria toxoids was
92% (CI = 32%--99%) for adults and adolescents in a randomized, controlled trial
(340); these results were not considered in
the evaluation of Tdap for licensure in the United States.
Selected results from the prelicensure trials are summarized below. Additional information can be found in previous
ACIP statements discussing use of Tdap among adults and adolescents and in the package labels of the specific products
ADACEL® contains the same tetanus toxoid, diphtheria toxoid, and five pertussis antigens as those in
DAPTACEL® (pediatric DTaP, also made by sanofi pasteur), but
ADACEL® is formulated with reduced quantities of diphtheria toxoid
and detoxified PT. Prelicensure trials in the United States evaluated the immunogenicity and the safety of
adults aged 18--64 years and among adolescents aged 11--17 years, randomized to receive a single dose of
ADACEL® or a single dose of Td made by the same manufacturer (Table 1)
(1,2,212,333). Pregnant women were excluded.
Tetanus and Diphtheria Toxoids. The rates of seroprotection and booster response for both antitetanus and
antidiphtheria among adults and adolescents who received a single dose of
ADACEL® were noninferior to rates among those who
received Td. Nearly all (>99%) subjects in the
ADACEL® and Td groups achieved seroprotective antitetanus levels
(>0.1 IU/mL), and >94% of adults and >99% of
adolescents achieved seroprotective antidiphtheria levels
(>0.1 IU/mL) in ADACEL® and
Td groups (212,341).
Pertussis Antigens. The efficacy of the pertussis components was inferred by comparing the immune responses (GMCs)
of adults and adolescents vaccinated with a single dose of
ADACEL® to those of infants vaccinated with 3 doses
of DAPTACEL® in a Swedish vaccine efficacy trial
(338,342). The efficacy of 3 doses of pediatric
DAPTACEL® against WHO-defined pertussis
(>21 days of paroxysmal cough with confirmation of
B. pertussis infection by culture or serologic testing,
or an epidemiologic link to a household member with culture-confirmed pertussis) was 85% (CI = 80%--89%)
(338,342). The GMCs of anti-PT, anti-FHA, anti-PRN, and anti-FIM among adults and adolescents after a single dose of
ADACEL® were noninferior to those of infants after 3 doses of
DAPTACEL.® The prespecified criteria
for booster responses also were met
The safety of ADACEL® was evaluated in four clinical studies with data from 2,448 adults aged 18--64 years and
3,393 adolescents aged 11--17 years (212).
Immediate Events. No anaphylaxis was reported. Five adults reported an immediate event within 30 minutes of
vaccination (four persons [0.2%] for ADACEL® and one person [0.2%] for Td); three of these five events were classified as
nervous system disorders (hypoesthesia/paresthesia). Eleven adolescents reported an immediate event (six persons [0.5%]
for ADACEL® and five persons [0.6%] for Td); these events included dizziness, syncope, or vasovagal reactions in addition
to pain and erythema at the injection site. All events
resolved without sequelae (338,341,343).
Solicited Local and Systemic Adverse Events. Rates of erythema and swelling
(Figures 3 and 4), or systemic (headache, generalized body aches, and tiredness [data not presented]) adverse events reported to occur during 0--14 days
following vaccination with Td or Tdap were similar
(>38°C) was reported with the same
frequency by adults vaccinated with Td and with Tdap (Figure 3)
(212); the rate of any fever reported by adolescents vaccinated
with Tdap (5%) was higher than the rate for those vaccinated with Td (3%) but met the noninferiority criterion (Figure 4) (212,341). No case of whole-arm swelling was reported
Serious Adverse Events. Among adults, serious adverse events (e.g., appendicitis) within 6 months after vaccination
were reported for 33 (2%) of 1,752 persons in the ADACEL® group and for 11 (2%) of 573 persons in the Td group
(338,341). Two serious adverse events in
ADACEL® recipients were neuropathic and were assessed by the investigators as possibly
related to vaccination. In both cases, the symptoms resolved completely over several days
(1,212,338, 341,343). Among adolescents, serious adverse events within 6 months after vaccination were reported for 11 (1%) of 1,184 persons in the
ADACEL® group and for eight (1%) of 792 persons in the Td group. All events were reported by investigators to be unrelated to the
study vaccine (341). No physician-diagnosed Arthus reaction (see Important Local Reactions) or case of Guillain-Barré
syndrome (see Neurologic and Systemic Events) was reported
Simultaneous Administration of Tdap with Other
Trivalent Inactivated Influenza Vaccine. The safety and immunogenicity of
ADACEL® co-administered with
trivalent inactivated influenza vaccine ([TIV]
Fluzone,® sanofi pasteur, Swiftwater, Pennsylvania) were evaluated in nonpregnant
adults aged 19--64 years randomized to simultaneous administration in different arms (n = 359), or to TIV administered
first, followed by ADACEL® 4--6 weeks later (n = 361). Rates of fever and injection site erythema and swelling were
similar following ADACEL® administered concurrently with TIV or separately. Pain at the
ADACEL® injection site occurred
more frequently after simultaneous administration than after separate administration (67% and 61%, respectively)
(338). Immunogenicity criteria were met with the following exceptions: the GMC of anti-PRN was lower in the simultaneous
group than in the sequential group (338,344), and the tetanus booster response rates were lower after simultaneous
than after sequential administration (79% and 83%, respectively). However, more than 98% of subjects in both
groups achieved seroprotective levels (>0.1 IU/mL) of tetanus antitoxin
Hepatitis B Vaccine. The safety and immunogenicity of
ADACEL® administered with hepatitis B (Hep B)
vaccine (Recombivax HB,® Merck and Co., White House Station, New Jersey) were evaluated among nonpregnant adolescents
aged 11--14 years randomized to simultaneous administration (n = 206) or to
ADACEL® administered first, followed by
hepatitis B vaccine 4--6 weeks later (n = 204). Rates of solicited erythema and swelling at the
ADACEL® injection site were higher
in the simultaneous group than in the sequential group, and noninferiority was not achieved
(1,338). No interference was observed in the immune responses to any of the vaccine antigens when
ADACEL® and hepatitis B vaccine were
administered concurrently or separately
BOOSTRIX® contains the same tetanus toxoid, diphtheria toxoid, and three pertussis antigens as those in
INFANRIX® (pediatric DTaP, also made by
GlaxoSmithKline), but BOOSTRIX® is formulated with reduced quantities of
antigens. Prelicensure trials conducted in the United States evaluated the immunogenicity and safety of
BOOSTRIX® among adolescents aged 10--18 years
(213,337), randomized to receive a single dose of
BOOSTRIX® or a single dose of Td (Massachusetts Public Health Biologic Laboratory, Mattapan, Massachusetts) (Table 1)
(213,334,337). Pregnant adolescents were excluded.
Tetanus and Diphtheria Toxoids. The rates of seroprotection and booster response for both antitetanus and
antidiphtheria among adolescents who received a single dose of
BOOSTRIX® were noninferior to those who received
Td. All adolescents had seroprotective antitetanus levels
(>0.1 IU/mL); >99% of adolescents had seroprotective antidiphtheria levels
(>0.1 IU/mL) (1,213,336).
Pertussis Antigens. The efficacy of the pertussis components was inferred by comparing the immune responses
of adolescents vaccinated with a single dose of
BOOSTRIX® with the immune responses of infants vaccinated with 3 doses
of INFANRIX® in a German vaccine efficacy trial
(213,336, 345). The efficacy of 3 doses of pediatric
INFANRIX® against WHO-defined pertussis was 89% (CI = 77%--95%)
(213,345). The GMCs of anti-PT, anti-FHA, and anti-PRN after
a single dose of BOOSTRIX® were noninferior to those of infants after 3 doses of
INFANRIX.® The prespecified criteria
for booster responses also were met
A total of 3,080 adolescents aged 10--18 years received
BOOSTRIX® in the primary safety study
(213). No immediate events (i.e., those occurring within 30 minutes of vaccination) were reported
Solicited Local and Systemic Adverse Events. No substantial differences were observed between the BOOSTRIX® and Td recipients in the rates of solicited local (redness, swelling, and increase in arm circumference above baseline)
(Figure 5) or systemic (headache, fatigue, gastrointestinal systemic events, fever
[>38.0°C] [data not presented]) adverse
events (1,213,336,337). No case of whole-arm swelling was reported
Serious Adverse Events. Serious adverse events within
6 months after vaccination were reported among 14 (0.4%) of
3,005 adolescents vaccinated with BOOSTRIX® and two (0.2%) of 1,003 adolescents vaccinated with Td. All events were
reported by the investigators to be unrelated to the study vaccine
(213,336,337,346). No physician-diagnosed Arthus reaction or
case of Guillain-Barré syndrome was reported
Pregnant Women Vaccinated with Tdap
Pregnant women were excluded from prelicensure trials of Tdap. The outcome of pregnancy among six women who
were administered ADACEL® inadvertently during or within 1 month of conception was a healthy full-term infant (n = 3),
a preterm infant (n = 1), or a miscarriage (n = 2). No infant was born with a congenital anomaly (sanofi-pasteur,
unreported data, 2007). Two pregnancies occurred in
BOOSTRIX® recipients >4 months postvaccination; one subject experienced
a spontaneous abortion within the first trimester, and the other subject delivered a healthy infant
Regulatory Considerations for Tdap in Pregnant
As with the majority of vaccines, Tdap is labeled pregnancy category C. This designation indicates that no adequate
and well-controlled studies have been conducted with the vaccine in pregnant women to determine the product's safety
Safety Considerations for Adult and Adolescent Use of Td or Tdap
Prelicensure studies in nonpregnant adults and adolescents evaluated the safety of Tdap with respect to local and
systemic adverse events (212,213). The sample sizes were insufficient to detect rare adverse events. Enrollment criteria excluded
persons who were pregnant; had received vaccines containing tetanus toxoid, diphtheria toxoid, or pertussis components more
recently than either the preceding 5 years for
ADACEL® (212) or the preceding 10 years for
BOOSTRIX® (213); or had
certain neurologic conditions or events
(336--338,341,346). Safety data are being collected by the Vaccine Adverse Event
Reporting System (VAERS), and postlicensure studies continue to monitor for potential adverse reactions following widespread use
of Tdap in adults and adolescents (16,17). Registries have been established by both Tdap manufacturers for reporting
women vaccinated with Tdap during pregnancy.
Interval between Td and Tdap
ACIP has made several recommendations for intervals
between tetanus toxoid-- and diphtheria toxoid--containing
vaccines that balance the benefits of protection against the risks of moderate and severe local reactions. Moderate and severe
local reactions, including Arthus reaction, are associated with frequent dosing at short intervals and larger doses of toxoid.
High antitoxin levels are more likely to result when the interval between doses is short and the number of doses increases
(349--354). High preexisting antibody titers to tetanus or diphtheria toxoids also are associated with increased rates and severity
of local reactions to booster doses in adults
ACIP recommends a 10-year interval for routine administration of Td (e.g., decennial Td booster), and a 5-year interval
for Td when indicated for wounds management
(1,2,357). Administering Td more often than every 10 years (5 years for
certain nonclean, nonminor wounds) is not necessary to provide protection against tetanus or diphtheria; however,
administering a single dose of Tdap at an interval shorter than 5 years after Td could provide a health benefit by adding protection
against pertussis (Table 2) (1,2). When Tdap is
administered to add protection against pertussis, ACIP encourages an interval of
>5 years between the most recent Td and the Tdap dose for adolescents because they might receive other recommended
vaccines containing tetanus or diphtheria toxoids (including quadrivalent meningococcal conjugate vaccine [MCV4]
[Menactra,® sanofi pasteur, Swiftwater, Pennsylvania])
(2). An interval as short as 2 years is recommended between the most recent Td
and the single dose of Tdap for health-care personnel with direct patient contact, and a
2-year interval between the most recent Td and Tdap is suggested for adults in close contact with infants
(1). ACIP allows for a shorter interval between the most
recent Td and administration of Tdap in certain circumstances that might require urgent protection
Several studies have suggested that an interval as short as
2 years between Td and a single dose of Tdap is acceptably safe.
Three studies conducted among Canadian children and adolescents evaluated the safety of Tdap
(ADACEL®) at an interval shorter than 5 years after Td or after pediatric DTP or DTaP
(358--360).The largest was an open-label study of 7,001 students aged
7--19 years. Rates of local reactions were not increased
among students who had received the most recent of 5 pediatric DTP
or DTaP doses, or a Td dose, >2 years before Tdap, compared with >10 years before Tdap (358). The other Canadian
studies demonstrated similar safety when Tdap was administered at an interval of <5 years after the previous
tetanus toxoid-- and diphtheria toxoid--containing
Adverse reactions after Tdap
(ADACEL®) administered at an interval of <2 years from the most recent Td were evaluated in
a retrospective survey of 4,524 health-care personnel who received Tdap at a median age of 46 years during an outbreak
of pertussis-like illness in New Hampshire in 2006
(118,215,361). For the 2,676 (59%) responses, the rates of
reactions were analyzed by interval from Td to Tdap as either >2 years (n = 1,792) or <2 years (n = 370). The rates of pain, redness, or
swelling of moderate or severe intensity, subjective fever, and medical visits were not higher among respondents with an interval of <2
years between administration of Td and that of Tdap. Three serious adverse events were reported among adults who received Tdap
at an interval >2 years after the most recent dose of Td; causality was not assessed. The events were a case of
Guillain-Barré syndrome (not requiring hospitalization) with onset 11 days after Tdap, a case of anaphylaxis-like reaction with onset 6 days
Tdap, and a case of eosinophilic nephritis with onset 6 days after Tdap in a health-care worker with a history of a renal
Important Local Reactions
Arthus reaction (type III hypersensitivity reaction) can
occur after tetanus toxoid-- or diphtheria toxoid--containing
vaccines (354,357,362--366; CDC, unpublished data, 2005). Arthus reaction is a local vasculitis with deposition
of immune complexes and activation of complement; it occurs in the setting of high local concentration of vaccine antigens
and high circulating antibody concentration (354,362,
363,367). The reaction is characterized by severe pain, swelling,
induration, edema, and hemorrhage, and occasionally by local necrosis. Vaccine-related arthus reaction typically resolves without
sequelae. The onset of symptoms and signs is 4--12 hours after vaccination, compared with anaphylaxis (immediate type
I hypersensitivity reaction), which has onset within minutes after vaccination. ACIP recommends that persons who
experience an Arthus reaction after administration of a
tetanus toxoid--containing vaccine not receive Td or other
tetanus toxoid--containing vaccine more frequently than
every 10 years, even for tetanus prophylaxis as part of wound management
Extensive Limb Swelling
Extensive limb swelling reactions have been reported to VAERS following administration of Td
(368,369) and are described following dose 4 or dose 5 of pediatric DTaP
(23,208,368,370--373). Extensive limb swelling after pediatric DTaP
resolves without complication within 4--7 days
(370), and is not considered a precaution or contraindication for Tdap
Neurologic and Systemic Events
Concerns regarding a possible role of pertussis vaccine components in causing neurologic reactions or
exacerbating underlying neurologic conditions in infants and children are long-standing
(29,374). In 1991, the Institute of
Medicine (IOM) concluded that evidence favored acceptance of a causal relation between pediatric DTP vaccine and
acute encephalopathy (365). A subsequent retrospective analysis of >2 million children in the United States did not
demonstrate that pediatric DTP was associated with an increased risk for
encephalopathy after vaccination (375). Active surveillance
in Canada during 1993--2002 also failed to identify any acute encephalopathy cases causally related to whole-cell or
acellular pertussis vaccines among a population administered 6.5 million doses of pertussis-containing vaccines
(376). Results of one recent investigation suggested that some acute encephalopathies
attributed previously to pertussis-containing vaccines could
be the result of genetically determined epileptic encephalopathies related to mutations in the sodium channel gene
SCN1A (377,378). A history of encephalopathy (e.g., coma or prolonged seizures) not attributable to an identifiable cause within
7 days of administration of a vaccine with pertussis components remains a contraindication for Tdap (but not Td) in adults
The possibility that Tdap would complicate neurologic evaluation of chronic progressive neurologic disorders that are
stable in adults (e.g., dementia) is of limited clinical concern and does not constitute a reason to delay administration of Tdap
(1). Unstable or evolving neurologic conditions (e.g., cerebrovascular events or acute encephalopathic conditions) would be
reason to delay administration of Tdap until the condition has stabilized
(1). Among adolescents who have progressive
or uncontrolled underlying neurologic disease, concerns regarding administering Tdap must be weighed against the
morbidity from pertussis, which could be severe
(2). ACIP does not consider a history of well-controlled seizures or a family history
of seizures (febrile or afebrile) or other neurologic disorder to be a contraindication or precaution to vaccination with
pertussis components (22).
