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This chapter should be cited as follows:
Maertens K, Leuridan E, Glob. libr. women's med.,
ISSN: 1756-2228; DOI 10.3843/GLOWM.419423

The Continuous Textbook of Women’s Medicine SeriesObstetrics Module

Volume 17

Maternal immunization

Volume Editors: Professor Asma Khalil, The Royal College of Obstetricians and Gynaecologists, London, UK; Fetal Medicine Unit, Department of Obstetrics and Gynaecology, St George’s University Hospitals NHS Foundation Trust, London, UK
Professor Flor M Munoz, Baylor College of Medicine, TX, USA
Professor Ajoke Sobanjo-ter Meulen, University of Washington, Seattle, WA, USA



First published: May 2023

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Neonates are most susceptible to severe pertussis-related morbidity and mortality. Despite high global vaccination coverage of pertussis-containing vaccines, pertussis incidence has increased, particularly in documented high-income countries. This increasing incidence does not only affect young infants, but also older age categories who are, however, less affected by clinical consequences of pertussis disease.

During the past decade, immunization of pregnant women with acellular pertussis (aP)-containing vaccines has been implemented in a number of countries worldwide to reduce the burden of pertussis disease in young infants and thus to protect them during the early, vulnerable first months of life. Vaccination against pertussis in pregnancy induces pertussis-specific antibodies in the mother, which are transferred across the placenta or via breastmilk towards the neonate, until protection by infant vaccination is provided. A large body of evidence has been generated in the last decade that support the safety, immunogenicity, and effectiveness of pertussis vaccination during pregnancy and that endorse the implementation of this vaccination strategy on a broad scale.


The epidemiology of pertussis has a cyclical nature, peaking every 3–5 years and the disease is endemic in all countries worldwide. Despite the availability of successful universal pertussis vaccination programs, the disease remains an important public health problem and is nowadays still one of the most common vaccine-preventable diseases in the world.1 In recent years, some countries have experienced an increase in the incidence of pertussis.2,3 The reasons for this resurgence are likely multifactorial, including an increase in disease awareness due to strengthening of surveillance systems, an increase in overall laboratory capacity and testing and an enhanced sensitivity of the PCR diagnostic methods, waning immunity both after natural infection and vaccination, the switch from whole cell pertussis (wP) to acellular pertussis (aP)-containing vaccines in many high-income countries resulting in a shift from a T-Helper-1 (Th1) and Th17 driven immune response to a Th2 driven immune response, pathogen adaptation with changes in the antigenic and genotypic characteristics of circulating Bordetella pertussis strains resulting in the emergence of Pertactin (Prn)-deficient strains, particularly in countries using aP-containing vaccines, and additional factors such as variable vaccine uptake and inadequate booster vaccination coverage.4 However, the relative contribution of each of these individual factors is not entirely clear.

The majority of data on the burden of pertussis disease still come from high-income countries. Therefore, assessing the global burden of pertussis is more challenging as comprehensive and reliable data from low- and middle-income countries (LMIC) are often lacking. Global figures from the World Health Organization (WHO) for 2018 projected 169,240 pertussis cases,5 which is likely a serious underestimation of the true burden of the disease. A WHO modeling study including data from 2014 was used to estimate global pertussis cases and deaths. This modeling study estimated that there were 24.1 million pertussis cases and 160,700 deaths from pertussis in children younger than 5 years in 2014, with the African region contributing the largest proportions.6

Pertussis disease occurs at all ages. Yet, the incidence, clinical presentation and potential complications of the disease vary across different age groups as outlined in Table 1.


