Updated Recommendations for Use of Tetanus Toxoid, Reduced Diphtheria Toxoid, and Acellular Pertussis Vaccine (Tdap) in Pregnant Women  Advisory Committee on Immunization Practices (ACIP), 2012



# Methods
In monthly teleconferences during 2012, the ACIP Pertussis Vaccines Work Group considered published, peer-reviewed literature and unpublished data relevant to vaccinating pregnant women with Tdap. When data were not available, expert opinion was considered. Summaries of the data reviewed and work group discussions were presented to ACIP before recommendations were proposed. The proposed Tdap recommendation for pregnant women was presented at the October 2012 ACIP meeting and approved by ACIP.

## Summary of acip deliberations and rationale
A dose of Tdap during each pregnancy Very young infants are dependent solely on maternal antibodies and lack the ability to mount a cell-mediated response [bib_ref] Importance of timing of maternal Tdap immunization and protection of young infants, Healy [/bib_ref]. The effectiveness and optimal concentration of maternal antipertussis antibodies in newborns are not yet known, but high levels of antibodies in the first weeks after birth likely confer protection and might prevent pertussis or modify disease severity [bib_ref] Role of maternal pertussis antibodies in infants, Van Rie [/bib_ref] [bib_ref] How can we best prevent pertussis in infants?, Libster [/bib_ref]. Studies on the persistence of antipertussis antibodies following a dose of Tdap show antibody levels in healthy, nonpregnant adults peak during the first month after vaccination, with substantial antibody decay after 1 year [bib_ref] A decennial booster dose of reduced antigen content diphtheria, tetanus, acellular pertussis..., Booy [/bib_ref] [bib_ref] Humoral immunity 10 years after booster immunization with an adolescent and adult..., Tomovici [/bib_ref]. Antibody kinetics in pregnant women likely would be similar. One study evaluated persistence of maternal ACIP is chartered as a federal advisory committee to provide expert external advice and guidance to the Director of the Centers for Disease Control and Prevention (CDC) on use of vaccines and related agents for the control of vaccine-preventable diseases in the civilian population of the United States. Recommendations for routine use of vaccines in children and adolescents are harmonized to the greatest extent possible with recommendations made by the American Academy of Pediatrics, the American Academy of Family Physicians (AAFP), and the American College of Obstetricians and Gynecologists. Recommendations for routine use of vaccines in adults are reviewed and approved by the American College of Physicians, AAFP, the American College of Obstetricians and Gynecologists, and the American College of Nurse-Midwives. ACIP recommendations adopted by the CDC Director become agency guidelines on the date published in the Morbidity and Mortality Weekly Report (MMWR).

## Updated recommendations for use of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine (tdap) in pregnant women -advisory committee on immunization practices (acip), 2012
antipertussis antibody concentrations from maternal delivery and cord blood pairs from women who received Tdap within the prior 2 years (4). The estimated antipertussis antibody concentrations at birth in most of these infants were considered unlikely to provide adequate protection. These findings indicate that maternal antibodies from women immunized before pregnancy waned quickly and the concentration of maternal antibodies was unlikely to be high enough to provide passive protection to infants (4). Because antibody levels wane substantially during the first year after vaccination, ACIP concluded a single dose of Tdap at one pregnancy would be insufficient to provide protection for subsequent pregnancies.

## Potential impact of tdap during pregnancy
For the 2011 ACIP recommendation, ACIP reviewed a decision analysis model developed to assess the impact and cost effectiveness of Tdap vaccination during pregnancy compared with immediately postpartum vaccination (1). The model showed that Tdap vaccination during pregnancy would prevent more infant cases, hospitalizations, and deaths compared with the postpartum dose [bib_ref] Preventing infant pertussis: a decision analysis comparing prenatal vaccination to cocooning, Terranella [/bib_ref].
For this updated recommendation, the model was rereviewed and the analysis updated. To estimate the potential impact of Tdap given either during pregnancy or postpartum, percent mean reductions were applied to the annual mean number of reported pertussis cases in infants aged <12 months dur-

## Birth statistics in the united states
To address the likelihood that women might receive Tdap during consecutive pregnancies in a short period, and therefore theoretically be at greater risk for adverse reactions, ACIP reviewed available data on birth statistics. In the United States, approximately 4 million births are reported each year, and an average of 2.06 children are born per woman in a lifetime. Among women with more than one pregnancy, only 2.5% have an interval 12 months between births [bib_ref] Fertility of men and women aged 15-44 years in the United States:..., Martinez [/bib_ref]. The majority of women, who have two pregnancies, have an interval of 13 months between births [bib_ref] Fertility of men and women aged 15-44 years in the United States:..., Martinez [/bib_ref]. For women of lower socioeconomic status, the interval between pregnancies generally is 18 months. Approximately 5% of women have four or more babies. ACIP concluded that the interval between subsequent pregnancies is likely longer than the persistence of maternal antipertussis antibodies, and were reassured that most women would receive only 2 Tdap doses and a small proportion of women would receive 4 doses of Tdap.