Tetanus Toxoid Component
ACIP considers Guillain-Barré syndrome within 6 weeks after receipt of a tetanus toxoid--containing vaccine to be
a precaution (see Precautions and Reasons to Defer Td or
Tdap)for administration of subsequent tetanus
toxoid--containing vaccines (23). Although IOM concluded that evidence favored acceptance of a causal relation between tetanus
toxoid--containing vaccines and Guillain-Barré syndrome on the
basis of a single well-documented case
analysis of data from both adult and pediatric populations failed to demonstrate an association
(380). As of January 29, 2007, eight patients with Guillain-Barré syndrome temporally associated with receipt of Tdap or of Tdap administered on the
same day with other vaccines had been reported to VAERS. The onsets were not clustered by the interval since vaccination or by
a single pattern of vaccine exposure (361).
ACIP does not consider a history of brachial neuritis to be a precaution or contraindication for administration of
tetanus toxoid--containing vaccines (23,381). IOM concluded that evidence from case reports and uncontrolled studies
involving tetanus toxoid--containing vaccines did favor a causal
relation between tetanus toxoid--containing vaccines and brachial
neuritis (365); however, brachial neuritis typically is self-limited
(23,381). Brachial neuritis is a compensable event through the
Vaccine Injury Compensation Program (VICP)
No study has evaluated the disease morbidity and societal costs associated with pertussis among pregnant women
or modeled the cost benefit or cost effectiveness of a Tdap strategy that includes vaccination of pregnant women. The
morbidity and societal cost of pertussis in adults is substantial
(1,2). A retrospective assessment of medical costs of confirmed pertussis
in 936 adults in Massachusetts during 1998--2000, and a prospective assessment of nonmedical costs in 203 adults during
2001--2003 (31) indicated that the mean medical and nonmedical cost per case was $326 and $447, respectively, for a societal
cost of $773. If the cost of antimicrobials to treat contacts and the cost of personal time were included, the
societal cost could be as high as $1,952 per adult case (31).
Cost-benefit and cost-effectiveness analyses of adult Tdap vaccination have varied in their results
(382,383). When discrepancies in the models were addressed, an adult Tdap vaccination program was cost-effective when incidence of
pertussis exceeded 120 cases per 100,000 population, using a benchmark of $50,000 per quality-adjusted life year saved
(384--386). After adjusting for the severity of the illness at high disease incidence, little effect was observed on the overall cost effectiveness of
a vaccination program. Similar results were obtained when program costs and benefits were analyzed over the lifetime of the
adult cohort for decennial booster strategies
Administering a dose of Tdap during routine wellness visits of adult and adolescent women of childbearing age, if
indicated, is the most effective programmatic strategy to ensure that women are protected against pertussis in addition to tetanus
and diphtheria and minimizes any theoretical effect of vaccination on infant immune responses should the woman
become pregnant (see Immunity to Pertussis and Kinetics of
Pertussis Booster Vaccination in Nonpregnant Adults and
Adolescents) (1,388--392). Because Tdap contains only toxoids and purified bacterial components, women who receive Tdap do not
need to wait after vaccination to become pregnant
(23). Assessments provide repeated opportunities for documenting the history
of past doses of Td (or TT) and any serious adverse reactions to tetanus, diphtheria, and pertussis vaccines. To access
and maintain immunization records, state-based immunization information systems (IIS) are increasingly becoming available
to clinicians and public health officials. These confidential, computerized information systems, which consolidate
vaccination data from multiple health-care providers, can generate reminder and
recall notifications, assist with vaccine management
and adverse events reporting, and capture lifespan vaccination histories
(393). Additional guidance regarding administration
of vaccines during routine assessments, record keeping, vaccine storage, and
related topics has been published previously
Prenatal Visits: Deferring Td During Pregnancy to Substitute Tdap in
the Immediate Postpartum Period
In 2004, a total of 96% of pregnant women started prenatal care in the first or second trimester
(394). Prenatal visits provide additional opportunities for assessing the history of past vaccination with Tdap, Td, or TT and any
serious adverse reactions to tetanus, diphtheria, and pertussis vaccines. Women who have not received a previous dose of Tdap can
advised that ACIP recommends Tdap postpartum before discharge from the hospital or birthing center to provide
personal protection and reduce the risk for transmitting pertussis to their infants.
Health-care providers can monitor pregnant women for respiratory illness consistent with pertussis or for recent exposure
to pertussis, either to themselves or to family members, and prescribe a macrolide antimicrobial for treatment of pertussis
or postexposure prophylaxis, if indicated. Women and their partners should receive counseling regarding the severity of
infant pertussis and ACIP's recommendation for a single dose of Tdap for adults and adolescents who anticipate contact with
an infant (1,2). In a 2005 national survey of obstetricians, 72% of respondents affirmed the belief that
obstetricians, pediatricians, adult primary care providers, and public health providers share responsibility to promote
administration of Tdap for adults who anticipate contact with an infant, including fathers and close relatives
(395). Ideally, health-care providers delivering prenatal care will encourage persons likely to have contact with an infant, including child care providers, to
receive Tdap first.
When pregnant women who have not received Tdap have indications for tetanus or diphtheria booster
protection (>10 years since the most recent Td), ACIP recommends
receipt of Td during pregnancy (Table 2). ACIP has
developed criteria for safely deferring administration of Td until delivery among women who have received past tetanus
toxoid--containing vaccinations, so the majority of these women can substitute Tdap in the immediate postpartum period
for Td during pregnancy (see Deferring Td During Pregnancy to Substitute Tdap in the Immediate Postpartum Period). When
the history of tetanus toxoid vaccination for the women is uncertain or lacking, health-care providers can determine
the concentration of tetanus antitoxin to ensure protective concentrations of tetanus antitoxin
(>0.1 IU/mL by ELISA). Because diphtheria is rare in the United States, serologic screening for diphtheria antitoxin typically is not necessary. A woman
who anticipates travel to an area in which diphtheria is
endemic can improve protection against diphtheria by receiving a
booster dose of Td during pregnancy or a dose of Tdap postpartum. Serologic screening to establish immunity to pertussis is
In special situations in which a pregnant woman has
increased risk for tetanus, diphtheria, or pertussis,
ACIP acknowledges that health-care providers may choose to
administer Tdap instead of Td during pregnancy to add
protection against pertussis, after discussing the theoretical benefits and risks for her, her fetus, and the pregnancy outcome with
the woman before vaccination (see Considerations for Use of Tdap in Pregnant Women in Special Situations). Data to inform
this decision are scarce. No theoretical risk for harm to the mother or fetus exists from Tdap, and administration of Tdap in
the pregnant woman might provide a degree of early protection to the infant against pertussis. However, a theoretical risk for
the infant is that the dose of Tdap in pregnancy might not result in early protection against pertussis or could
increase transplacental pertussis-specific antibodies to levels that would have a negative effect on the infant's response to
immunization with pediatric DTaP or with conjugate vaccines containing tetanus toxoid or diphtheria toxoid (e.g.,
Haemophilus influenzae type b pneumococcal conjugate vaccine)
(222). Health-care providers who choose to vaccinate pregnant women with Tdap
are encouraged to report such administration to the manufacturers' pregnancy registry.
In 2004, a reported 99% of live births in the United States occurred in a hospital. Of out-of-hospital live births,
27% occurred at a free-standing birthing center and 65% at a residence
(394). In these settings, attendants can implement
protocols to ensure that postpartum women who have not received Tdap previously receive it before discharge. They also can
encourage previously unvaccinated adults and adolescents who anticipate contact with an infant to receive Tdap. Tdap vaccination of
the women and potential contacts before discharge rather than at a follow-up visit has the advantage of decreasing the time
when new mothers and contacts of the newborns could
acquire and transmit pertussis to the infants
(1,2). Standing orders for postpartum Tdap vaccination before discharge have successfully raised vaccination rates to more than 80% of
eligible women (396). Although obtaining a history of the most recent Td vaccination was anticipated to be a barrier to
postpartum vaccination with Tdap, in practice it was not identified as a barrier
Vaccination of parents and household contacts of premature infants has been advocated to ensure that such persons
receive Tdap (397). Premature and low birth weight infants are at increased risk for severe and complicated pertussis. The
case-fatality rate for pertussis is increased compared with term infants, and premature infants might respond less well than term infants
to initial doses of DTaP vaccine because of comorbidities or treatments (e.g., dexamethasone)
Parents should be reminded of other measures to protect infants from pertussis. To the extent feasible, parents can
limit infant exposures to persons who have respiratory illness until they are determined to be noninfectious
(99,219,321). When pertussis exposure occurs, antimicrobial prophylaxis of exposed contacts can be effective in preventing transmission
of pertussis (42,99,404,405). Ensuring that infants begin the pediatric DTaP vaccination series at the recommended chronologic age of
6--8 weeks is critical to protection and reducing the severity of pertussis
(8,45,397,406). Administration of 2 or 3 doses of pediatric
DTP or DTaP can prevent hospitalization for pertussis and its complications
Recommendations for routine use of Td and Tdap among women of childbearing age who might become pregnant
have been published previously (1,2) and have been summarized (Table 2). Women are encouraged to receive a single dose of
Tdap either as ADACEL® (adults and adolescents aged
11--64 years) or as BOOSTRIX® (adolescents aged 11--18 years)
before conception (e.g., during routine wellness visits) if they have not already received Tdap. Recommendations for adults
and adolescents who anticipate or have household contact with an infant aged <12 months also have been published
previously (1,2) and summarized (Table 2). The dose of Tdap will provide active booster immunization against tetanus, diphtheria,
and pertussis and will replace the next dose of Td
according to routine recommendations. A single preconception dose of Tdap
will prevent pertussis, reduce morbidity associated with pertussis, and might prevent exposing persons at increased risk
for pertussis and its complications, including infants. The risk for pertussis death and severe pertussis is highest among infants
in the first months of life and remains elevated until an infant has received 1--2 doses of
pediatric DTaP (8,45,47).
The following sections present recommendations for use of Td and Tdap among pregnant and postpartum
women, including routine vaccination, contraindications, precautions, and special situations. As with most inactivated vaccines
and toxoids, pregnancy is not a contraindication for use of Tdap. Although the safety and immunogenicity of Tdap is expected
to be similar in pregnant and nonpregnant women, few data on the safety of Tdap for women, fetuses, and pregnancy
outcomes are available, and no information is available on the immunogenicity of Tdap in pregnant women. Vaccinating
pregnant women with a single dose of Tdap might provide a degree of protection against pertussis to the infant in early life
through transplacental maternal antibody, but evidence supporting this hypothesis is lacking. A concern is the unknown effect
of potential interference by maternal antibody on the ability of the infant to mount an adequate immune response when
the infant receives pediatric DTaP or conjugate vaccines containing tetanus toxoid or diphtheria toxoid.
In special situations, administration of Tdap during pregnancy might be warranted for pregnant women who were
not vaccinated previously with Tdap. Health-care providers who choose to administer Tdap to pregnant women should
discuss with the women the potential risks and benefits of
immunization including the lack of data on Tdap administered
during pregnancy or its unknown effects on active immunization
of their infant. The following recommendations are intended
to provide guidance to clinicians until additional information is available.
1. Routine Tdap Vaccination
1-A. Recommendations for Use of Postpartum Tdap
For women who have not received Tdap previously (including women who are breastfeeding), Tdap is recommended
as soon as feasible in the immediate postpartum period to protect the women from pertussis and reduce the risk for
exposing their infants to pertussis. The postpartum Tdap should be administered before discharge from the hospital or birthing
center. If Tdap cannot be administered at or before discharge, the dose should be administered as soon as feasible thereafter.
Elevated levels of pertussis antibodies in the mother are likely within 1--2 weeks after vaccination.
Although an interval of 10 years since receipt of the most recent Td dose is recommended for the next routine Td
booster, to reduce the risk for women exposing their infants to pertussis, an interval as short as 2 years
between the most recent Td and administering
Tdap¶ is suggested for postpartum women. The safety of such an interval is supported by three
Canadian studies among adolescents and by a study among nonpregnant adult health-care personnel
(215,358--360), an interval shorter than 2 years may be used (see Postpartum Tdap When <2 Years Have Elapsed Since the Most Recent Td). In this setting,
the benefit of Tdap to protect against pertussis typically outweighs the risk for local and systemic reactions after
Routine postpartum Tdap recommendations are supported by evidence from randomized controlled clinical
trials, nonrandomized open-label trials and a retrospective survey, observational studies, and
expert opinion (Box 2).
1-B. Dosage and Administration
The dose of Tdap or, if indicated, the dose of Td is 0.5 mL, administered intramuscularly (IM), preferably into
the deltoid muscle.
1-C. Simultaneous Vaccination with Tdap and Other Vaccines
If two or more vaccines are indicated, they typically should be administered during the same visit (i.e.,
simultaneous vaccination). Each vaccine should be administered using a separate syringe at a different anatomic site. Certain
experts recommend administering no more than two injections per muscle, separated by at least one inch. Administering all
indicated vaccines during a single visit increases the likelihood that pregnant and postpartum women will receive
recommended vaccinations (23).
1-D. Interchangeable Use of Tdap Vaccines
A single dose of ADACEL® may be used for adults aged 19--64 years, and a single dose of either
BOOSTRIX® may be used for adolescents aged 11--18 years, regardless of the type or manufacturer of pediatric DTP
or pediatric DTaP used for childhood vaccination.
1-E. Preventing Adverse Events
Attention to proper immunization technique, including use of an appropriate needle length and standard routes
of administration (i.e., IM for Td and Tdap) might minimize the risk for adverse events. Guidance for administration of
vaccines is available (23).
Syncope can occur after vaccination and might be more common among young adults and adolescents than among
other age groups. Syncope rarely has resulted in serious injury
(23,410--412). Vaccine providers should strongly consider
observing patients for 15 minutes after they are vaccinated
(23,412). If syncope occurs, patients should be observed
until symptoms resolve.
1-F. Inadvertent Administration of Pediatric DTaP,
BOOSTRIX® Tdap, or Purified
Protein Derivative (PPD)
The potential for administration errors involving tetanus toxoid--containing vaccines
(413) and other vaccines is well-documented
(414--416). Pediatric DTaP and pediatric diphtheria toxoid and tetanus toxoid vaccine (DT)
formulations indicated for use in children aged 6 weeks--6 years should not be administered to adults or adolescents; these vaccines can
be associated with more severe local reactions than adult formulations
(350,417). Packaging of adult and adolescent
Tdap vaccines, pediatric DTaP, and purified protein derivative (PPD) might appear similar. Only one formulation of
Tdap, ADACEL,® is licensed and recommended for adults aged
19--64 years. Both formulations of Tdap
ADACEL®) are licensed and recommended for adolescents aged 11--18 years. Providers should review product
labels before administering these vaccines. If pediatric DTaP is
administered inadvertently to an adult or adolescent, or
if BOOSTRIX® is administered inadvertently to an adult aged
>19 years, the dose should be counted as the Tdap dose, and
the person should not receive an additional dose of Tdap. Adults or adolescents who receive PPD instead of Tdap should receive
a dose of Tdap.
1-G. Record Keeping
Health-care providers who administer vaccines to adults and adolescents are required to keep permanent vaccination
records of vaccines covered under the National Childhood Vaccine Injury Compensation Act. ACIP has recommended that
this practice include all vaccines (23). Encouraging adults and adolescents to maintain a personal vaccination record
is important to minimize administration of unnecessary vaccinations. Ideally, the personal vaccine record will document the
type of the vaccine, manufacturer, anatomic site, route, and date of administration, and the name of the administering facility
2. Contraindications and Precautions for Use of Td and Tdap
The following conditions are contraindications for Td or Tdap:
Td and Tdap are contraindicated for persons with a history of serious allergic reaction (i.e., anaphylaxis) to
any component of the vaccine. Because of the importance of tetanus vaccination, persons with a history of anaphylaxis
to components included in any Td or Tdap vaccines should be referred to an allergist to determine whether they have
a specific allergy to tetanus toxoid and whether they can safely receive TT vaccination.