Clinical presentation and complications of pertussis per age group (adapted from Pink book CDC:

Pertussis clinical features

Pertussis among children, adolescents, and adults

Pertussis complications in children

Incubation period 7–10 days (range 4–21 days)

Insidious onset, similar to the common cold with non-specific cough

Fever usually minimal throughout course of illness

Catarrhal stage: 1–2 weeks

Paroxysmal cough stage: 1–6 weeks

Convalescence stage: weeks to months

Presentation in infants may be with cough and apnoea

The typical "whoop" is often absent

Disease in older children and adults is often milder than in infants and young children

Infection may be asymptomatic, or may present as classic pertussis

Persons with mild disease may transmit the infection

Older persons often source of infection for children

Secondary bacterial pneumonia – most common

Neurologic complications – seizures, encephalopathy, more common among infants

Otitis media





Subdural hematomas


Rectal prolapse

The highest incidence of pertussis disease can be found in infants below 6 months of age, too young to be completely protected by the currently available infant vaccines and vaccination schedules and most vulnerable to severe pertussis-related disease and mortality. The clinical spectrum of pertussis disease in infants alters from trivial to severe illness with life-threatening complications, sometimes resulting in death.7

Pertussis also occurs in older children, adolescents, and adults who frequently serve as an important source of infection for infants.8 Serologic surveys indicate that pertussis is more common than generally appreciated with a discrepancy in the number of individuals with elevated antibody titers to pertussis antigens compared to the actual reported pertussis incidence.9,10,11 Some of these serologic surveys included pregnant women who had not been recently vaccinated documenting low levels of pertussis-specific antibodies in pregnant women and the lack of transplacental transported antibodies to their infants to protect them from disease.12,13,14

Symptoms of pertussis infections in this older age group tend to be less severe than in infants but are often associated with a persistent cough. Occasionally pertussis can even be asymptomatic. Only limited data are available on the impact of pertussis on pregnant women. A small US study showed comparable pertussis incidence in pregnant compared to non-pregnant women, but found a higher hospitalization rate and a higher likelihood of symptoms in pregnant compared to non-pregnant women.15 On the other hand, a study by Murphy et al. observed no increased morbidity and mortality, abnormal fetal development or adverse pregnancy outcomes after pertussis infection in pregnancy and comparable clinical symptoms and pertussis incidence between pregnant and non-pregnant women.16


Globally, two general types of pertussis vaccines are currently in use.17 The wP-containing vaccines are suspensions of the inactivated whole Bordetella pertussis organism combined with other antigens. These wP vaccines are only licensed for use in young children, with booster doses administered to adolescents and adults being all aP based vaccines. The pertussis components in the aP containing vaccines include one or more highly purified pertussis antigens. All contain pertussis toxin (PT), and in different combinations, they also contain filamentous hemagglutinin (FHA), pertactin (PRN) or fimbriae (FIM) in addition to other non-pertussis antigens.18

In most parts of the world, the first-generation, wP-containing vaccines are still used, whereas most high-income countries have gradually switched to the second-generation aP-containing vaccines due to the improved reactogenicity profile of the aP-containing vaccines. However, it has become apparent that immunity induced by the aP-containing vaccines wanes significantly faster than that induced by wP-containing vaccines. Therefore, the WHO currently recommends that countries using wP-containing vaccines for their primary immunization schedule should continue to do so, since these vaccines appear to provide longer lasting protection.18 Currently, there is no serological correlate of protection known for pertussis, but higher antibody titers against PT and to a lesser extent to PRN, have been associated with better protection against pertussis disease.19

There are several aP-containing vaccines available that may be used in adolescents and adults, and are thus included in national-level recommendations for use in pregnancy.

Adacel© (marketed in Europe as Covaxis© or Triaxis©) is a five-component aP-containing vaccine. It contains PT (2.5 μg), FHA (5 μg), PRN (3 μg), FIM type 2 and 3 (5 μg), tetanus toxoid (5 Lf [limit of flocculation], diphtheria toxoid (2 Lf) and adjuvant (0.33 mg aluminum). Adacel© is licensed for use in most countries for persons of 4 years or older. Combined with inactivated polio vaccine (IPV), the product is marketed as Repevax©.20 Boostrix© is a three-component aP containing vaccine. It contains PT (8 μg), FHA (8 μg), PRN (2.5 μg), tetanus toxoid (5 Lf) and diphtheria toxoid (2.5 Lf) and adjuvant (<0.39 mg aluminum). Boostrix© is licensed in most countries for persons 4 years of age or older. It is also available combined with IPV as Boostrix-IPV©.21


As a result of the resurgence of pertussis disease, with young infants disproportionately affected by severe morbidity and mortality, national advisory bodies [e.g., USA (2011),22 UK (2012),23 Belgium (2013)24 and others] started to recommend immunization with tetanus, diphtheria, and acellular pertussis (Tdap) vaccine for all pregnant women, at every pregnancy.25 In the meanwhile, pertussis vaccination during pregnancy is already implemented in a variety of other countries worldwide including Argentina,26 Australia,27 Canada,28 Italy,29 Mexico,30 The Netherlands,31 and Portugal32 amongst others.