## Safety of repeat tdap administration to pregnant women
In 2011, ACIP concluded that available data did not suggest any elevated frequency or unusual patterns of adverse events in pregnant women who received Tdap and that the few serious adverse events reported were unlikely to have been caused by the vaccine; at that time, a dose of Tdap for every pregnancy was not considered [bib_ref] A decennial booster dose of reduced antigen content diphtheria, tetanus, acellular pertussis..., Booy [/bib_ref]. Published data on receipt of 2 doses of Tdap and multiple doses of tetanus toxoid-containing vaccines were reviewed. Receipt of a second dose of Tdap at a 5-or 10-year interval in healthy nonpregnant adolescents and adults was well tolerated; injection site pain was the most commonly reported adverse event [bib_ref] Tolerability and antibody response in adolescents and adults revaccinated with tetanus toxoid,..., Halperin [/bib_ref] [bib_ref] Immune responses in adults to revaccination with a tetanus toxoid, reduced diphtheria..., Halperin [/bib_ref] [bib_ref] Decennial administration of a reduced antigen content diphtheria and tetanus toxoids and..., Mertsola [/bib_ref]. The frequency of reported adverse events for the second dose was similar to the first dose in these same subjects and in naive controls receiving Tdap for the first time. Of the few serious adverse events reported, none were attributed to the vaccine. Fever was reported in 2.4%-6.5% of recipients of a Tdap booster; the frequency of fever was similar to that in the same subjects after their first Tdap dose and in naive controls [bib_ref] Tolerability and antibody response in adolescents and adults revaccinated with tetanus toxoid,..., Halperin [/bib_ref] [bib_ref] Immune responses in adults to revaccination with a tetanus toxoid, reduced diphtheria..., Halperin [/bib_ref]. Studies on short intervals (i.e., within 21 days or 2 years) between receipt of tetanus and diphtheria toxoids (Td) and Tdap or Tdap-inactivated polio vaccine in healthy, nonpregnant adolescents and adults found no serious adverse events [bib_ref] How soon after a prior tetanusdiphtheria vaccination can one give adult formulation..., Halperin [/bib_ref] [bib_ref] Safety of Tdap-IPV given one month after Td-IPV booster in healthy young..., Beytout [/bib_ref] [bib_ref] The safety of immunizing with tetanus-diphtheria-acellular pertussis vaccine (Tdap) less than 2..., Talbot [/bib_ref]. Fever was reported in 1.7%-6.8% of subjects who received Tdap 2 years after Td; rates were comparable to the control group and to cohorts that received Tdap longer after receipt of Td [bib_ref] How soon after a prior tetanusdiphtheria vaccination can one give adult formulation..., Halperin [/bib_ref] [bib_ref] Safety of Tdap-IPV given one month after Td-IPV booster in healthy young..., Beytout [/bib_ref]. The number of subjects in these studies was small, and therefore, the findings do not rule out the possibility of rare but serious adverse events.
A theoretical risk exists for severe local reactions (e.g., Arthus reactions, whole limb swelling) for pregnant women who have multiple closely spaced pregnancies. Arthus reactions and whole limb swelling are hypersensitivity reactions that have been associated with vaccines containing tetanus toxoid, tetanus and diphtheria toxoids, and/or pertussis antigens. Historical data on multiple doses of Td and tetanus toxoid vaccines (TT) indicate that hypersensitivity was associated with higher levels of preexisting antibody [bib_ref] Excessive use of tetanus toxoid boosters, Edsall [/bib_ref] [bib_ref] Adult immunization. Preparation and evaluation of combined fluid tetanus and diphtheria toxoids..., Levine [/bib_ref]. The frequency of side effects depended on antigen content, product formulation, preexisting antibody levels related to the interval since last dose, and the number of doses [bib_ref] Excessive use of tetanus toxoid boosters, Edsall [/bib_ref] [bib_ref] Adult immunization. Preparation and evaluation of combined fluid tetanus and diphtheria toxoids..., Levine [/bib_ref]. Challenges to reviewing historical data on multiple doses of TT and Td include differences in adjuvant and toxoid amounts in vaccines over time and severity of adverse events by number of vaccines received [bib_ref] Excessive use of tetanus toxoid boosters, Edsall [/bib_ref] [bib_ref] Adult immunization. Preparation and evaluation of combined fluid tetanus and diphtheria toxoids..., Levine [/bib_ref]. Most of the data are historical, and the risk for severe adverse events likely has been reduced with current formulations that contain lower doses of TT.
TT and Td have been used extensively in pregnant women worldwide to prevent neonatal tetanus; large studies on use of TT during pregnancy have not reported clinically significant severe adverse events [bib_ref] Neonatal tetanus in New Guinea. Effect of active immunization in pregnancy, Schofield [/bib_ref] [bib_ref] Garces Osoria N. The use of toxoid for the prevention of tetanus..., Newell [/bib_ref] [bib_ref] Immunization against neonatal tetanus in New Guinea: 2. Duration of primary antitoxin..., Hardegree [/bib_ref] [bib_ref] Immunization against neonatal tetanus in New Guinea. Antitoxin response of pregnant women..., Maclennan [/bib_ref]. Safety data on use of Td during multiple pregnancies have not been published. ACIP believes the potential benefit of preventing pertussis morbidity and mortality in infants outweighs the theoretical concerns of possible severe adverse events.
ACIP concluded that experience with tetanus-toxoid containing vaccines suggests no excess risk for severe adverse events for women receiving Tdap with every pregnancy. ACIP stated the need for safety studies of severe adverse events when Tdap is given during subsequent pregnancies. Plans for safety monitoring in pregnant women following Tdap administration include enhanced monitoring in Vaccine Adverse Event Reporting System (VAERS) and utilizing the Vaccine Safety Datalink (VSD) to assess acute adverse events, adverse pregnancy outcomes affecting the mother, and birth outcomes; assessing risks for rare adverse events in pregnant women after Tdap will require data collection for several years [bib_ref] Adverse event reports after tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis..., Zheteyeva [/bib_ref].