Tdap (but not Td) is contraindicated for adults and adolescents with a history of encephalopathy (e.g., coma or
prolonged seizures) not attributable to an identifiable cause within 7 days of administration of a vaccine with pertussis
components. This contraindication is for the pertussis components, and these persons should receive Td instead of Tdap.
2-B. Precautions and Reasons to Defer Td or Tdap
A precaution is a condition in a vaccine recipient that might increase the risk for a serious adverse reaction
(23). In the following situations, vaccine providers should evaluate the risks and benefits of administering Td or Tdap:
Guillain-Barré syndrome with onset <6 weeks after previous dose of a tetanus toxoid--containing vaccine;
moderate or severe acute illness with or without fever until the acute illness resolves;
history of an Arthus reaction (see Important Local
Reactions) after a previous dose of a tetanus
toxoid--containing and/or diphtheria toxoid--containing vaccine, including MCV4. The vaccine provider should review the patient's medical
history to verify the diagnosis of Arthus reaction and consult with an allergist or immunologist. If an Arthus reaction was
likely, vaccine providers should consider deferring Td or Tdap vaccination until at
least10 years have elapsed since the last tetanus toxoid-- or diphtheria toxoid--containing vaccine was received. If the Arthus reaction was associated with a
vaccine that contained diphtheria toxoid without tetanus toxoid (e.g., MCV4), deferring
Td or Tdap might leave the adult or adolescent woman and her neonate unprotected against tetanus. In this situation, if the last tetanus
toxoid--containing vaccine was administered >10 years previously, vaccine providers may obtain a serum tetanus antitoxin level to
evaluate the need for tetanus vaccination (tetanus antitoxin levels
>0.1 IU/mL by ELISA are considered protective) or
administer TT; and
Tdap (but not Td) for adults aged 19--64 years with
unstable neurologic conditions (e.g., cerebrovascular events or
acute encephalopathic conditions) (1) and adolescents aged 11--18 years with any progressive neurologic disorder
including progressive encephalopathy, or uncontrolled epilepsy (until the condition has stabilized)
(2) (see Neurologic and Systemic Events).
2-C. Conditions Under Which Td or Tdap May Be Administered If Otherwise Indicated
The following conditions are not contraindications or precautions for Td or Tdap:
stable neurologic disorder, including well-controlled seizures, a history of a seizure disorder that has resolved, or
brachial neuritis after a previous dose of tetanus toxoid-- or diphtheria toxoid-- containing vaccine;
a history of an extensive limb swelling reaction that was not an Arthus hypersensitivity reaction after pediatric DTP
or DTaP or after Td;
immunosuppression, including persons with human
immunodeficiency virus (HIV) (the immunogenicity of Tdap
in persons with immunosuppression has not been studied and could be suboptimal);
intercurrent minor illness; and
use of antimicrobials.
Latex allergies other than anaphylactic allergies (e.g., a history of contact allergy to latex gloves) are not a contraindication
or precaution to Tdap (417). The tip and rubber plunger of the
BOOSTRIX® needleless syringe contain latex.
The BOOSTRIX® single dose vial and
ADACEL® preparations contain no latex. Certain Td products contain latex. The
package inserts should be consulted for details (Table 1).
3. Special Situations
3-A. Deferring Td during Pregnancy to Substitute
Tdap in the Immediate Postpartum Period
Tetanus and diphtheria booster vaccination is recommended for pregnant women if
>10 years have elapsed since the previous Td vaccination
(1,2). To add protection against pertussis, health-care providers may defer the Td vaccination
during pregnancy to substitute Tdap as soon as feasible postpartum if the woman is likely to have sufficient tetanus and
diphtheria protection until delivery.
Sufficient tetanus protection is likely if:
a pregnant woman aged <31 years has received a complete childhood series of immunization (4--5 doses of
pediatric DTP, DTaP, and DT) and >1 Td booster dose during adolescence or as an adult (a primary series consisting of 3 doses of Td
(or TT) administered during adolescence or as an adult substitutes for the childhood series of
a pregnant woman aged >31 years has received a complete childhood series of immunization (4--5 doses of
pediatric DTP, DTaP, and/or DT) and >2 Td booster doses,
a primary series consisting of 3 doses of Td (or TT) was administered during adolescence or as an adult substitute for
the childhood series of immunization,** or
a pregnant woman has a protective level of serum tetanus antitoxin
(>0.1 IU/mL by ELISA).
A woman should receive Td during pregnancy if she
does not have sufficient tetanus immunity to protect against maternal and neonatal tetanus, or
requires urgent booster protection against diphtheria (e.g., for travel to an area in which diphtheria is
Alternatively, health-care providers may choose to administer Tdap instead of Td during pregnancy (see Considerations
for Use of Tdap in Pregnant Women in Special Situations).
3-B. Postpartum Tdap When <2 Years Have Elapsed Since the Most Recent Td
Certain postpartum women (e.g., those who have received Td or TT within 2 years of the immediate postpartum
period) might benefit from Tdap for pertussis protection. Few subjects have been evaluated to determine the risk for adverse local
and systemic reactions after Tdap at intervals <2 years since the most recent Td (or other tetanus toxoid-- or diphtheria
toxoid--containing vaccine) (215). After obtaining a history to exclude women with moderate or severe adverse reactions
following previous doses, health-care providers may choose to administer Tdap in postpartum women who
received tetanus toxoid-- or diphtheria toxoid--containing
vaccine§§ <2 years previously (see Precautions and Reasons to Defer Td and Tdap).
Health-care providers should encourage vaccination of household and child care provider contacts of infants aged
<12 months for protection against pertussis, according to current recommendations (Table 2)
(1,2). Women should be advised of the symptoms of pertussis and the effectiveness of early antimicrobial prophylaxis for themselves, their infant, and members
of their household, if pertussis is suspected
3-C. History of Pertussis
Postpartum women who have a history of pertussis should receive Tdap according to the routine recommendation
(see Recommendations for Use of Postpartum Tdap). This practice is preferred because the duration of protection induced
by pertussis is unknown (waning might begin as early as 5--10 years after infection)
(4), and a diagnosis of pertussis often is
not reliably confirmed. Administering pertussis vaccine to persons with a history of pertussis presents no theoretical
3-D. Considerations for Use of Tdap in Pregnant
Women in Special Situations
ACIP recommends administration of Td for booster protection against tetanus and diphtheria in pregnant
women. However, health-care providers may choose to administer Tdap instead of Td during pregnancy to add protection
against pertussis in special situations. In these situations, the pregnant woman should be informed of the lack of data confirming
the safety and immunogenicity of Tdap in pregnant women, the unknown potential for early protection of the infant
against pertussis by transplacental maternal antibodies, and the possible adverse effect of maternal antibodies on the ability of
the infant to mount an adequate immune response to antigens in pediatric DTaP or conjugate vaccines containing tetanus
toxoid or diphtheria toxoid.
Special situations in which Tdap might be used might
include instances when
a pregnant woman has insufficient tetanus or diphtheria protection until delivery, or
a pregnant woman is at increased risk for pertussis.
Persons at increased risk for pertussis might include adolescents aged 11--18 years, health-care personnel, and
women employed in institutions in which a pertussis outbreak is
occurring or living in a community in which a pertussis outbreak
Adverse pregnancy outcomes are most common in the first trimester
(418). To minimize the perception of an association
of vaccine with an adverse outcome, vaccinating with tetanus toxoid--containing vaccines during the second or third trimester
Because information on the use of Tdap in pregnant women is lacking, both manufacturers of Tdap have established
a pregnancy registry. Health-care providers are encouraged to
report vaccination of pregnant women with Tdap, regardless
of trimester, to the appropriate manufacturer's registry. For
ADACEL,® vaccination should be reported to sanofi
pasteur, telephone 1-800-822-2463 (1-800-VACCINE), and for
BOOSTRIX,® vaccination should be reported to
GlaxoSmithKline Biologicals, telephone 1-888-825-5249.
3-E. Tetanus Prophylaxis for Wound Management
ACIP has recommended administering tetanus
toxoid--containing vaccine and tetanus immune globulin (TIG) as part
of standard wound management to prevent tetanus
(Table 11) (357). A Td booster might be recommended for
wound management in pregnant women if 5 years or more have elapsed since the previous Td
(1,2). Health-care providers may choose to substitute Tdap for Td during pregnancy in these women (see Considerations for Use of Tdap in Pregnant
Women in Special Situations). For pregnant women vaccinated previously with Tdap, Td should be used if a tetanus
toxoid--containing vaccine is indicated for wound care. Pregnant women who have completed the 3-dose primary tetanus
vaccination series and have received a tetanus toxoid--containing vaccine within the preceding 5 years are protected against tetanus and
do not require a tetanus toxoid--containing vaccine as part of wound management.
To avoid unnecessary vaccination, health-care providers should attempt to determine whether the woman has completed
the 3-dose primary tetanus vaccination series. Pregnant women with unknown or uncertain previous tetanus vaccination
histories should be considered to have had no prior tetanus toxoid--containing vaccine and they should complete a 3-dose
primary series of immunization to prevent maternal and neonatal tetanus (see Pregnant Women with Unknown or Incomplete
Tetanus Vaccination). Pregnant women who have not completed the primary series might require tetanus toxoid and
passive vaccination with TIG at the time of wound management (Table 11). When both TIG and a tetanus
toxoid--containing vaccine are indicated, each product should be administered using a separate syringe at different anatomic sites.
Pregnant women with a history of Arthus reaction after a previous dose of a tetanus toxoid--containing vaccine should not receive
a tetanus toxoid--containing vaccine until 10 years or more after the most recent dose, even if they have a wound that is
neither clean nor minor. If the Arthus reaction was associated with a vaccine that contained diphtheria toxoid without tetanus
toxoid (e.g., MCV4), deferring Td or Tdap might leave the pregnant women inadequately protected against tetanus, and TT
should be administered (see Precautions and Reasons to Defer Td or Tdap). In all circumstances, the decision to administer TIG
is based on the primary vaccination history for tetanus (Table 11).
3-F. Pregnant Women with Unknown or Incomplete
Pregnant women who never have been vaccinated against tetanus (i.e., have received no dose of pediatric DTP, DTaP, or
DT or of adult Td or TT) should receive a series of three vaccinations containing tetanus and diphtheria toxoids starting
during pregnancy to ensure protection against maternal and neonatal tetanus. A primary series consists of a first dose administered
as soon as feasible, a second dose at least 4 weeks later, and a third dose 6 calendar months after the second dose. If
feasible, pregnant women who have received fewer than 3 doses of tetanus toxoid--containing vaccine should complete the
3-dose primary series during pregnancy. Td is preferred for the doses during pregnancy. Health-care providers may choose
to substitute a single dose of Tdap for 1 dose of Td during pregnancy and complete the series with Td. In such cases, the
women should be informed of the lack of data on safety, immunogenicity, and pregnancy outcomes for pregnant women who
receive Tdap (see Considerations for Use of Tdap in Pregnant Women in Special Situations).
Reporting Adverse Events after Vaccination
As with any newly licensed vaccine, surveillance for rare adverse events associated with administration of Tdap
is important for assessing its safety in large-scale use. The
National Childhood Vaccine Injury Act of 1986 requires
health-care providers to report specific adverse events that follow tetanus, diphtheria, or pertussis vaccination. A table of reportable
events following vaccination is available from VAERS at
http://vaers.hhs.gov/reportable.htm. All clinically significant adverse
events should be reported to VAERS even if causal relation to vaccination is not certain. VAERS reporting forms and information
are available electronically at http://www.vaers.hhs.gov or by telephone, 1-800-822-7967.
To promote better timeliness and quality of safety data, providers are encouraged to report electronically by using web-based reporting
Vaccine Injury Compensation Program
VICP is a system established by the National Childhood Vaccine Injury Act of 1986 that enables compensation to be
paid on behalf of a person thought to have been injured or died as a result of receiving a vaccine covered by the program.
Anyone receiving a covered vaccine, regardless of age, can file a petition under VICP. The program is intended as an alternative to
civil litigation under the traditional tort system because negligence need not be proven.
The Act establishes 1) a vaccine injury table that lists the vaccines covered by the program; 2) the injuries, disabilities,
and conditions (including death) for which compensation might be paid without proof of causation; and 3) the period
after vaccination during which the first symptom or substantial aggravation of the injury must appear. Persons might
be compensated for an injury listed in the table or one that can be demonstrated to result from administration of a listed
vaccine. All tetanus toxoid--containing vaccines and vaccines with pertussis components (e.g., Tdap, Td, and pediatric DTaP)
are covered under the Act. Additional information regarding the program is available at
http://www.hrsa.gov/vaccine compensation or by telephone, 1-800-338-2382.
Areas for Future Research
Interest in vaccinating pregnant women to prevent infant pertussis declined in the late 1940s when whole-cell vaccine
trials demonstrated pertussis-specific antibodies in as many as 75% of infants vaccinated starting at birth or in the first few
months of life (38,186,188,218,237) and infant and childhood vaccination was adopted as the primary national strategy
for protection against childhood diseases
(419,420). Aside from initiatives to eliminate neonatal tetanus and more recently
to prevent influenza during pregnancy, limited attention has been focused on vaccinating pregnant women as a strategy
to prevent disease in the women and their infants during the first few months of life
(290,421--430). A major barrier to conducting vaccine trials in pregnant women is the potential liability from expected adverse pregnancy outcomes that
might be related temporally to vaccination
(388,431,432). However, the high morbidity and mortality of certain infections
that affect pregnant women and neonates warrant renewed consideration of the strategy of vaccinating pregnant women.
Ensuring the safety of vaccination for mother and fetus and for pregnancy outcomes is a public health priority. In
addition, important considerations include understanding whether a degree of protection might be achieved for the mother and for
her newborn by vaccinating during pregnancy, whether maternal vaccination would be required with each pregnancy to
achieve these benefits (if any), and whether change in the levels of transplacental maternal antibody might affect infant responses
to routine vaccination (159,222,224,228). Because few vaccines are currently recommended for pregnant women (e.g., Td
and influenza), the effects of the transplacental maternal
antibodies on the subsequent infant responses to routine vaccination
with the same antigens are not known for most vaccines. Change in the levels of transplacental antibody can affect
infant susceptibility to disease at a population level. For example, a decrease over time in the level of transplacental maternal
antibody from women who were immunized with measles vaccine during childhood (rather than by measles disease) resulted
in susceptibility to measles among their infants at an earlier age, and to the decision to recommend infant measles vaccination
at age 12 months rather than age 15--18 months in the United States
Major gaps exist in the knowledge of how best to prevent pertussis in early infancy. These include 1) the safety of
pertussis vaccines for pregnant women, their fetuses, and pregnancy outcomes; 2) the immunogenicity of acellular pertussis vaccines
pregnant women and transplacental maternal antibodies with respect to the timing of immunization during pregnancy; 3)
the degree and duration of protection against pertussis in early infancy through transplacental maternal antibodies; and 4)
the effects of transplacental maternal antibodies (induced by pertussis, DTP, DTaP, and/or Tdap) on the infant responses to
active immunization with pediatric DTaP and conjugate vaccines containing tetanus toxoid or diphtheria
toxoid (159,222,234,235,435). To understand the range of options for protecting women and infants from pertussis, studies
are needed to determine the safety and any benefits of accelerated infant pertussis vaccination schedules or dosing (e.g.,
pertussis vaccination starting at birth or employing acellular vaccines that do not contain diphtheria toxoid and tetanus
toxoid) (221,436,437). Alternative infant vaccination strategies examined independently or in conjunction with vaccinating
pregnant women will determine the most effective and practical approaches to reduce the morbidity and mortality of pertussis.
This report was prepared in collaboration with ACIP's Pertussis Working Group and consultants from academic institutions,
state health departments, other federal agencies, and private industry. Additional contributions were provided by Beth Bell, MD, Office of
the Director, and Pamela U. Srivastava, MS, Division of Bacterial Diseases, National Center for Immunization and Respiratory Diseases;
and by Barry I. Sorotkin, MS, Strategic Science and Program Unit, Coordinating Center for Infectious Diseases, CDC.