The vaccination strategy offers passive protection to infants from birth until the start of their primary immunization series in the first months of life, thereby closing the neonatal susceptibility gap for pertussis infection.

Safety of pertussis vaccination during pregnancy

The first large prospective safety study on Tdap vaccination during pregnancy was published soon after the implementation of the strategy in the United Kingdom. In that report, safety data from 20,074 pregnant women vaccinated with Tdap during pregnancy were compared to a historical control group of unvaccinated women. These data showed no increased risk for adverse pregnancy and neonatal outcomes following Tdap vaccination during pregnancy.33 Also in the US, shortly after the implementation of the strategy, data from 123,494 singleton pregnancies monitored for adverse reactions following Tdap vaccination during pregnancy were published. No association between Tdap vaccination during pregnancy and increased risk for preterm birth, small for gestational age or hypertensive disorders during pregnancy was found. Only a small increased relative risk for chorioamnionitis at delivery was noted.34

As more evidence on the safety of Tdap vaccination during pregnancy became available over the years, these data were summarized in a systematic review including data from a total of 1.4 million pregnant women, of which 199,846 women had received a pertussis-component-containing vaccine during pregnancy. In that review, no increased risk for all prespecified safety outcomes was found, with the exception of a slightly increased relative risk for postvaccination fever and chorioamnionitis at delivery.35 The increased risk of fever was only significant in one large US cohort study that included 438,487 live births and estimated that an additional six cases of fever per 100,000 vaccinated pregnant women occurred as compared to unvaccinated pregnant women.36 However, in another study, pregnant women experienced fever after Tdap vaccination at a similar or even lower frequency compared to non-pregnant women.37 Overall, six studies showed a small increase in the relative risk of chorioamnionitis after Tdap vaccination during pregnancy.34,37,38,39,40,41 This increase was only significant in three studies that all used the “presence of respective ICD-9 codes” in electronic patient data as the definition of chorioamnionitis.34,39,41 Whether there is a causal relationship between chorioamnionitis and Tdap vaccination during pregnancy is still controversial because an increased risk for preterm birth or sepsis in infants from Tdap vaccinated women would be expected as a consequence of the increased risk for chorioamnionitis. However, in all studies reporting the association, the rate of preterm birth was even lower in infants from Tdap vaccinated women compared to infants from unvaccinated women. In addition, in some studies, the risk for admission to the neonatal intensive care unit was also lower in infants from Tdap-vaccinated women compared to infants born to unvaccinated women. To further rule out the possible relationship between Tdap vaccination during pregnancy and maternal and neonatal safety outcomes, future studies should apply standardized definitions of safety outcomes as suggested by the Global Alignment on Immunization Safety Assessment in Pregnancy Consortium.42

Recently, a Canadian study looked at the long-term safety of exposure to Tdap vaccination during pregnancy. Of 625,643 live births, 12,045 were exposed to Tdap in utero and followed for up to 6 years of age. No significant increased risks of adverse childhood outcomes after prenatal Tdap exposure were observed. Children born from women vaccinated against Tdap in pregnancy even had a lower risk of upper respiratory tract and gastrointestinal infections and a lower chance of needing urgent and inpatient health services.43

Since vaccination against pertussis is recommended in every pregnancy regardless of previous vaccination status and the time that elapsed since the last pregnancy, Sukumaran et al. studied the possible adverse outcomes of repeat Tdap vaccines during subsequent pregnancies. Using the Vaccine Safety Datalink network in the United States including data from 29,155 pregnant women, no increased risk of large local reactions, premature delivery, small for gestational age, or other adverse events following immunization were found when repeated booster doses were administered in intervals of at least 2 years.44,45