## Vaccination during the third trimester
Tdap may be administered any time during pregnancy, but vaccination during the third trimester would provide the highest concentration of maternal antibodies to be transferred closer to birth [bib_ref] Importance of timing of maternal Tdap immunization and protection of young infants, Healy [/bib_ref]. After receipt of Tdap, a minimum of 2 weeks is required to mount a maximal immune response to the vaccine antigens [bib_ref] Kinetics of pertussis immune responses to tetanus-diphtheria-acellular pertussis vaccine in health care..., Kirkland [/bib_ref] [bib_ref] Kinetics of the antibody response to tetanus-diphtheria-acellular pertussis vaccine in women of..., Halperin [/bib_ref]. Active transport of maternal immunoglobulin G does not substantially take place before 30 weeks of gestation [bib_ref] The influence of maternal immunization on infant immune responses, Englund [/bib_ref]. One study of pregnant women who received Tdap within the prior 2 years noted that maternal antibodies waned quickly; even women immunized during the first or second trimester had low levels of antibodies at term [bib_ref] Importance of timing of maternal Tdap immunization and protection of young infants, Healy [/bib_ref]. Therefore, to optimize the concentration of vaccine-specific antipertussis antibodies transported from mother to infant, ACIP concluded that pregnant women should be vaccinated with Tdap during the third trimester.

## Acip recommendations for pregnant women
ACIP recommends that providers of prenatal care implement a Tdap immunization program for all pregnant women. Health-care personnel should administer a dose of Tdap during each pregnancy, irrespective of the patient's prior history of receiving Tdap.

## Guidance for use
To maximize the maternal antibody response and passive antibody transfer to the infant, optimal timing for Tdap administration is between 27 and 36 weeks gestation although Tdap may be given at any time during pregnancy. For women not previously vaccinated with Tdap, if Tdap is not administered during pregnancy, Tdap should be administered immediately postpartum.

## Special situations
Pregnant women due for tetanus booster. If a tetanus and diphtheria booster vaccination is indicated during pregnancy (i.e., >10 years since previous Td), then Tdap should be administered. Optimal timing is between 27 and 36 weeks gestation to maximize the maternal antibody response and passive antibody transfer to the infant.
Wound management for pregnant women. As part of standard wound management to prevent tetanus, a tetanus toxoid-containing vaccine might be recommended for wound management in a pregnant woman if 5 years have elapsed since the previous Td booster. If a Td booster is recommended for a pregnant woman, health-care providers should administer Tdap.
Pregnant women with unknown or incomplete tetanus vaccination. To ensure protection against maternal and neonatal tetanus, pregnant women who never have been vaccinated against tetanus should receive three vaccinations containing tetanus and reduced diphtheria toxoids. The recommended schedule is 0, 4 weeks, and 6 through 12 months. Tdap should replace 1 dose of Td, preferably between 27 and 36 weeks gestation to maximize the maternal antibody response and passive antibody transfer to the infant.

## Cocooning
ACIP recommends that adolescents and adults (e.g., parents, siblings, grandparents, child-care providers, and health-care personnel) who have or anticipate having close contact with an infant aged <12 months should receive a single dose of Tdap to protect against pertussis if they have not received Tdap previously. Guidance will be forthcoming on revaccination of persons who anticipate close contact with an infant, including postpartum women who previously have received Tdap.

## Research needs
Future research needs will address the effectiveness of Tdap vaccination of pregnant women to prevent infant pertussis morbidity and mortality, the impact of timing of Tdap during pregnancy on infant pertussis, and safety of multiple doses of Tdap in pregnant women. CDC will monitor and assess the safety of Tdap use during pregnancy. Results from these studies and monitoring systems will inform future considerations made by ACIP on use of Tdap in preventing infant pertussis morbidity and mortality.
[fig] Mark: Sawyer, MD, Univ of California, San Diego, La Jolla, California. Jennifer L. Liang, DVM, Nancy Messonnier, MD, Thomas A. Clark, MD, Div of Bacterial Diseases, National Center for Immunization and Respiratory Diseases, CDC. Corresponding contributor: Jennifer L. Liang, jliang@cdc.gov, 404-639-2301. [/fig]