Food and Drug Administration. Product approval information---licensing action: ADACEL. Rockville, MD: US Department of Health
and Human Services, Food and Drug Administration; 2005. Available
Food and Drug Administration. Product approval information---licensing action: Boostrix. Rockville, MD: US Department of Health and
Human Services, Food and Drug Administration; 2005. Available at
Halperin SA. Canadian experience with implementation of an acellular pertussis vaccine booster-dose program in adolescents: implications for
the United States. Pediatr Infect Dis J 2005;24:S141--6.
Wirsing von König C-H, Campins-Marti M, Finn A, Guiso N, Mertsola J, Liese JG. Pertussis Immunization in the Global Pertussis
Initiative European Region: recommended strategies and implementation considerations. Pediatr Infect Dis J 2005;24:S87--S92.
National Health and Medical Research Council. The Australian immunization handbook. 8th ed. Canberra, Australia: Australian
Government Publishing Service; 2003.
Goldman WE, Klapper DG, Baseman JB. Detection, isolation, and analysis of a released
Bordetella pertussis product toxic to cultured tracheal
cells. Infect Immun 1982;36:782--94.
Morse SI, Morse JH. Isolation and properties of the leukocytosis- and lymphocytosis-promoting factor of
Bordetella pertussis. J Exp Med 1976;143:1483--502.
Liese JG, Renner C, Stojanov S, Belohradsky BH, The Munich Vaccine Study Group. Clinical and epidemiological picture of B pertussis and
B parapertussis infections after introduction of acellular pertussis vaccines. Arch Dis Child 2003;88:684--7.
Wolfe DN, Goebel EM, Bjornstad ON, Restif O, Harvill ET. The O antigen enables
Bordetella parapertussis to avoid Bordetella
pertussis-induced immunity. Infect Immunity 2007;75:4972--9.
Lapin JH. Whooping cough. 1st ed. Springfield, IL: Charles C Thomas; 1943.
Gordon JE, Hood RI. Whooping cough and its epidemiological anomalies. Am J Med Sci 1951;222:333--61.
Lee GM, Lett S, Schauer S, et al. Societal costs and morbidity of pertussis in adolescents and adults. Clin Infect Dis 2004;39:1572--80.
Sotir MJ, Cappozzo DL, Warshauer DM, et al. A countywide outbreak of pertussis. Initial transmission in a high school weight room
with subsequent substantial impact on adolescents and adults. Arch Pediatr Adolesc Med 2008;162:79--85.
Thomas PF, McIntyre PB, Jalaludin BB. Survey of pertussis morbidity in adults in western Sydney. Med J Aust 2000;173:74--6.
Cortese MM, Baughman AL, Brown K, Srivastava P. A "new age" in pertussis prevention. New opportunities though adult vaccination. Am J
Prev Med 2007;32:177--85.
Knoepfelmacher W. Whooping cough. In: Pfaundler M, Schlossmann A, eds. The diseases of children. Vol. III. Philadelphia, PA: J.B.
Lippincott Company; 1935:326--51.
Bortolussi R, Miller B, Ledwith M, Halperin S. Clinical course of pertussis in immunized children. Pediatr Infect Dis J 1995;14:870--4.
Rambar AC, Howell K, Denenholz EJ, Goldman M, Stanard R. Studies in immunity to pertussis. An evaluation of pertussis vaccination by
clinical means and by the opsonocytophagic test. JAMA 1941; 117:79--85.
Sako W, Treuting WL, Witt DB, Nichamin SJ. Early immunization against pertussis with alum precipitated vaccine. JAMA 1945;127: 379--84.
De Serres G, Shadmani R, Duval B, et al. Morbidity of pertussis in adolescents and adults. J Infect Dis 2000;182:174--9.
MacLean DW, Calder MA. Pertussis in pregnancy. Scott Med J 1981;26:250--3.
Beiter A, Lewis K, Pineda EF, Cherry JD. Unrecognized maternal peripartum pertussis with subsequent fatal neonatal pertussis. Obstet
Granström G, Granström M, Sterner G. Whooping cough in late pregnancy. Scand J Infect Dis, 1990;71(Suppl):27--9.
Bonnefoy O, Maugey-Laulom B, Diris B, Dallay D, Diard F. Fetal extradural hematoma: prenatal diagnosis and postmortem examination.
Fetal Diagn Ther 2005;20:262--5.
Haugen G, Jenum PA, Scheie D, Sund S, Stray-Pedersen B. Prenatal diagnosis of tracheal obstruction: possible association with maternal
pertussis infection. Ultrasound Obstet Gynecol 2000;15:69--73.
Cortese MM, Baughman AL, Zhang R, Srivastava P, Wallace GS. Pertussis hospitalizations among infants in the United States, 1993 to
2004. Pediatrics 2008;121:484--92.
Vincent JM, Wack RP, Person DA, Bass JW. Pertussis as the cause of recurrent bradycardia in a young infant. Pediatr Infect Dis J 1991;10; 340--2.
Vitek CR, Pascual FB, Baughman AL, Murphy TV. Increase in deaths from pertussis among young infants in the United States in the
1990s. Pediatr Infect Dis J 2003;22:628--34.
Gan VN, Murphy TV. Pertussis in hospitalized children. Am J Dis Child 1990;144:1130--4.
Bhatt P, Halasa N. Increasing rates of infants hospitalized with pertussis. Tenn Med 2007;100:37--9, 42.
Farizo KM, Cochi SL, Zell ER, Brink EW, Wassilak SG, Patriarca PA. Epidemiological features of pertussis in the United States, 1980--1989.
Clin Infect Dis 1992;14:708--19.
Paddock CD, Sanden GN, Cherry JD, et al. Pathology and pathogenesis of fatal
Bordetella pertussis infection in infants. Clin Infect Dis 2008.
Wortis N, Strebel PM, Wharton M, Bardenheier B, Hardy IRB. Pertussis deaths: report of 23 cases in the United States, 1992 and 1993.
Halasa NB, Barr FE, Johnson JE, Edwards KM. Fatal pulmonary hypertension associated with pertussis in infants: does extracorporeal
membrane oxygenation have a role? Pediatrics 2003;112:1274--8.
Donoso A, León J, Ramirez M, Rojas G, Oberpaur B. Pertussis and fatal pulmonary hypertension: a discouraged entity. Scand J Infect
Donoso AF, Cruces PI, Camacho JF, León JA, Kong JA. Exchange transfusion to reverse severe pertussis-induced cardiogenic shock. Pediatr
Infect Dis J 2006;25:846--8.
Goulin GD, Kaya KM, Bradley JS. Severe pulmonary hypertension associated with shock and death in infants infected with
Bordetella pertussis. Crit Care Med 1993;21:1791--4.
Tiwari TSP, Iqbal K, Brown K, Srivastava P, Baughman AL. Reported pertussis-related deaths to the National Notifiable Diseases
Surveillance System (NNDSS) and the Centers for Disease Control and Prevention (CDC) in the United States, 2000--2005 [Abstract 82]. Presented at
the 42nd National Immunization Conference, Atlanta, Georgia; March 17--20, 2008.
Izurieta HS, Kenyon TA, Strebel PM, Baughman AL, Shulman ST, Wharton M. Risk factors for pertussis in young infants during an outbreak
in Chicago in 1993. Clin Infect Dis 1996;22:503--7.
Halperin SA, Wang EEL, Law B, et al. Epidemiological features of pertussis in hospitalized patients in Canada, 1991--1997: report of
the immunization monitoring program---Active (IMPACT). Clin Infect Dis 1999;28:1238--43.
Elliott E, McIntyre P, Ridly G, et al. National study of infants hospitalized with pertussis in the acellular vaccine era. Pediatr Infect Dis
Bamberger E, Starets-Haham O, Greenberg D, et al. Adult pertussis is hazardous for the newborn. Infect Control Hosp Epidemol 2006;27: 623--5.
Schellekens J, Wirsing von König C-H, Gardner P. Pertussis sources of infection and routes of transmission in the vaccination era. Pediat Infect
Dis J 2005:24:S19--S24.
Christie CD, Peds DM, Baltimore RS. Pertussis in neonates. Am J Dis Child 1989;143:1199--202.
Surridge J, Segedin ER, Grant CC. Pertussis requiring intensive care. Arch Dis Child 2007;92:970--5.
Kowalzik F, Barbosa AP, Fernandes VR, et al. Prospective multinational study of pertussis infection in hospitalized infants and their
household contacts. Pediatr Infect Dis J 2007;26:238--42.
Roush S, Birkhead G, Koo D, Cobb A, Fleming D. Mandatory reporting of diseases and conditions by health care professionals and
laboratories. JAMA 1999;282:164--70.
Broutin H, Guégan JF, Elguero E, Simondon F, Cazelles B. Large-scale comparative analysis of pertussis population dynamics:
periodicity, synchrony, and impact of vaccination. Am J Epidemiol 2005;161:1159--67.
Aoyama T, Harashima M, Nishimura K, Saito Y. Outbreak of pertussis in highly immunized adolescents and secondary spread to their
families. Acta Paediatrica Japonica 1995;37:321--4.
Güris D. Strebel PM, Bardenheier B, et al. Changing epidemiology of pertussis in the United States: increasing reported incidence among
adolescents and adults, 1990--1996. Clin Infect Dis 1999;28:1230--7.
Lambert HJ. Epidemiology of a small pertussis outbreak in Kent County, Michigan. Public Health Rep 1965;80:365--9.
Edwards KM, Talbot TR. The challenges of pertussis outbreaks in healthcare facilities: is there a light at the end of the tunnel? Infect Control
Hosp Epidemiol 2006;27:537--40.
Wright EP, Joce R, Whincup G. Management of pertussis in a nurse at a special care baby unit. Commun Dis Public Health 2004;7:128--31.
McCall BJ, Tilse M, Burt B, Watt P, Barnett M, McCormack JG. Infection control and public health aspects of a case of pertussis infection in
a maternity health care worker. Commun Dis Intell 2002;26:584--6.
Baggett HC, Duchin JS, Shelton W, et al. Two nosocomial pertussis outbreaks and their associated costs---King County, Washington, 2004.
Infect Control Hosp Epidemiol 2007;28:537--43.
Spearing NM, Horvath RL, McCormack JG. Pertussis: adults as a source in healthcare settings. Med J Aust 2002;177:568--9.
Friedman DS, Curtis R, Schauer SL, et al. Surveillance for transmission and antibiotic adverse events among neonates and adults exposed to
a healthcare worker with pertussis. Infect Control Hosp Epidemiol 2004;25:967--73.
Honein MA, Paulozzi LJ, Himelright IM, et al. Infantile hypertrophic pyloric stenosis after pertussis prophylaxis with erythromycin: a case
review and cohort study. Lancet 1999;354:2101--5.
Bonacorsi S, Farnoux C, Bidet P, et al. Treatment failure of nosocomial pertussis infection in a very-low-birth-weight neonate. J Clin
Bryant KA, Humbaugh K, Brothers K, et al. Measures to control an outbreak of pertussis in a neonatal intermediate care nursery after exposure to
a healthcare worker. Infect Control Hosp Epidemiol 2006;27:541--5.
Altemeier WA, III, Ayoub EM. Erythromycin prophylaxis for pertussis. Pediatrics 1977;59:623--5.
Linnemann CC Jr., Ramundo N, Perlstein PH, et al. Use of pertussis vaccine in an epidemic involving hospital staff. Lancet 1975;2:540--3.
Vranken P, Pogue M, Romalewski C, Ratard R. Outbreak of pertussis in a neonatal intensive care unit---Louisiana, 2004. Am J Infect
Allen CW, Jeffery HE. Pertussis in the neonatal nursery. J Paediatr Child Health 2005;41:140--2.
Kutty PK, Lamias MJ, Murphy TV, et al. A nationwide assessment of pertussis and pertussis exposures in acute-care hospitals, United States,
2003--2005 [Abstract]. Presented at the 17th Annual Scientific Meeting of the Society for Health Care Epidemiology of America, Baltimore,
Maryland; April 14--17, 2007.
Matlow AG, Nelson S, Wray R, Cox P. Nosocomial acquisition of pertussis diagnosis by polymerase chain reaction. Infect Control Hosp
Calugar A, Ortega-Sánchez IR, Tiwari T, Oakes L, Jahre JA, Murphy TV. Nosocomial pertussis: costs of an outbreak and benefits of
vaccinating health care workers. Clin Infect Dis 2006;42:981--8.
Valenti WM, Pincus PH, Messner MK. Nosocomial pertussis: possible spread by a hospital visitor. Am J Dis Child 1980;134:520--1.
Kurt TL, Yeager AS, Guenette S, Dunlop S. Spread of pertussis by hospital staff. JAMA 1972;221:264--7.
Giugliani C, Vidal-Trécan G, Traore S, et al. Feasibility of azithromycin prophylaxis during a pertussis outbreak among healthcare workers in
a university hospital in Paris. Infect Control Hosp Epidemiol 2006;27: 626--9.
Phillips J. Whooping-cough contracted at the time of birth, with report of two cases. Am J Medical Sci 1921;161:163--5.
Granström G, Sterner G, Nord C-E, Granström M. Risk of pertussis-infected adults infecting newborn children [Reply]. J Infect
Williams WO. Risk of pertussis-infected adults infecting newborn children. J Infect Dis 1988;157:607--8.
Granström G, Sterner G, Nord CE, Granström M. Use of erythromycin to prevent pertussis in newborns of mothers with pertussis. J Infect
Council of State and Territorial Epidemiologists. CSTE position statement 1997--ID-9: Committee: Infectious Disease. Public health
surveillance, control and prevention of pertussis. Atlanta, GA: Council of State and Territorial Epidemiologists; 1997. Available at
Lind-Brandberg L, Welinder-Olsson C, Laggergård T, Taranger J, Trollfors B, Zackrisson G. Evaluation of PCR for diagnosis of
Bordetella pertussis and Bordetella
parapertussis infections. J Clin Microbiol 1998;36:679--83.
Cherry JD, Grimprel E, Guiso N, Heininger U, Mertsola J. Defining pertussis epidemiology. Clinical, microbiologic and serologic
perspectives. Pediatr Infect Dis J 2005;24:S25--34.
Sotir MJ, Cappozzo DL, Warshauer DM, et al. Evaluation of polymerase chain reaction and culture for diagnosis of pertussis in the control of
a county-wide outbreak focused among adolescents and adults. Clin Infect Dis 2007;44:1216--9.
Young SA, Anderson GL, Mitchell PD. Laboratory observations during an outbreak of pertussis. Clin Microbiol Newsletter 1987;9:176--9.
Grimprel E, Bégué P, Anjak I, Betsou F, Guiso N. Comparison of polymerase chain reaction, culture, and Western immunoblot serology
for diagnosis of Bordetella pertussis infection. J Clin Microbiol 1993;31:2745--50.
van der Zee A, Agterberg C, Peeters M, Mooi F, Schellekens J. A clinical validation of
Bordetella pertussis and Bordetella
parapertussis polymerase chain reaction: comparison with culture and serology using samples from patients with suspected whooping cough from a highly
immunized population. J Infect Dis 1996;174:89--96.
Viljanen MK, Ruuskanen O, Granberg C, Salmi TT. Serological diagnosis of pertussis: IgM, IgA and IgG antibodies against
Bordetella pertussis measured by enzyme-linked immunosorbent assay (ELISA). Scand J Infect Dis 1982;14:117--22.
Hallander HO. Microbiological and serological diagnosis of pertussis. Clin Infect Dis 1999;28(Suppl 2):S99--106.
Meade BD, Bollen A. Recommendations for use of the polymerase chain reaction in the diagnosis of
Bordetella pertussis infections. J Med
Loeffelholz MJ, Thompson CJ, Long KS, Gilchrist MJ. Comparison of PCR, culture, and direct fluorescent-antibody testing for detection
of Bordetella pertussis. J Clin Microbiol 1999;37:2872--6.
Dragsted DM, Dohn B, Madsen J, Jensen JS. Comparison of culture and PCR for detection of
Bordetella pertussis and Bordetella
parapertussis under routine laboratory conditions. J Med Microbiol 2004;53:749--54.
Lievano FA, Reynolds MA, Waring AL, et al. Issues associated with and recommendations for using PCR to detect outbreaks of pertussis. J
Clin Microbiol 2002;40:2801--5.