Immunogenicity of pertussis vaccination during pregnancy

Upon Tdap vaccination of pregnant women, vigorous antibody responses against all vaccine included antigens are induced. Yet, the persistence of these Tdap-specific antibodies is relatively short with already significant waning of antibody levels 1 year after vaccination. However, antibody levels 1 year after vaccination were still significantly higher than antibody levels in women not vaccinated with Tdap during pregnancy. These data illustrate that Tdap vaccination during pregnancy possibly does not provide optimal protection to the newborn during subsequent pregnancies46,47 and that vaccination in every pregnancy is needed, regardless of the interval between subsequent pregnancies.

Limited data on the comparison of immune responses to Tdap between pregnant and non-pregnant women are available. Two relatively small studies reported similar antibody responses between pregnant and non-pregnant women.46,48 However, one of the two studies reported lower T-cell responses to pertussis antigens in pregnant as compared to non-pregnant women.46 On the other hand, a third study involving a larger sample size observed lower antibody responses to PT and FHA in pregnant as compared to non-pregnant women.49 Therefore, data on possible differences in immune responses between pregnant and non-pregnant women are still inconclusive and further research is needed. Certainly because still no clear correlate of protection for pertussis is available.

To date, studies on the immunogenicity of Tdap vaccination in pregnant women were solely performed on women primed with wP-containing vaccines in infancy. However, women exclusively primed with aP-containing vaccines are slowly entering childbearing age. A US study50 found that type of pertussis vaccine a woman received during childhood significantly impacted maternal responses to vaccination during pregnancy, efficiency of transplacental transfer of antibodies, and infant antibody levels at birth. Infants born to aP-primed women had an anti-PT GMC that was less than half that of those born to wP-primed women. Anti-FHA GMCs as well as the efficiency of transplacental anti-PT transfer were significantly lower in infants born to aP-primed women compared with wP-primed women. These data suggest that infants born to aP-primed women may be more vulnerable to pertussis prior to their primary DTaP series. However, the exact clinical implications of these findings are unknown.

Tdap vaccination mainly induces IgG1 antibodies,51,52 which are actively transported across the placenta to the newborn resulting in higher antibody levels in the term neonate than in the mother.47,48,53,54,55 A reduction in this transplacental transport is seen in the case of a premature delivery. Yet, preterm infants born to women vaccinated with Tdap during pregnancy have significantly higher cord blood antibody levels compared to preterm infants born to unvaccinated women showing that despite the reduction in transplacental transport, there is still an acceptable level of transport of maternal antibodies from mother to infant in case of preterm delivery.56 Therefore, it is meaningful to vaccinate pregnant women against pertussis, even when a preterm delivery is threatening, since preterm infants do benefit from Tdap vaccination during pregnancy and especially because preterm infants are more vulnerable for pertussis-related complications.57,58,59

The vaccine-induced pertussis-specific maternal antibodies transported from mother to infant across the placenta offer protection to the newborn until the infant primary vaccination is started. However, high concentrations of maternal antibodies present at the moment of the infants’ immunization can have a suppressive effect on the infants’ immune response to their own vaccination.

To date, most studies looking at blunting were performed in high-income countries, where aP-containing vaccines are used for infant immunization. In these studies, data are conflicting regarding the antigen-specific antibodies affected, the degree, quantity and duration of such modifications in infant immune responses.47,48,54,56,60,61,62,63,64 Therefore, an individual-participant data meta-analysis of ten studies investigating infants’ antibody responses to routine immunization after Tdap vaccination during pregnancy was performed showing blunting for all vaccines including pertussis antigens after primary immunization with aP-containing vaccines in infants born to women vaccinated with Tdap during pregnancy. This blunting even persisted for some antigens beyond booster immunization  in the first or second year of life.

