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Prevention of Pertussis, Tetanus, and Diphtheria Among
Pregnant and Postpartum Women and Their Infants
Recommendations of the Advisory Committee on Immunization
Practices (ACIP)
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: tkm4@cdc.gov.
Summary
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.
Introduction
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
with
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
(1,2).
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.
Methods
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
organizations.
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.
Pertussis
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
(26,27).
Clinical Features
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
one
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)
(31).
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
(39).
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
(44).
Infantile Pertussis
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
(5,7,34).
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.
Disease Burden
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
adults (1,34,76).
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
(79,80,85--88,93,94).
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.
Antimicrobial
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
(42,99).
Diagnosis
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
(101,102).
Culture
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
results (103,114).
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
United States.
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
(127).
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
(42,99).
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),
serious side 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
(4,75,144--150).
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
(152,156,157,172,173).
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
(140,141,149,158,178,180,181,183,185).
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
8)
(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
(99).
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
Tdap
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
outcomes
among women when an adverse outcome of pregnancy already might have occurred (e.g., an infant born with a birth
defect) (214).
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
third trimester.
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)
(190,192,193,217).
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
(37,186--191,193).
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
(35,189,190,192,193,219
). 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
(99,219).
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
(222,229).
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
<0.05) (233).
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
pediatric
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
(158,238--241).
Lactation
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
(23).
Tetanus
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
convalescence (251,252).
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
(254).
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
(254).
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).
Burden
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
consultation (251,252,269).
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
Postpartum Period
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
in
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
(1,2,252,271--273).
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
birthing center.
Vaccinating to Prevent Obstetric and Neonatal
Tetanus
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
(259,285,286).
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)
(288).
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
(292,304).
Lactation
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
(305).
Diphtheria
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%
(307,308).
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
(310).
Burden
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).
Diphtheria Immunity
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
(286,307,322).
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
(274,276).
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
is immune (226,250,321,325).
Safety
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
mother-child
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
doses
(229,237,292,293,295,
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
(229,237,324,329,330).
Lactation
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
(ADACEL® and
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
http://www.fda.gov/cber/vaccines.htm .
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
(1,2,212,213).
ADACEL®
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
ADACEL® among
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.
Immunogenicity
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
(1,2,212,336,341).
Safety
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
(1,2,212,338,341). Fever
>100.4°F
(>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
(341).
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
(1).
Simultaneous Administration of Tdap with Other
Vaccines
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
administration
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
(338,344).
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
(212).
BOOSTRIX®
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.
Immunogenicity
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
(1,213,336,337).
Safety
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
(1,213,336,337).
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
>100.4°F
[>38.0°C] [data not presented]) adverse
events (1,213,336,337). No case of whole-arm swelling was reported
(1).
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
(1,213,337,346).
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
(337).
Regulatory Considerations for Tdap in Pregnant
Women
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
(347,348).
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
(349,354--356).
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
(1,2).
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
vaccine (359,360).
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
after
Tdap, and a case of eosinophilic nephritis with onset 6 days after Tdap in a health-care worker with a history of a renal
transplant (215,216).
Important Local Reactions
Arthus Reaction
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
(1,357).
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
(23).
Neurologic and Systemic Events
Pertussis Components
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
and adolescents.
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
(365,379), subsequent
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)
(365).
Economic Considerations
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
(1,387).
Implementing Tdap
Preconception Assessments
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
(23).
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
be
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
not useful.
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.
Postpartum Tdap
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
(395,396).
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)
(47,53, 398--403).
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
(5,8,407--409).
Recommendations
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
vaccination.
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 Va |