He Q, Viljanen MK, Arvilommi H, Aittanen B, Mertsola J. Whooping cough caused by
Bordetella pertussis and Bordetella parapertussis
in an immunized population. JAMA 1998;280:635--7.
Wadowsky RM, Michaels RH, Libert T, Kingsley LA, Ehrlich GD. Multiplex PCR-based assay for detection of
Bordetella pertussis in nasopharyngeal swab specimens. J Clin Microbiol 1996;34:2645--9.
Houard S, Hackel C, Herzog A, Bollen A. Specific identification of
Bordetella pertussis by the polymerase chain reaction. Res
Farrell DJ, McKeon M, Daggard G, Loeffelholz MJ, Thompson CJ, Mukkur TKS. Rapid-cycle PCR method to detect
Bordetella pertussis that fulfills all consensus recommendations for use of PCR in diagnosis of pertussis. J Clin Microbiol 2000;38:4499--502.
Muyldermans O, Soetens O, Antoine M, et al. External quality assessment for molecular detection of
Bordetella pertussis in European laboratories.
J Clin Microbiol 2005;43:30--5.
Qin X, Galanakis E, Martin ET, Englund JA. Multitarget PCR for diagnosis of pertussis and its clinical implications. J Clin
Sirko DA, Ehrlich GD. Laboratory facilities, protocols, and operations. In: Ehrlich GD, Greenberg SJ, eds. PCR-based diagnostics in
infectious disease. Boston, MA: Blackwell Scientific Publications; 1994:19--43.
Gilchrist MJR. Bordetella. In Balows A, Hausler WJ Jr, Herrman KL, Isenberg HD, Shadomy HJ, eds. Manual of clinical microbiology. 5th
ed. Washington, DC: American Society for Microbiology; 1991:471--7.
Meade BD, Deforest A, Edwards KM, et al. Description and evaluation of serologic assays used in a multicenter trial of acellular pertussis
vaccines. Pediatrics 1995;96(Pt 2):570--5.
Mattoo S, Cherry JD. Molecular pathogenesis, epidemiology, and clinical manifestations of respiratory infections due to
Bordetella pertussis and other
Bordetella subspecies. Clin Microbiol Rev 2005;18: 326--82.
Ward JI, Cherry JD, Chang S-J, et al.
Bordetella pertussis infections in vaccinated and unvaccinated adolescents and adults, as assessed in a
national prospective randomized acellular pertussis vaccine trial (APERT). Clin Infect Dis 2006;43:151--7.
Hauben M, Amsden GW. The association of erythromycin and infantile hypertrophic pyloric stenosis: causal or coincidental? Drug
SanFilippo JA. Infantile hypertrophic pyloric stenosis related to ingestion of erythromycine estolate: a report of five cases. J Pediatr
Stang H. Pyloric stenosis associated with erythromycin ingested through breastmilk. Minn Med 1986;69:669--70, 682.
Mahon BE, Rosenman MB, Kleinman MB. Maternal and infant use of erythromycin and other macrolide antibiotics as risk factors for
infantile hypertrophic pyloric stenosis. J Pediatr 2001;139:380--4.
Morrison W. Infantile hypertrophic pyloric stenosis in infants treated with azithromycin. Pediatr Infect Dis J 2007;26:186--8.
Mills KHG, Ryan M, Ryan E, Mahon BP. A murine model in which protection correlates with pertussis vaccine efficacy in children
reveals complementary roles for humoral and cell-mediated immunity in protection against
Bordetella pertussis. Infect Immun 1998;66:594--602.
Mills KHG. Immunity to Bordetella
pertussis. Microbes Infect 2001;3: 655--77.
Ausiello CM, Lande R, Urbani F, et al. Cell-mediated immunity and antibody responses to
Bordetella pertussis antigens in children with a history
of pertussis infection and in recipients of an acellular pertussis vaccine. J Infect Dis 2000;181:1989--95.
Cassone A, Ausiello CM, Urbani F, et al. Cell-mediated and antibody responses to
Bordetella pertussis antigens in children vaccinated with
acellular or whole-cell pertussis vaccines. Arch Pediatr Adolesc Med 1997;151:283--9.
Taranger J, Trollfors B, Lagergård T, et al. Correlation between pertussis toxin IgG antibodies in postvaccination sera and subsequent
protection against pertussis. J Infect Dis 2000;181:1010--3.
Roduit C, Bozzotti P, Mielcarek N, et al. Immunogenicity and protective efficacy of neonatal vaccination against
Bordetella pertussis in a murine model: evidence for early control of pertussis. Infect Immun 2002;70:3521--8.
Jenkinson D. Duration of effectiveness of pertussis vaccine: evidence from a 10 year community study. Br Med J (Clin Res Ed) 1988;296: 612--4.
Gustafsson L, Hessel L, Storsaeter J, Olin P. Long-term follow-up of Swedish children vaccinated with acellular pertussis vaccines at 3, 5, and
12 months of age indicates the need for a booster dose at 5 to 7 years of age. Pediatrics 2006;118:978--84.
Van der Wielen M, Van Damme P, Van Herck K, Schlegel-Haueter S, Siegrist C-A. Seroprevalence of
Bordetella pertussis antibodies in Flanders (Belgium). Vaccine 2003:21:2412--7.
Lugauer S, Heininger U, Cherry JD. Stejr K. Long-term clinical effectiveness of an acellular pertussis component vaccine and a whole cell
pertussis component vaccine. Eur J Pediatr 2002;161:142--6.
Guiso N, Njamkepo E, Vié le Sage F, et al. Long-term humoral and cell-mediated immunity after acellular pertussis vaccination compares
favorably with whole-cell vaccines 6 years after booster vaccination in the second year of life. Vaccine 2007;25:1390--7.
Mishulow L, Siegel M, Leifer L, Berkey SR. A study of pertussis antibodies. Protective, agglutinating and complement-fixing antibodies in
patients with pertussis, persons exposed to pertussis and persons with no known exposure. Am J Dis Child 1942;63:875--90.
Bradford WL, Day E, Martin F. Humoral antibody formation in
infants aged one to three months injected with a triple
(diphtheria-tetanus-pertussis) alum-precipitated antigen. Pediatrics 1949;4:711--7.
Cherry JD, Gornbein J, Heininger U, Stehr K. A search for serologic correlates of immunity to
Bordetella pertussis cough illnesses.
Cherry JD. Immunity to pertussis. Clin Infect Dis 2007;44:1278--9.
Di Sant'Agnese PA. Combined immunization against diphtheria, tetanus and pertussis in newborn infants. I. Production of antibodies in
early infancy. Pediatrics 1949;3:20--33.
Miller JJ Jr, Silverberg RJ, Saito TM, Humber JB. An agglutinative reaction for
Hemophilus pertussis. II. Its relation to clinical immunity. J
Granoff DM, Rappuoli R. Are serological responses to acellular pertussis antigens sufficient criteria to ensure that new combination vaccines
are effective for prevention of disease? Dev Biol Stand 1997;89:379--89.
Storsaeter J, Hallander HO, Gustafsson L, Olin P. Levels of anti-pertussis antibodies related to protection after household exposure to
Bordetella pertussis. Vaccine 1998;16:1907--16.
Zepp F, Knuf M, Habermehl P, et al. Pertussis-specific cell-mediated immunity in infants after vaccination with a tricomponent acellular
pertussis vaccine. Infect Immun 1996;64:4078--84.
Mooi FR, de Greeff SC. The case for maternal vaccination against pertussis. Lancet Infect Dis 2007;7:614--24.
Morris D, McDonald JC. Failure of hyperimmune gamma globulin to prevent whooping cough. Arch Dis Child 1957;32:236--9.
Granström M, Olinder-Nielsen AM, Holmblad P, Mark A, Hanngren K. Specific immunoglobulin for treatment of whooping cough.
Bradford WL. Use of convalescent blood in whooping cough. Am J Dis Child 1935;50:918--28.
Balagtas RC, Nelson KE, Levin S, Gotoff SP. Treatment of pertussis with pertussis immune globulin. J Pediatr 1971;79:203--8.
Bruss JB, Malley R, Halperin S, et al. Treatment of severe pertussis: a study of the safety and pharmacology of intravenous
pertussis immunoglobulin. Pediatr Infect Dis J 1999;18:505--11.
Halperin SA, Vaudry W, Boucher FD, et al. Is pertussis immune globulin efficacious for the treatment of hospitalized infants with pertussis?
No answer yet. Pediatr Infect Dis J 2007;26:79--81.
Granström M, Granström G. Serological correlates in whooping cough. Vaccine 1993;11:445--48.
Edwards KM. Acellular pertussis vaccines---a solution to the pertussis problem? J Infect Dis 1993;168:15--20.
Crowcroft NS, Pebody RG. Recent developments in pertussis. Lancet 2006;367:1926--36.
Pittman M. Pertussis toxin: the cause of the harmful effects and prolonged immunity of whooping cough. A hypothesis. Rev Infect
Trollfors B, Taranger J, Lagergård T, et al. A placebo-controlled trial of a pertussis-toxoid vaccine. New Engl J Med 1995;333:1045--50.
Hellwig SMM, Rodriquez ME, Berbers GAM, van de Winkel JGJ, Mooi FR. Crucial role of antibodies to pertactin in
Bordetella pertussis immunity. J Infect Dis 2003;188:738--42.
Storsaeter J, Olin P. Relative efficacy of two acellular pertussis vaccines during three years of passive surveillance. Vaccine 1992;10:142--4.
Knight JB, Huang YY, Halperin SA, et al. Immunogenicity and protective efficacy of a recombinant filamentous haemagglutinin from
Bordetella pertussis. Clin Exper Immunol 2006;144:543--51.
Hewlett EL, Halperin SA. Serological correlates of immunity to
Bordetella pertussis. Vaccine 1998;16:1899--900.
Cheers C, Gray DF. Macrophage behavior during the complaisant phase of murine pertussis. Immunology 1969;17:875--87.
Byrne P, McGuirk P, Todryk S, Mills KHG. Depletion of NK cells results in disseminating lethal infection with
Bordetella pertussis associated with a reduction of antigen-specific Th1 and enhancement of Th2, but not Tr1 cells. Eur J Imunol 2004;34:2579--88.
Carbonetti NH. Immunomodulation in the pathogenesis of
Bordetella pertussis infection and disease. Curr Opin in Pharmacol 2007;7:272--8.
Tran Minh NN, Edelman K, He Q, Viljanen MK, Arvilommi H, Mertsola J. Antibody and cell-mediated immune responses to
booster immunization with a new acellular pertussis vaccine in school children. Vaccine 1998;16:1604--10.
Mascart F, Hainaut M, Peltier A, Verscheure V, Levy J, Locht C. Modulation of the infant immune responses by first pertussis
vaccine administrations. Vaccine 2007;25:391--8.
Edelman KJ, He Q, Makinen JP, et al. Pertussis-specific cell-mediated and humoral immunity in adolescents 3 years after booster
immunization with acellular pertussis vaccine. Clin Infect Dis 2004;39:179--85.
Edelman K, He Q, Mäkinen J, et al. Immunity to pertussis 5 years after booster immunization during adolescence. Clin Infect Dis
Reynolds E, Walker B, Xing D, et al. Laboratory investigation of immune responses to acellular pertussis vaccines when used for
boosting adolescents after primary immunisation with whole cell pertussis vaccines: a comparison with data from clinical study. Vaccine 2006;24:3248--57.
Meyer CU, Zepp F, Decker M, et al. Cellular immunity in adolescents and adults following acellular pertussis vaccine administration. Clin
Vaccine Immunol 2007;14:288--92.
Ausiello CM, Lande R, la Sala A, Urbani F, Cassone A. Cell-mediated immune response of healthy adults to
Bordetella pertussis vaccine antigens. J Infect Dis 1998;178:466--70.
Giuliano M, Mastrantonio P, Giammanco A, Piscitelli A, Salmaso S, Wassilak SGF. Antibody responses and persistence in the two years
after immunization with two acellular vaccines and one whole-cell vaccine against pertussis. J Pediatr 1998;132:983--8.
Adams JM, Kimball AC, Adams FH. Early immunization against pertussis. Am J Dis Child 1947;74:10--8.
Bradford WL, Slavin B. Opsono-cytophagic reaction of the blood in pertussis. J Clin Invest 1937;16:825--8.
Goerke LS, Roberts P, Chapman JM. Neonatal response to DTP vaccines. Publ Health Rep 1958;73:511--9.
Kendrick P, Thompson M, Eldering G. Immunity response of mothers and babies to injections of pertussis vaccine during pregnancy. Am J
Dis Child 1945;70:25--8.
Lichty JA Jr, Slavin B, Bradford WL. An attempt to increase resistance to pertussis in newborn infants by immunizing their mothers
during pregnancy. J Clin Investigation 1938;17:613--21.
Miller JJ Jr, Faber HK, Ryan ML, Silverberg RJ, Lew E. Immunization against pertussis during the first four months of life. Pediatrics
Mishulow L, Leifer L, Sherwood C, Schlesinger SL, Berkey SR. Pertussis antibodies in pregnant women. Protective, agglutinating
and complement-fixing antibodies before and after vaccination. Am J Dis Child 1942;64:608--17.
Cohen P, Scadron SJ. The placental transmission of protective antibodies against whooping cough by inoculation of the pregnant mother.
Weichsel M, Douglas HS. Complement fixation tests in pertussis. J Clin Invest 1937;16:15--22.
Van Savage J, Decker MD, Edwards KM, Sell SH, Karzon DT. Natural history of pertussis antibody in the infant and effect on vaccine response.
J Infect Dis 1990;161:487--92.
Belloni C, De Silvestri A, Tinelli C, et al. Immunogenicity of a three-component acellular pertussis vaccine administered at birth.
Healy CM, Munoz FM, Rench MA, Halasa NB, Edwards KM, Baker CJ. Prevalence of pertussis antibodies in maternal delivery, cord, and
infant serum. J Infect Dis 2004;190:335--40.
Healy CM, Rench MA, Edwards KM, Baker CJ. Pertussis serostatus among neonates born to Hispanic women. Clin Infect Dis 2006;42: 1439--42.
Gonik B, Puder KS, Gonik N, Kruger M. Seroprevalence of
Bordetella pertussis antibodies in mothers and their newborns. Infect Dis
Obstet Gynecol 2005;13:59--61.
Novotny P, Macaulay ME, Hart TC, Skvaril F. Analysis of antibody profiles in children with whooping cough. Dev Biol Stand 1991;73:267--73.
Cattaneo LA, Reed GW, Haase DH, Wills MJ, Edwards KM. The seroepidemiology of
Bordetella pertussis infections: a study of persons ages
1--65 years. J Infect Dis 1996;173:1256--9.
Heininger U, Cherry JD, Stehr K. Serologic response and antibody-titer decay in adults with pertussis. Clin Infect Dis 2004;38:591--4.
Cherry JD, Chang S-J, Klein D, et al. Prevalence of antibody to
Bordetella pertussis antigens in serum specimens obtained from 1793
adolescents and adults. Clin Infect Dis 2004;39:1715--8.
Baughman AL, Bisgard KM, Edwards KM, et al. Establishment of diagnostic cutoff points for levels of serum antibodies to pertussis toxin,
filamentous hemagglutinin, and fimbriae in adolescents and adults in the United States. Clin Diag Lab Immunol 2004;11:1045--53.
de Melker HE, Versteegh FGA, Schellekens JFP, Teunis PFM, Kretzschmar M. The incidence of
Bordetella pertussis infections estimated in
the population from a combination of serological surveys. J Infect 2006;53:106--13.
Tran Minh NN, He Q, Edelman K, et al. Immune responses to pertussis antigens eight years after booster immunization with acellular vaccines
in adults. Vaccine 2000;18:1971--4.
Halperin B, McNeil SA, Langley JM, Mutch J, Mackinnon-Cameron D, Halperin SA. Kinetics of the serum IgG and IgA antibody response
(AbR) in healthy women of child-bearing age after immunization with Tdap [Abstract O20]. Can J Infect Dis Med Microbiol 2006;17:353.
Halperin SA, Scheifele D, Mills E, et al. Nature, evolution, and appraisal of adverse events and antibody response associated with the
fifth consecutive dose of a five-component acellular pertussis-based combination vaccine. Vaccine 2003;21:2298--306.