Few data on possible modification of infant immune responses after Tdap vaccination during pregnancy are available for wP-containing vaccines, the vaccines most exclusively used in low-middle income countries (LMICs). In a study conducted in Thailand, infants born to women vaccinated against Tdap in pregnancy and vaccinated with wP-containing vaccines for their infant vaccination showed significantly lower pertussis-specific antibody levels after the completion of their primary immunization schedule compared to infants vaccinated with aP-containing vaccines.55 These results might provide clues that more interference is present if infants are vaccinated with wP compared to aP-containing vaccines. Therefore, it is important to investigate whether these data are confirmed in larger studies and whether the increase in interference is clinically significant in LMICs.

Vaccines against pertussis that are currently used in pregnancy also contain tetanus toxoid (TT) and diphtheria toxoid (DT), so there is a theoretical potential interference with infant vaccines containing tetanus and diphtheria components. However, studies evaluating this aspect showed mixed and inconsistent results. Both for tetanus and diphtheria, some studies showed lower whereas others showed equal or even higher antibody levels after completion of the primary immunization in infants born to Tdap-vaccinated women compared to infants from unvaccinated women. For both diseases, this reduction in antibody levels had no impact on the clinical protection as the percentage of infant with seroprotective antibody levels was comparable between infants from Tdap vaccinated compared to unvaccinated women.47,48,54,60,61,62,63,68

Another important aspect of potential modification of infants’ immune responses is that some vaccines given during infancy are conjugated to TT or DT as a carrier protein, and thus a modification of the immune response to these vaccinations occur. After primary immunization with Haemophilus influenzae type b (Hib)-containing vaccine, Hib anti-polyribosylribitol phosphate levels were higher in infants born to women vaccinated with Tdap during pregnancy compared with infants of unvaccinated women, both after vaccination with aP- and wP-containing infant vaccines.63,68,69 However, no impact on clinical protection against Hib was observed.68 After primary immunization with meningococcal C-containing vaccines, anti-meningococcus C antibody levels did not differ between infants born to Tdap-vaccinated women versus unvaccinated pregnant women.69 However, Tdap immunization during pregnancy was associated with lower anti-pneumococcal capsular polysaccharide levels after immunization with pneumococcal conjugate vaccine (PCV)-13, a vaccine that is conjugated to CRM197, though this was not associated with lower seroprotection rates for most serotypes.63,70 In contrast to interference to PCV-13, no interference has been observed to nine of ten pneumococcal serotypes that are conjugated to protein D (as part of PCV-10) in infants born to Tdap-vaccinated women and vaccinated with PCV-10.71

Breastfeeding might provide additional protection against pertussis to the lactating infant via the transfer of vaccine-induced pertussis-specific antibodies in breast milk.72 Pertussis-specific secretory IgA and to a smaller extent IgG antibodies were detected in breastmilk of women vaccinated against pertussis during pregnancy, both after term and preterm delivery, with the highest antibody levels present in colostrum and then gradually declining until 12 weeks postpartum.73,74,75 However, whether these elevated pertussis-specific antibody levels in breastmilk could potentially contribute to protection against pertussis disease has not yet been demonstrated.

Effectiveness of pertussis vaccination during pregnancy

The effectiveness of Tdap vaccination during pregnancy for the prevention of pertussis in newborns has been well studied. In a systematic review, data from 855,546 mother–infant pairs from the United Kingdom, Spain, Australia, and United States were summarized.35 In all studies considering laboratory-confirmed pertussis infection, vaccine effectiveness was high, ranging from 69% to 91% for the prevention of pertussis infection in infants below 3 months of age,66,67,76,77,78,79,80 from 91% to 94% for the prevention of pertussis-related hospitalization,78,80 and 95% for the prevention of pertussis-related deaths.66 In a study by Becker-Dreps et al., slightly lower vaccine effectiveness rates were reported, probably because of the inclusion of clinically suspected cases on top of laboratory-confirmed cases in the analysis.81 Since prematurity is an important risk factor for pertussis-related complications, Tdap vaccination during pregnancy also needs to protect this vulnerable group. In the US, vaccination against pertussis in pregnancy was associated with a 91% vaccine effectiveness in preventing pertussis in preterm born infants below 6 months of age.82

Optimal timing of pertussis vaccination during pregnancy

The optimal timing of vaccination against pertussis in pregnancy is the time window in pregnancy where administration of an aP-containing vaccine is associated with (1) the highest transfer of pertussis-specific antibodies across the placenta to the fetus, (2) the highest vaccine effectiveness in young infants, and (3) the least inhibition of the infants’ immune response to their own vaccines. This optimal time window is still under debate, which is reflected in the varying national recommendations on pertussis vaccination during pregnancy. In general, Tdap vaccination during pregnancy is recommended in most countries for all pregnant women during every pregnancy in the late second or early third trimester of pregnancy.