Le T, Cherry JD, Chang S-J, Knoll MD, et al. Immune responses and antibody decay after immunization of adolescents and adults with
an acellular pertussis vaccine: the APERT study. J Infect Dis 2004;190: 535--44.
Kirkland KB, Talbot EA, Decker MD, Edwards KM. Timing of immune responses to tetanus-diphtheria-acellular pertussis vaccine (Tdap)
in healthcare providers (HCP): implications for outbreak control [Abstract 858]. Presented at the 45th Annual Meeting of the Infectious
Diseases Society of America, San Diego, California; October 4--7, 2007.
Keitel WA. Muenz LR, Decker MD, et al. A randomized clinical trial of acellular pertussis vaccines in healthy adults: dose-response comparisons
of 5 vaccines and implications for booster immunization. J Infect Dis 1999:180:397--403.
Food and Drug Administration. Prescribing information. Tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine
adsorbed. ADACEL. Rockville, MD: US Department of Health and Human Services, Food and Drug Administration; 2005. Available at
Food and Drug Administration. Prescribing information.
BOOSTRIX® (tetanus toxoid, reduced diphtheria toxoid and acellular pertussis
vaccine, adsorbed). Rockville, MD: US Department of Health and Human Services, Food and Drug Administration; 2005. Available at
Food and Drug Administration. Guidance for industry: establishing pregnancy exposure registries. Rockville, MD: US Department of Health
and Human Services, Food and Drug Administration; 2002. Available at
Talbot EA, Brown K, Kirkland K, et al. Safety of mass immunization with tetanus-diphtheria-acellular pertussis vaccine (Tdap) during a
NH hospital pertussis outbreak [Abstract LB-36]. Presented at the 44th Annual Meeting of the Infectious Diseases Society of America,
Toronto, Canada; October 12--15, 2006.
Brown KH, Talbot EA, Kirkland KB, et al. Safety of Tdap for mass immunization of health-care personnel (HCP) [Abstract 40]. Presented at
the 41st National Immunization Conference, Kansas City, Missouri; March 5--8, 2007. Available at
Sako W. Studies on pertussis immunization. J Pediatr 1947;30:29--40.
Krugman S, Ward R. Pertussis. In: Infectious diseases of children. 4th ed. St. Louis, MO: The C.V. Mosby Company; 1968:31--45.
Cohen P, Scadron SJ. The effects of active immunization of the mother upon the offspring. J Pediatr 1946;29:609--19.
Siegrist C-A. The challenges of vaccine responses in early life: selected examples. J Comp Path 2007;137:S4--9.
Siegrist C-A. Mechanisms by which maternal antibodies influence infant vaccine responses: review of hypotheses and definition of
main determinants. Vaccine 2003;21:3406--12.
Crowe JE Jr. Influence of maternal antibodies on neonatal immunization against respiratory viruses. Clin Infect Dis 2001;33:1720--7.
Dagan R, Amir J, Mijalovsky A, et al. Immunization against hepatitis A in the first year of life: priming despite the presence of maternal
antibody. Pediatr Infect Dis J 2000;19:1045--52.
Björkholm B, Granström M, Taranger J, Wahl M, Hagber L. Influence of high titers of maternal antibody on the serologic response of infants
to diphtheria vaccination at three, five and twelve months of age. Pediatr Infect Dis J 1995;14:846--50.
Liebling J, Youmans GP, Schmitz HE. The occurrence of diphtheria antitoxin in the human pregnant mother, newborn infant, and the
placenta. Am J Obstet Gynecol 1941;41:641--52.
Letson GW, Shapiro CN, Kuehn D, et al. Effect of maternal antibody on immunogenicity of hepatitis A vaccine in infants. J
Redd SC, King GE, Heath JL, Forghani B, Bellini WJ, Markowitz LE. Comparison of vaccination with measles-mumps-rubella vaccine at 9, 12,
and 15 months of age. J Infect Dis 2004;189(Suppl 1):S116--22.
Di Sant'Agnese PA. Combined immunization against diphtheria, tetanus and pertussis in newborn infants: II. Duration of antibody
levels. Antibody titers after booster dose. Effect of passive immunity to diphtheria on active immunization with diphtheria toxoid. Pediatrics
Heininger U, Cherry JD, Christenson PD, et al. Comparative study of Lederle/Takeda acellular and Lederle whole-cell
pertussis-component diphtheria-tetanus-pertussis vaccines in infants in Germany. Vaccine 1994;12:81--6.
Baraff LJ, Leake RD, Burstyn DG, et al. Immunologic response to early and routine DTP immunization in infants. Pediatrics 1984;73:37--42.
Burstyn DG, Baraff LJ, Peppler MS, Leake RD, St Geme J Jr, Manclark CR. Serological response to filamentous hemagglutinin and
lymphocytosis-promoting toxin of Bordetella
pertussis. Infect Immun 1983;41:1150--6.
Englund JA, Anderson EL, Reed GF, et al. The effect of maternal antibody on the serologic response and the incidence of adverse reactions
after primary immunization with acellular and whole-cell pertussis vaccines combined with diphtheria and tetanus toxoids. Pediatrics 1995;96:580--4.
Ibsen PH. The effect of formaldehyde, hydrogen peroxide and genetic detoxification of pertussis toxin on epitope recognition by
murine monoclonal antibodies. Vaccine 1996;14:359--68.
Heron I, Chen FM, Fusco J. DTaP vaccines from North American Vaccine (NAVA): composition and critical parameters. Biologicals
Rappuoli R. The vaccine containing recombinant pertussis toxin
induces early and long-lasting protection. Biologicals 1999;27:99--102.
Di Sant'Agnese PA. Simultaneous immunization of newborn infants against diphtheria, tetanus and pertussis. Production of antibodies
and duration of antibody levels in an eastern metropolitan area. Am J Public Health 1950;40:674--80.
Anderson P, Ingram DL, Pichichero ME, Peter G. A high degree of natural immunologic priming to the capsular polysaccharide may not
prevent Haemophilus influenzae type b meningitis. Pediatr Infect Dis J 2000;19:589--91.
Kelly DF, Pollard AJ, Moxon ER. Immunological memory. The role of B cells in long-term protection against invasive bacterial pathogens.
Lucas AH, Granoff DM. Imperfect memory and the development of
Haemophilus influenzae type b disease. Pediatr Infect Dis J 2001;20: 235--9.
McVernon J, Johnson PDR, Pollard AJ, Slack MPE, Moxon ER. Immunologic memory in
Haemophilus influenzae type b conjugate vaccine
failure. Arch Dis Child 2003;88:379--83.
Helmy MF, Hammam M, El Kholy MS, Guirguis N.
Bordetella pertussis FHA antibodies in maternal/infants sera and colostrum. J Egyptian
Public Health Assoc 1992;67:195--212.
Oda M, Izumiya K, Sato Y, Hirayama M. Transplacental and transcolostral immunity to pertussis in a mouse model using acellular
pertussis vaccine. J Infect Dis 1983;148:138--45.
Oda M, Cowell JL, Burstyn DG, Thaib S, Manclark CR. Antibodies to
Bordetella pertussis in human colostrum and their protective activity
against aerosol infection of mice. Infect Immun 1985;47:441--5.
Elahi S, Buchanan RM, Babiuk LA, Gerdts V. Maternal immunity provides protection against pertussis in newborn piglets. Infect
Newburg DS, Walker WA. Protection of the neonate by the innate immune system of developing gut and of human milk. Pediatr Res
Hanson LÅ. Breastfeeding provides passive and likely long-lasting active immunity. Ann Allergy Asthma Immunol 1998;81:523--37.
Van de Perre P. Transfer of antibody via mother's milk. Vacccine 2003;21:3374--6.
Chappuis G. Neonatal immunity and immunisation in early age: lessons from veterinary medicine. Vaccine 1998;16:1468--72.
Kuttner A, Ratner B. The importance of colostrum to the new-born infant. Am J Dis Child 1923;25:413--34.
Cook TM, Protheroe RT, Handel JM. Tetanus: a review of the literature. Br J Anaesth 2001;87:477--87.
Axnick NW, Alexander ER. Tetanus in the United States: a review of the problem. Am J Public Health Nations Health 1957;47:1493--501.
Heath CW Jr, Zusman J, Sherman IL. Tetanus in the United States, 1950--1960. Am J Public Health Nations Health 1964;54:769--79.
Kretsinger K, Chen J, Nakao JH, Bingcang AL, Brown K, Srivastava P. Tetanus epidemiology in the United States, 2002--2006 [Abstract
995]. Presented at the 45th Annual Meeting of the Infectious Diseases Society of America, San Diego, California; October 4--7, 2007.
Craig AS, Reed GW, Mohon RT, et al. Neonatal tetanus in the United States: a sentinel event in the foreign-born. Pediatr Infect Dis
Kumar S, Malecki JM. A case of neonatal tetanus. Southern Med J 1991;84:396--8.
Edmondson RS, Flowers MW. Intensive care in tetanus: management, complications, and mortality in 100 cases. Br Med J 1979;1:1401--4.
Steinegger T, Wiederkehr M, Ludin HP, Roth F. Elektromyogramm als diagnostische Hilfe beim Tetanus. Schweiz Med Wochenschr
Bassin SL. Tetanus. Current treatment options in neurology 2004; 6:25--34.
Galazka AM. Tetanus. Module 3. In: The immunological basis for immunization series. Global Programme for Vaccines and
Immunization. Expanded Program on Immunization. Geneva, Switzerland: World Health Organization; 1993.
CDC. Diphtheria, tetanus, and pertussis vaccines. Tetanus prophylaxis in wound management: recommendation of the Public Health
Service Advisory Committee on Immunization Practices. MMWR 1966;15:416--8.
Edsall G. Current status of tetanus immunization. Arch Environ Health 1964;8:731--41.
Gardner P. Issues related to the decennial tetanus-diphtheria toxoid booster recommendations in adults. Infect Dis Clinics of North
McQuillan GM, Kruszon-Moran D, Deforest A, Chu SY, Wharton M. Serologic immunity to diphtheria and tetanus in the United States.
Ann Intern Med 2002;136:660--6.
Gergen PJ, McQuillan GM, Kiely M, Ezzati-Rice TM, Sutter RW, Virella G. A population-based serologic survey of immunity to tetanus in
the United States. N Engl J Med 1995;332:761--6.
Kruszon-Moran DM, McQuillan GM, Chu SY. Tetanus and diphtheria immunity among females in the United States: Are
recommendations being followed? Am J Obstet Gynecol 2004;190:1070--6.
Talan DA, Abrahamian FM, Moran GJ, et al. Tetanus immunity and physician compliance with tetanus prophylaxis practices among
emergency department patients presenting with wounds. Ann Emerg Med 2004;43:305--14.
Hinman AR, Foster SO, Wassilak SGF. Neonatal tetanus: potential for elimination in the world. Pediatr Infect Dis J 1987;6:813--6.
Vandelaer J, Birmingham M, Gasse F, Kurian M, Shaw C, Garnier S. Tetanus in developing countries: an update on the maternal and
neonatal tetanus elimination initiative. Vaccine 2003;21:3442--5.
Schofield FD, Tucker VM, Westbrook GR. Neonatal tetanus in New Guinea: effect of active immunization in pregnancy. Br Med J
Newell KW, Dueñas Lehmann A, LeBlanc DR, Garces Osorio N. The use of toxoid for the prevention of tetanus neonatorum. Final report of
a double-blind controlled field trial. Bull World Health Organ 1966;35:863--71.
Maclennan R, Schofield FD, Pittman M, Hardegree MC, Barile MF. Immunization against neonatal tetanus in New Guinea. Antitoxin response
of pregnant women to adjuvant and plain toxoids. Bull World Health Organ 1965;32:683--97.
Hardegree MC, Barile MF, Pittman M, Schofield FD, Maclennan R, Kelly A. Immunization against neonatal tetanus in New Guinea 2.
Duration of primary antitoxin response to adjuvant and plain toxoids and comparison of booster responses to adjuvant and plain toxoids. Bull World
Health Organ 1970;43:439--51.
Koenig MA, Roy NC, McElrath T, Shahidullah MD, Wojtyniak B. Duration of protective immunity conferred by maternal tetanus
toxoid immunization: further evidence from Matlab, Bangladesh. Am J Public Health 1998;88:903--7.
Vandelaer J, Shafique F, Nyandagazi P, Gasse F. Maternal and neonatal tetanus. Global Immunization News 2006 (May 24, 2006):2--3.
World Health Organization. Meeting of the immunization Strategic Advisory Group of Experts, Geneva, 10--11 April 1006: conclusions
and recommendations. Wkly Epidemiol Rec 2006:81:210--20.
Czeizel AE, Rockenbauer M. Tetanus toxoid and congenital abnormalities. Internat J Gynecol Obstet 1999;64:253--8.
Silverira CM, Cáceres VM, Dutra MG, Lopes-Camelo J, Castilla EE. Safety of tetanus toxoid in pregnant women: a hospital-based
case-control study of congenital anomalies. Bull World Health Organ 1995;73:605--8.
Chen ST, Edsall G, Peel MM, Sinnathuray TA. Timing of antenatal tetanus immunization for effective protection of the neonate. Bull
World Health Organ 1983;61:159--65.
Englund JA, Mbawuike IN, Hammill H, Holleman MC, Baxter BD, Glezen WP. Maternal immunization with influenza or tetanus toxoid
vaccine for passive antibody protection in young infants. J Infect Dis 1993;168:647--56.
Sarvas H, Seppälä I, Kurikka S, Siegberg R, Mäkelä O. Half-life of the maternal IgG1 allotype in infants. J Clin Immunol 1993;13:145--51.
Halsey N, Galazka A. The efficacy of DPT and oral poliomyelitis immunization schedules initiated from birth to 12 weeks of age. Bull
World Health Organ 1985;63:1151--69.
Sarvas H, Kurikka S, Seppälä IJT, Mäkelä PH, Mäkelä O. Maternal antibodies partly inhibit an active antibody response to routine tetanus
toxoid immunization in infants. J Infect Dis 1992;165:977--9.
Sangpetchsong V, Impat A, Dhiensiri K, Podhipak A. Effect of passive immunity to tetanus in DTP vaccinated infants. Southeast Asian J Trop
Med Public Health 1985;16:117--23.
Booy R, Aitken SJM, Taylor S, et al. Immunogenicity of combined diphtheria, tetanus, and pertussis vaccine given at 2, 3, and 4 months versus
3, 5, and 9 months of age. Lancet 1992;339:507--10.
Nohynek H, Gustafsson L, Capeding MRZ, et al. Effect of transplacentally acquired tetanus antibodies on the antibody responses to
Haemophilus influenzae type b-tetanus toxoid conjugate and tetanus toxoid vaccines in Filipino infants. Pediatr Infect Dis J 1999:18:25--30.
Claesson BA, Schneerson R, Robbins JB, et al. Protective levels of serum antibodies stimulated in infants by two injections of
Haemophilus influenzae type b capsular polysaccharide-tetanus toxoid conjugate. J Pediatr 1989;114:97--100.
Kurikka S, Ölander R-M, Eskola J, Käyhty H. Passively acquired anti-tetanus and
anti-Haemophilus antibodies and the response to
Haemophilus influenzae type b-tetanus toxoid conjugate vaccine in infancy. Pediatr Infect Dis J 1996;15:530--5.
Cooke JV, Holowach J, Atkins JE Jr., Powers JR. Antibody formation in early infancy against diphtheria and tetanus toxoids. J Pedatr
Kütükçüler N, Kurugöl Z, Egemen A, Yenigün A, Vardar F. The effect of immunization against tetanus during pregnancy for protective
antibody titers and specific antibody responses of infants. J Trop Pediatr 1996;42:308--9.
Panpipat C, Thisyakorn U, Chotpitayasunondh T, et al. Elevated levels of maternal anti-tetanus toxoid antibodies do not suppress the
immune response to a Haemophilus influenzae type b polyribosylphosphate-tetanus toxoid conjugate vaccine. Bull World Health Organ 2000;78:364--71.
Rowe J, Macaubas C, Monger T, et al. Heterogeneity in diphtheria-tetanus-acellular pertussis vaccine-specific cellular immunity during
infancy: relationship to variations in the kinetics of postnatal maturation of systemic Th1 function. J Infect Dis 2001;184:80--8.
Rowe J, Poolman JT, Macaubas C, Sly PD, Loh R, Holt PG. Enhancement of vaccine-specific cellular immunity in infants by passively
acquired maternal antibody. Vaccine 2004;22:3986--92.
Edwards KM, Meade BD, Decker MD, et al. Comparison of 13 acellular pertussis vaccines: overview and serologic response.
Stephens S, Kennedy CR, Lakhani PK, Brenner MK. In-vivo immune responses of breast- and bottle-fed infants to tetanus toxoid antigen and
to normal gut flora. Acta Paediatr Scand 1984;73:426--32.
Tiwari TSP, Golaz A, Yu DT, et al. Investigations of 2 cases of diphtheria-like illness due to toxigenic
Corynebacterium ulcerans. Clin Infect Dis 2008;46:395--401.
Galazka AM. Diphtheria. Module 2. In: The immunological basis for immunization series. Global Programme for Vaccines and
Immunization. Expanded Program on Immunization. Geneva, Switzerland: World Health Organization; 1993.
World Health Organization. Diphtheria vaccine. Wkly Epidemiol Rec 2006:81:24--32.
Andérodias J. Diphtérie et gravidisme. (Recherches cliniques et expérimentales.) Revue Mensuelle de Gynecologie, Obstetrique et Paediatrie
de Bourdeaux 1900;2:490--500.
Hersh J. A case of laryngeal diphtheria complicating the puerperium. Am J Obstret Gynecol 1933;25:133--6.
El Seed AM, Dafalla AA, Abboud OI. Fetal immune response following maternal diphtheria during early pregnancy. Ann Trop
Dexeus Font S. 2 cases of diphtheria in cases of cesarean section. Acta Ginecol (Madr) 1965;16:393--402
Dabrowski E. Diphtheritic vulvovaginitis in the course of pregnancy. Ginekol Pol 1956;27:705--8.
Andérodias J. Diphtérie puerpérale due au bacille de Loeffler. Gazette Hebdomadire des Sciences Medicales 1900;36:422--4.
Farizo KM, Strebel PM, Chen RT, Kimbler A, Cleary TJ, Cochi SL. Fatal respiratory disease due to
Corynebacterium diphtheriae: case report
and review of guidelines for management, investigation, and control. Clin Infect Dis 1993;16:59--68.
Vitek CR, Wharton M. Diphtheria in the former Soviet Union:
reemergence of a pandemic disease. Emerg Infect Dis 1998;4:539--50.
Vahlquist B. Studies on diphtheria. I. The decrease of natural antitoxic immunity against diphtheria. Acta Paediatrica 1948;35:117--29.
Vahlquist B. Response of infants to diphtheria immunization. Lancet 1949;1:16--8.
Ipsen J. Circulating antitoxin at the onset of diphtheria in 425 patients. J Immunol 1946;54:325--47.
Liebling J, Schmitz HE. Protection of infant against diphtheria during first year of life following the active immunization of the pregnant mother.
J Pediatr 1943;23:430--6.
Vahlquist B, Murray U, Persson NG. Studies on diphtheria. II. Immunization against diphtheria in newborn babies and in infants. Acta
Schick B. Diphtheria. In: Pfaundler M, Schlossmann A, eds. The diseases of children. Vol. III. Philadelphia, PA: J.B. Lippincott Company;
Slone D, Heinonen OP, Monson RR, Shapiro S, Hartz SC, Rosenberg L. Maternal drug exposure and fetal abnormalities. Materials and
methods. Clin Pharmacol Ther 1973;14:648--53.
Heinonen OP, Slone D, Shapiro S. Immunization agents. In: Kaufman DW, ed. Birth defects and drugs in pregnancy. Littleton, MA:
Publishing Sciences Group, Inc.; 1977:314--21.
Barr M, Glenny AT, Randall KJ. Diphtheria immunisation in young babies. Lancet 1950;1:6--10.
Christie A, Peterson JC. Immunization in the young infant. Response to combined vaccines. V. Am J Dis Child 1951;81:501--17.
Osborn JJ, Dancis J, Julia JF. Studies of the immunology of the newborn infant. II. Interference with active immunization by passive
transplacental circulating antibody. Pediatrics 1952;10:328--34.
Butler NR, Barr M, Glenny AT. Immunization of young babies against diphtheria. Br Med J 1954;1:476--81.
Bell JA. Diphtheria immunization. Use of an alum-precipitated mixture of pertussis vaccine and diphtheria toxoid. JAMA 1948;137: 1009--16.
Food and Drug Administration. Product approval information---licensing action, package insert: Td. Tetanus and diphtheria toxoids adsorbed
for adult use, sanofi pasteur. Rockville, MD: US Department of Health and Human Services, Food and Drug Administration; 2003.
Food and Drug Administration. Product approval information---licensing action, package insert: Td. Tetanus and diphtheria toxoids adsorbed
for adult use, Massachusetts Public Health Biologic Laboratories. Rockville, MD: US Department of Health and Human Services, Food and
Drug Administration; 2000.
Institute of Medicine, Committee on the Children's Vaccine Initiative. Planning alternative strategies toward full U.S. participation. In:
Mitchell VS, Philipose NM, Sanford JP, eds. The Children's Vaccine Initiative: achieving the vision. Washington, DC: National Academy Press; 1993.
Pichichero ME, Casey JR. Acellular pertussis vaccines for adolescents. Pediatr Infect Dis J 2005;24:S117--26.
Food and Drug Administration. FDA clinical briefing document for GlaxoSmithKline (GSK) Biologicals. Tetanus toxoid, reduced
diphtheria toxoid and acellular pertussis vaccine, adsorbed, BOOSTRIX. Rockville, MD: US Department of Health and Human Services, Food and
Drug Administration; 2005. Available at
Food and Drug Administration. FDA clinical briefing document for tetanus toxoid, reduced diphtheria toxoid and acellular pertussis
vaccine adsorbed (Tdap, ADACEL) adventis pasteur, limited and Corrections to errata in the FDA clinical briefing document. Rockville, MD:
US Department of Health and Human Services, Food and Drug
Administration; 2005. Available at
Food and Drug Administration. Proceedings of the Vaccines and Related Biologicals Products Advisory Committee, June 5, 1997. Rockville,
MD: US Department of Health and Human Services, Food and Drug Administration; 1997. Available at
Ward JI, Cherry JD, Chang S-J, et al. Efficacy of an acellular pertussis vaccine among adolesents and adults. New Engl J Med 2005;353: 1555--63.
Pichichero ME, Rennels MB, Edwards KM, et al. Combined tetanus, diphtheria, and 5-component pertussis vaccine for use in adolescents
and adults. JAMA 2005;293:3003--11.
Gustafsson L, Hallander HO, Olin P, Reizenstein E, Storsaeter J. A controlled trial of a two-component acellular, a five-component acellular, and a
whole-cell pertussis vaccine. N Engl J Med 1996;334:349--55.
sanofi pasteur limited. ADACEL Tdap vaccine (tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed).
VRBPAC briefing document. Rockville, MD: US Department of Health and Human Services, Food and Drug Administration; 2005. Available at
McNeil SA, Noya F, Dionne M, et al. Comparison of the safety and immunogenicity of concomitant and sequential administration of an
adult formulation tetanus and diphtheria toxoids adsorbed combined with acellular pertussis (Tdap) vaccine and trivalent inactivated influenza
vaccine in adults. Vaccine 2007;25:3464--74.
Schmitt HJ, von König CH, Neiss A, et al. Efficacy of acellular pertussis vaccine in early childhood after household exposure. JAMA
GlaxoSmithKline. BOOSTRIX (tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed, Tdap). VRBPAC
briefing document. Rockville, MD: US Department of Health and Human Services, Food and Drug Administration; 2005. Available at
Gruber MF. Maternal immunization: US FDA regulatory considerations. Vaccine 2003;21:3487--91.
Edsall G, Elliott MW, Peebles TC, Levine L, Eldred MC. Excessive use of tetanus toxid boosters. JAMA 1967;202:111--3.
Björkholm B, Granström M, Wahl M, Hedström C-E, Hagberg L. Adverse reactions and immunogenicity in adults to regular and increased
dosage of diphtheria vaccine. Eur J Clin Microbiol 1987;6:637--40.
Edsall G, Altman JS, Gaspar AJ. Combined tetanus-diphtheria immunizatioan of adults: use of small doses of diphtheria toxoid. Am J
Public Health 1954;44:1537--45.
Galazka AM, Robertson SE. Immunization against diphtheria with special emphasis on immunization of adults. Vaccine 1996;14:845--57.
Pappenheimer AM Jr., Edsall G, Lawrence HS, Banton HJ. A study of reactions following administration of crude and purified diphtheria
toxoid in an adult population. Am J Hyg 1950;52:353--70.
Relyveld EH, Bizzini B, Gupta RK. Rational approaches to reduce adverse reactions in man to vaccines containing tetanus and diphtheria
toxoids. Vaccine 1998;16:1016--23.
James G, Longshore WA Jr, Hendry JL. Diphtheria immunization studies of students in an urban high school. Am J Hyg
Lloyd JC, Haber P, Mootrey GT, et al. Adverse event reporting rates following tetanus-diphtheria and tetanus toxoid vaccinations: data from
the Vaccine Adverse Event Reporting System (VAERS), 1991--1997. Vaccine 2003;21:3746--50.
Halperin SA, Sweet L, Baxendale D. et al. How soon after a prior tetanus-diphtheria vaccination can one give adult-formulation
tetanus-diphtheria-acellular pertussis vaccine? Pediatr Infect Dis J 2006;25:195--200.
David ST, Hemsley C, Pasquali PE, Larke B, Buxton JA, Lior LY. Enhanced surveillance for vaccine-associated adverse events: dTap catch-up
of high school students in Yukon. Can Commun Dis Rep 2005;31:117--26.
Public Health Agency of Canada. Interval between administration of vaccines against diphtheria, tetanus, and pertussis: an Advisory
Committee Statement (ACS). National Advisory Committee on Immunization (NACI). Canada Communicable Disease Report 2005; 31:17--22.
Iskander J. New vaccines safety surveillance updates. Atlanta, GA: US Department of Health and Human Services, CDC, Advisory Committee
on Immunization Practices; 2007.
Froehlich H, Verma R. Arthus reaction to recombinant hepatitis B virus vaccine. Clin Infect Dis 2001;33:906--8.
Moylett EH, Hanson IC. Mechanistic actions of the risks and adverse events associated with vaccine administration. J Allergy Clin
Nikkels AF, Nikkels-Tassoudji N, Piérard G. Cutaneous adverse reactions following anti-infective vaccinations. Am J Clin Dermatol
Vaccine Safety Committee, Division of Health Promotion and Disease Prevention, Institute of Medicine. Executive summary from Adverse
effects of pertussis and rubella vaccines. In: Stratton KR, Howe CJ, Johnston JR Jr, eds. Adverse events associated with childhood vaccines:
evidence bearing on causality. Washington, DC: National Academy Press; 1994:309--17.
Terr AI. Immune-complex allergic diseases. In: Parslow TG, Stites DP, Terr AI, Imboden JB, eds. Medical immunology. 10th ed. New York,
NY: Lange Medical Books/McGraw Hill Companies Inc; 2001.
Ponvert C, Scheinmann P. Vaccine allergy and pseudo-allergy. Eur J Dermatol 2003;13:10--5.
Woo EJ, Burwen DR, Gatumu SN, Ball R, Vaccine Adverse Event Reporting System Working Group. Extensive limb swelling after
immunization: reports to the Vaccine Adverse Event Reporting System. Clin Infect Dis 2003;37:351--8.
Slade BA, Edwards KM, Rock M, et al. Reactogenicity of fifth dose of diphtheria, tetanus acellular pertussis (DTaP) vaccine : relationship to
post-vaccination antibody titers and cytokine levels [Abstract 136]. Presented at the Eighth International Symposium, Saga of the Genus
Bordetella, 1906--2006. Paris, France; November 7--10, 2006.
Scheifele DW, Halperin SA, Ferguson AC. Assessment of injection site reactions to an acellular pertussis-based combination vaccine,
including novel use of skin tests with vaccine antigens. Vaccine 2001;19:4720--6.
Liese JG, Stojanov S, Zink TH, et al. Safety and immunogenicity of Biken acellular pertussis vaccine in combination with diphtheria and
tetanus toxoid as a fifth dose at four to six years of age. Pediatr Infect Dis J 2001;20:981--8.
Ray P, Hayward J, Michelson D, et al. Encephalopathy after whole-cell pertussis or measles vaccination: lack of evidence for a causal association
in a retrospective case-control study. Pediatr Infect Dis J 2006;25:768--73.
Moore DL, Le Saux N, Scheifele D, Halperin SA, Members of the Canadian Paediatric Society/Health Canada Immunization Monitoring
Program Active (IMPACT). Lack of evidence of encephalopathy related to pertussis vaccine: active surveillance by IMPACT, Canada, 1993--2002.
Pediatr Infect Dis J 2004;23:568--71.
Berkovic SF, Harkin L, McMahon JM, et al. De-novo mutations of the sodium channel gene SCN1A in alleged vaccine encephalopathy:
a retrospective study. Lancet Neurol 2005:5;488--492.
Brown NJ, Berkovic SF, Scheffer IE. Vaccination, seizures and `vaccine damage.' Curr Opin Neurol 2007;20:181--7.
Pollard JD, Selby G. Relapsing neuropathy due to tetanus toxoid. Report of a case. J Neurological Sciences 1978;37:113--25.
Tuttle J, Chen RT, Rantala H, Cherry JD, Rhodes PH, Hadler S. The risk of Guillain-Barré Syndrome after tetanus-toxoid-containing vaccines
in adults and children in the United States. Am J Public Health 1997;87:2045--8.
Fenichel GM. Assessment: neurologic risk of immunization: report of the Therapeutics and Technology Assessment Subcommittee of the
American Academy of Neurology. Neurology 1999;52:1546--52.
Lee GM, LeBaron C, Murphy TV, Lett S, Schauer S, Lieu TA. Pertussis in adolescents and adults: should we vaccinate? Pediatrics
Purdy KW, Hay JW, Botteman MF, Ward JI. Evaluation of strategies for use of acellular pertussis vaccine in adolescents and adults: a
cost-benefit analysis. Clin Infect Dis 2004;39:20--8.
Chapman RH, Stone PW, Sandberg EA, Bell C, Neumann PJ. A comprehensive league table of cost-utility ratios and a sub-table of
"panel-worthy" studies. Med Decis Making 2000;20:451--67.
Stone PW, Teutsch S, Chapman RH, Bell C, Goldie SJ, Neumann PJ. Cost-utility analyses of clinical preventive services: published ratios,
1976--1997. Am J Prev Med 2000;19:15--23.
Winkelmayer WC, Weinstein MC, Mittleman MA, Glynn RJ, Pliskin JS. Health economic evaluations: the special case of end-stage renal
disease treatment. Med Decis Making 2002;22:417--30.
Lee GM, Murphy TV, Lett S, et al. Cost-effectiveness of pertussis vaccination in adults. Am J Prev Med 2007;32:186--93.
Halsey NA, Klein D. Maternal immunization. Pediatr Infect Dis J 1990;9:574--81.
American College of Obstetricians and Gynecologists. ACOG committee opinion No. 282. Immunization during pregnancy. Obstet
American College of Obstetricians and Gynecologists. ACOG committee opinion No. 357. Primary and preventive care: periodic
assessments. Obstet Gynecol 2006;108:1615--22.
Faix RG. Maternal immunization to prevent fetal and neonatal infection. Clin Obstet Gynecol 1991;34:277--87.
Roush SW, Murphy TV, and the Vaccine-Preventable Disease Table Working Group. Historical comparisons of morbidity and mortality
for vaccine-preventable diseases in the United States. JAMA 2007;298:2155--63.
CDC. Health, United States, 2006. With chartbook on trends in the health of Americans. Hyattsville, MD: US Department of Health and
Human Services, CDC; 2006.
Clark SJ, Adolphe S, Davis MM, Cowan AE, Kretsinger K. Attitudes of US obstetricians toward a combined tetanus-diptheria-acellular
pertussis vaccine for adults. Infect Dis Obstet Gynecol 2006;87:1--5.