When looking at the impact of timing on transfer of pertussis-specific antibodies across the placenta to the fetus and thus the impact of timing on the presence of pertussis-specific antibodies in cord blood, a study conducted in Thailand showed that vaccination with Tdap earlier in pregnancy was associated with higher pertussis-specific antibody levels in cord blood.55 Also, three other studies83,84,85 found that Tdap vaccination in the early third trimester of pregnancy resulted in higher pertussis-specific antibody levels in cord blood compared to vaccination in the late third trimester of pregnancy. Besides antibody levels, also the avidity of cord blood anti-PT IgG antibodies was higher when women were vaccinated in the early third trimester compared to late third trimester of pregnancy.86 In addition, a Swiss study demonstrated higher anti-PT and anti-FHA IgG levels in cord blood of women vaccinated between 13 and 25 weeks' gestational age compared to women vaccinated after 25 weeks' gestational age.87 This observation was also confirmed in preterm born infants.88 Given the discrepancy in studies on the optimal timing of Tdap vaccination during pregnancy and to further elucidate the optimal timepoint for vaccination in pregnancy to afford maximal protection to newborns, a recent multi-country analysis aimed to model the impact of timing of vaccination during pregnancy on infant antibody titers at birth. This analysis showed that term born infants on average achieve the highest antibody levels at birth if women were vaccinated at 31 weeks' gestational age. When this analysis considered both term and preterm infants, they showed that an interval of at least 7.5 weeks between vaccination and delivery was needed to achieve the highest cord blood antibody levels.89

Recently, some studies have tried to look at the effect of timing of pertussis vaccination during pregnancy on vaccine effectiveness, but results have been inconclusive so far probably because most studies were not powered to measure differences in vaccine effectiveness based on timing of vaccination during pregnancy.

An observational study from the US showed that vaccination in the third trimester between 27 and 36 weeks' gestational age, the recommended vaccination timeframe in the US, was more protective in the prevention of laboratory-confirmed pertussis in term born infants below 8 and below 12 weeks of age compared to vaccination outside this timeframe. A further analysis within the same study unfortunately did not reach a definite conclusion on whether vaccination early in the third trimester, between 27 and 31 weeks' gestational age, was associated with higher protection than vaccination later in the third trimester, between 32 and 36 weeks' gestational age, likely due to the small number of pertussis cases in each category.90

In addition, another study from the US reported that infants below 18 months of age and whose mother received the pertussis vaccine before 27 weeks' gestational age did not have reductions in pertussis rates compared with infants from unvaccinated women.81 A study from Spain reported that the vaccine effectiveness of vaccination against pertussis in pregnancy was 88% in the prevention of laboratory-confirmed pertussis in infants below 2 months of age. No difference in vaccine effectiveness was found between infants from mothers vaccinated between 26 and 31 weeks' gestational age versus infants from mothers vaccinated after 32 weeks' gestational age.91

Given the fact that results regarding the optimal timing of vaccination during pregnancy are still inconclusive and some aspects of the optimal timing are not yet studies, more research on the optimal timing of Tdap vaccination during pregnancy and the impact of this timing on immunogenicity in both women and infant, transfer of vaccine-induced antibodies across the placenta and via breastfeeding and vaccine effectiveness is certainly needed.


  • Vaccination of pregnant women with an acellular pertussis (aP)-containing vaccine is recommended for all pregnant women during every pregnancy in a lot of countries worldwide.
  • Recommendations vary across countries in view of timing on when to vaccinate during pregnancy. However, in most countries, vaccination in the late second or early third trimester of pregnancy is recommended.


The author(s) of this chapter declare that they have no interests that conflict with the contents of the chapter.



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