Steele RW, Stanek L, Scarrow M. Inpatient standing orders for post-partum vaccination is an effective method to improve Tdap immunization
rates [Abstract P53]. Presented at the 10th Annual Conference on Vaccine Research, Baltimore, Maryland; April 30--May 2, 2007.
Shah S, Caprio M, Mally P, Henricks-Munoz K. Rationale for the administration of acellular pertussis vaccine to parents of infants in the
neonatal intensive care unit. J Perinatology 2007;27:1--3.
Bernbaum JC, Daft A, Anolik R, et al. Response of preterm infants to diphtheria-tetanus-pertussis immunizations. J Pediatr 1985; 107:184--8.
Robinson MJ, Heal C, Gardener E, Powell P, Sims DG. Antibody response to diphtheria-tetanus-pertussis immunization in preterm infants
who receive dexamethasone for chronic lung disease. Pediatrics 2004;113:733--7.
Berrington JE, Cant AJ, Matthews JNS, O'Keeffe M, Spickett GP, Fenton AC.
Haemophilus influenzae type b immunization in infants in
the United Kingdom: effects of diphtheria/tetanus/acellular pertussis/Hib combination vaccine, significant prematurity, and a fourth dose.
DiAngio CT, Maniscalco WM, Pichichero ME. Immunologic response of extremely premature infants to tetanus,
Haemophilus influenzae, and polio immunizations. Pediatrics 1995;96:18--22.
Omeaca F, Garcia-Sicilia J, García-Corbeira P, Boceta R, Torres V. Antipolyribosyl ribitol phosphate response of premature infants to primary
and booster vaccination with a combined diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated polio
virus/Haemophilus influenzae type b vaccine. Pediatrics 2007;119:179--85.
Ramsay ME, Miller E, Ashworth LAE, Coleman TJ, Rush M, Waight PA. Adverse events and antibody response to accelerated immunisation
in term and preterm infants. Arch Dis Child 1995;72:230--2.
Sprauer MA, Cochi SL, Zell ER, et al. Prevention of secondary transmission of pertussis in households with early use of erythromycin. Am J
Dis Child 1992;146:177--81.
Steketee RW, Wassilak SGF, Adkins WN, et al. Evidence for a high attack rate and efficacy of erythromycin prophylaxis in a pertussis outbreak in
a facility for developmentally disabled. J Infect Dis 1988;157:434--40.
Saari TN and the Committee on Infectious Diseases. Immunization of preterm and low birth weight infants. Pediatrics 2003;112:193--8.
Bisgard KM, Rhodes P, Connelly BL, et al. Pertussis vaccine effectiveness among children 6 to 59 months of age in the United States,
1998--2001. Pediatrics 2005;116:e285--94.
Hviid A, Stellfeld M, Andersen PH, Wohlfahrt J, Melbye M. Impact of routine vaccination with a pertussis toxoid vaccine in Denmark.
Juretzko P, von Kries R, Hermann M, Wirsing von König CH, Weil J, Giani G. Effectiveness of acellular pertussis vaccine assessed by
hospital-based active surveillance in Germany. Clin Infect Dis 2002;35:162--7.
Braun MM, Patriarca PA, Ellenberg SS. Syncope after immunization. Arch Pediatr Adolesc Med 1997;151:255--9.
Woo EJ, Ball R, Braun MN. Fatal syncope-related fall after immunization. Arch Pediatr Adolesc Med 2005;159:1083.
Edwards KM, Decker MD, Graham BS, Mezzatesta J, Scott J, Hackell J. Adult immunization with acellular pertussis vaccine. JAMA
Russell M, Pool V, Kelso JM, Tomazic-Jezic VJ. Vaccination of persons allergic to latex: a review of safety data in the Vaccine Adverse
Event Reporting System (VAERS). Vaccine 2004;23 :664--7.
March of Dimes Birth Defect Foundation. Fact sheets: miscarriage and birth defects. White Plains, NY: March of Dimes Birth Defect
American Academy of Pediatrics. In: Toomey J, ed. Report of the Committee on Therapeutic Procedures for Acute Infectious Diseases and
on Biologicals of the American Academy of Pediatrics. 8th ed. Evanston, IL: American Academy of Pediatrics; 1947.
Katz SL. Humoral antibody formation in infants aged one to three months injected with a triple (diphtheria-tetanus-pertussis)
alum-precipitated antigen [Commentary]. Pediatrics 1998;102 (Suppl pt. 2):207--9.
Munoz FM, Englund JA, Cheesman CC, et al. Maternal immunization with pneumococcal polysaccharide vaccine in the third trimester
of gestation. Vaccine 2002;20:826--37.
Munoz FM, Piedra PA, Glezen WP. Safety and immunogenicity of respiratory syncytial virus purified fusion protein-2 vaccine in pregnant
women. Vaccine 2003;21:3465--7.
Munoz FM, Greisinger AJ, Wehmanen OA, et al. Safety of influenza vaccination during pregnancy. Am J Obstet Gynecol 2005;192:1098--106.
Englund JA, Glezen WP, Thompson C, Anwaruddin R, Turner CS, Siber GR.
Haemophilus influenzae type b-specific antibody in infants after
maternal immunization. Pediatr Infect Dis J 1997;16:1122--30.
Englund JA, Glezen WP, Turner C, Harvery J, Thompson C, Siber GR. Transplacental antibody transfer following maternal immunization
with polysaccharide and conjugate Haemophilus
influenzae type b vaccines. J Infect Dis 1995;171:99--105.
O'Dempsey TJD, McArdle T, Ceesay SJ, et al. Meningococcal antibody titres in infants of women immunised with meningococcal
polysaccharide vaccine during pregnancy. Arch Dis Child 1996;74: F43--6.
McCormick JB, Gusmão HH, Nakamura S, et al. Antibody response to serogroup A and C meningococcal polysaccharide vaccines in infants
born of mothers vaccinated during pregnancy. J Clin Investigation 1980;65:1141--4.
Sumaya CV, Gibbs RS. Immunization of pregnant women with influenza A/New Jersey/76 virus vaccine: reactogenicity and immunogenicity
in mother and infant. J Infect Dis 1979;140:141--6.
Baker CJ, Rench MA, McInnes P. Immunization of pregnant women with group B streptococcal type III capsular polysachharide-tetanus
toxoid conjugate vaccine. Vaccine 2003;21:3468--72.
Baker CJ, Edwards MS. Group B streptococcal conjugate vaccines. Arch Dis Child 2003;88:375--8.
Trannoy E. Will ethical and liability issues and public acceptance allow maternal immunization? Vaccine 1998;16:1482--5.
Brent RL. Immunization of pregnant women: reproductive, medical and societal risks. Vaccine 2003;21:3413--21.
Gans HA, Yasukawa LL, Alderson A, et al. Humoral and cell-mediated immune responses to an early 2-dose measles vaccination regimen in
the United States. J Infect Dis 2004;190:83--90.
Markowitz LE, Albrecht P, Rhodes P, et al. Changing levels of measles antibody titers in women and children in the United States: impact
on reponse to vaccination. Kaiser Permanente Measles Vaccine Trial Team. Pediatrics 1996;97:53--8.
Nencioni L, Volpini G, Peppoloni S, et al. Properties of pertussis toxin mutant PT-9K/129G after formaldehyde treatment. Infect
McIntyre P, Wood N, Marshall H, Roberton D. Immunogenicity of birth and one month old acellular pertussis (Pa) vaccine [Abstract].
Presented at the 47th Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, Illinois; September 17--20, 2007.
Knuf M, Schmitt H-J, Wolter J, et al. Neonatal vaccination with an acellular pertussis vaccine accelerates the acquisition of pertussis antibodies
in infants. J Pediatr 2008;152:655--60e1.
* The recommended childhood schedule of pediatric DTaP is a dose at ages 6--8 weeks, at 4 months, and at 6 months and a booster dose at age 15--18
months and at age 4--6 years (23).
A list of members appears on inside back cover of this report.
§ Titers of >1:320 have been reported to correlate with protection in some studies
¶ An interval of 5 years since the most recent tetanus and diphtheria toxoids--containing vaccine is encouraged for routine vaccination of adolescents who
are not pregnant (2).
** Women who have had a 3-dose series as TT instead of Td will likely have protection against tetanus but might not be protected against diphtheria.
A protective titer of diphtheria antitoxin is >0.1 IU/mL by ELISA.
A list of areas in which diphtheria is endemic is available at www.cdc.gov/travel/diseases/dtp.htm.
§§ Tetanus toxoid-- and/or diphtheria toxoid--containing vaccines include pediatric DTP, DTaP, DT, other pediatric combination vaccines including
any of these components (e.g., pediatric DTaP--inactivated poliovirus vaccine--Hep B and pediatric
DTaP--Haemophilus influenzae type b), and adult
and adolescent Td, Tdap, and TT). MCV4 contains diphtheria toxoid but not tetanus toxoid
Advisory Committee on Immunization Practices Pertussis Working Group
Membership List, June 2006
Chairman: Dale Morse, MD, Albany, New York. Members: William L. Atkinson, MD, Atlanta, Georgia; Karen Broder, MD, Atlanta, Georgia; Angela Calugar, MD, Atlanta, Georgia; Allison R.
Christ, Falls Church, Virginia; Richard Clover, MD, Louisville, Kentucky; James Cheek, MD, Albuquerque, New Mexico; James D. Cherry, MD, Los
Angeles, California; Shelley Deeks, MD, Toronto, Ontario, Canada; Kristen R. Ehresmann, MPH, St Paul, Minnesota; Geoffrey Evans, MD,
Rockville, Maryland; Theresa Finn, PhD, Rockville, Maryland; Stanley Gall, MD, Louisville, Kentucky; Janet Gilsdorf, MD, Ann Arbor, Michigan; Andrea
D. Gelzer, MD, Bloomfield, Connecticut; Bernard Gonik, MD, Detroit, Michigan; Steve Gordon, MD, Cleveland, Ohio; John Iskander, MD,
Atlanta, Georgia; Marion F. Gruber, MD, Rockville, Maryland; Wayne E. Hachey, DO, MPH, Falls Church, Virginia; M. Patricia Joyce, MD, Atlanta,
Georgia; David L. Klein, PhD, Bethesda, Maryland; Grace M. Lee, MD, MPH, Boston, Massachusetts; Susan M. Lett, MD, Boston, Massachusetts; Sarah
S. Long, MD, Philadelphia, Pennsylvania; Bruce Meade, PhD, Rockville, Maryland; Trudy V. Murphy, MD, Atlanta, Georgia; Kathleen M. Neuzil,
MD, Seattle, Washington; Gregory A. Poland, MD, Rochester, Minnesota; Fran Rubin, PhD, Bethesda, Maryland; Abigail Shefer, MD, Atlanta,
Georgia; William Schaffner, MD, Nashville, Tennessee; Jane Siegel, MD, Dallas, Texas; Barbara A. Slade, MD, Atlanta, Georgia; Tejpratap Tiwari, MD,
Atlanta, Georgia; Gregory Wallace, MD, Atlanta, Georgia; Pat Whitley-Williams, MD, New Brunswick, New Jersey.
Advisory Committee on Immunization Practices
Membership List, June 24, 2006
Chairman: Jon Abramson, MD, Wake Forest University School of Medicine, Winston-Salem, North Carolina.
Executive Secretary: Larry Pickering, MD, CDC, Atlanta, Georgia.
Members: Ban Mishu Allos, MD, Vanderbilt University School of Medicine, Nashville, Tennessee; Judith Campbell, MD, Baylor College of
Medicine, Houston, Texas; Robert Beck, JD, Palmyra, Virginia; Reginald Finger, MD, Focus on the Family, Colorado Springs, Colorado; Janet Gilsdorf,
MD, University of Michigan, Ann Arbor, Michigan; Harry Hull, MD, Minnesota Department of Health, St. Paul, Minnesota; Tracy Lieu, MD,
Harvard Pilgrim Health Care and Harvard Medical School, Boston, Massachusetts; Edgar Marcuse, MD, Children's Hospital and Regional Medical
Center, Seattle, Washington; Dale Morse, MD, New York State Department of Health, Albany, New York; Julia Morita, MD, Chicago Department of
Public Health, Chicago, Illinois; Gregory Poland, MD, Mayo Medical School, Rochester, Minnesota; Patricia Stinchfield, MSN, Children's Hospitals
and Clinics of Minnesota, St. Paul, Minnesota; John J. Treanor, MD, University of Rochester, Rochester, New York; Robin Womeodu, MD,
University Hospital, Memphis, Tennessee. Ex-Officio Members: James E. Cheek, MD, Indian Health Services, Albuquerque, New Mexico; Wayne Hachey, DO, Department of Defense,
Falls Church, Virginia; Geoffrey S. Evans, MD, Health Resources and Services Administration, Rockville, Maryland; Bruce Gellin, MD, National
Vaccine Program Office, Washington, DC; Linda Murphy, Centers for Medicare and Medicaid Services, Baltimore, Maryland; George T. Curlin, MD,
National Institutes of Health, Bethesda, Maryland; Kristin Lee Nichol, MD, Department of Veterans Affairs, Minneapolis, Minnesota.
Liaison Representatives: American Academy of Family Physicians, Jonathan Temte, MD, Madison, Wisconsin, Doug Campos-Outcalt, MD,
Phoenix, Arizona; American Academy of Pediatrics, Keith Powell, MD, Akron, Ohio, Carol Baker, MD, Houston, Texas; America's Health Insurance
Plans, Andrea Gelzer, MD, Hartford, Connecticut; American College Health Association, James C. Turner, MD, Charlottesville, Virginia; American College
of Obstetricians and Gynecologists, Stanley Gall, MD, Louisville, Kentucky; American College of Physicians, Kathleen M. Neuzil, MD,
Seattle, Washington; American Medical Association, Litjen Tan, PhD, Chicago, Illinois; American Pharmacists Association, Stephan L. Foster,
PharMD, Memphis, Tennessee; Association of Teachers of Preventive Medicine, W. Paul McKinney, MD, Louisville, Kentucky; Biotechnology
Industry Organization, Clement Lewin, PhD, Cambridge, Massachusetts; Canadian National Advisory Committee on Immunization, Monica Naus,
MD, Vancouver, British Columbia; Health Care Infection Control Practices Advisory Committee, Steve Gordon, MD, Cleveland, Ohio; Infectious
Diseases Society of America, Samuel L. Katz, MD, Durham, North Carolina; London Department of Health, David Salisbury, MD, London, United
Kingdom; National Association of County and City Health Officials, Nancy Bennett, MD, Rochester, New York, Jeffrey S. Duchin, MD, Seattle,
Washington; National Coalition for Adult Immunization, David A. Neumann, PhD, Alexandria, Virginia; National Foundation for Infectious Diseases,
William Schaffner, MD, Nashville, Tennessee; National Immunization Council and Child Health Program, Romeo S. Rodriquez, Mexico City, Mexico;
National Medical Association, Patricia Whitley-Williams, MD, New Brunswick, New Jersey; National Vaccine Advisory Committee, Gary Freed,
MD, Swiftwater, Pennsylvania, Peter Paradiso, PhD, Collegeville, Pennsylvania; Society for Adolescent Medicine, Amy B. Middleman, MD, Houston,
Texas; Pharmaceutical Research and Manufacturers of America, Damian A. Araga, Swiftwater, Pennsylvania.
Use of trade names and commercial sources is for identification only and does not imply endorsement by the U.S. Department of
Health and Human Services.References to non-CDC sites on the Internet are
provided as a service to MMWR readers and do not constitute or imply
endorsement of these organizations or their programs by CDC or the U.S.
Department of Health and Human Services. CDC is not responsible for the content
of pages found at these sites. URL addresses listed in MMWR were current as of
the date of publication.
All MMWR HTML versions of articles are electronic conversions from typeset documents.
This conversion might result in character translation or format errors in the HTML version.
Users are referred to the electronic PDF version (http://www.cdc.gov/mmwr)
and/or the original MMWR paper copy for printable versions of official text, figures, and tables.
An original paper copy of this issue can be obtained from the Superintendent of Documents, U.S.
Government Printing Office (GPO), Washington, DC 20402-9371;
telephone: (202) 512-1800. Contact GPO for current prices.
**Questions or messages regarding errors in formatting should be addressed to