Article Text
Abstract
Objective This study is conducted to summarise and present the current knowledge on antenatal vaccination against pertussis with regard to national recommendations, coverage, immunogenicity, safety and effectiveness of the current available vaccines.
Methods A systematic review of the literature in English was undertaken from January 2011 to May 2016 with searches in four databases. The review conformed to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.
Results 47 studies fulfilled the inclusion criteria. Antenatal vaccination against pertussis induces high antibody concentrations in pregnant women, which are efficiently transferred transplacentally to the fetus and protect newborns when they are most vulnerable to pertussis. This strategy has been demonstrated to be safe, with no evidence of adverse pregnancy, birth or neonatal outcomes. Several countries have already introduced antenatal pertussis vaccination into their national immunisation programme with varying vaccination coverage influenced by various factors. Barriers to achieving high immunisation rates could be improved through better education of the public and healthcare professionals.
Conclusions There is now an increasing body of evidence to support the safety, immunogenicity and effectiveness of antenatal vaccination to reduce the morbidity and mortality associated with pertussis in neonates and young infants before they receive their primary immunisations. Narrowing the gap between scientific evidence and public health policies is critical in order to protect the most vulnerable as quickly as possible. The lessons learnt have important implications for implementation of new vaccines into the antenatal immunisation programme.
- Maternal vaccination
- pertussis
- safety
- immunogenicity
- effectiveness
- pregnancy
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Introduction
Bordetella pertussis continues to circulate and cause major epidemics both in the developed and the developing world despite the widespread use of pertussis vaccines. In 2008, WHO estimated that 16 million cases of pertussis occurred worldwide, with 95% of cases occurring in developing countries and nearly 200 000 children dying from the disease.1 In 2013, pertussis was still causing around 63 000 deaths in children aged <5 years,2 whereas in 2015, WHO reported 142 512 cases of pertussis worldwide.3 Changes in the circulating organism strains, improved diagnostic methods, waning of both vaccine and natural immunity as well as decreased effectiveness of the acellular compared with the whole cell vaccine have been proposed to explain the continuing circulation of B. pertussis. Adults and adolescents are considered to be the main and persistent transmitters of pertussis in the community, but the highest morbidity and mortality is among the young infants. In particular, the majority of severe pertussis cases, hospitalisations, intensive care admissions and deaths occur in infants younger than 2 months (ie, prior to receiving their primary immunisations).4 5 Proposed strategies to decrease pertussis disease burden in this vulnerable group include adolescent vaccination, cocooning and antenatal and neonatal vaccination.6 7 Neonatal vaccination inevitably leaves the infant at risk until they have responded to the first or subsequent doses,8–10 while cocooning relies on vaccination of everyone likely to have contact with the newborn with the aim of preventing infection in adults in order to reduce transmission to the infant and is difficult to implement.11 Maternal vaccination, on the other hand, not only protects the pregnant woman but also offers passive immunity to the newborn via transplacental transport of maternal antibodies and is currently considered as the most successful and effective intervention to prevent infant disease.6 12
In view of the public health importance of pertussis particularly in young infants, the importance of maternal vaccination in reducing disease burden and the recent pertussis epidemics during the last 5 years, we undertook this review to systematically summarise and present the recently published data on maternal vaccination against pertussis with regard to national recommendations, coverage, immunogenicity, safety and effectiveness of the current available vaccines.
Methods
Review methods and eligibility criteria
This review was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.13 We reviewed all published literature in the English language on maternal vaccination against pertussis in humans from January 2011 to May 2016. All publications were eligible for review, with particular emphasis on observational and interventional studies. The high volume of reviews already published in the field was also assessed for their context and references. They were included in the present systematic review only if they contained original results or had exceptional content.
Information sources
The search was conducted in the MEDLINE, EMBASE, Scopus and Cochrane library. The last search was performed on 31 May 2016. We used the following key words and combinations of these words for the search: pertussis, pregnan*, vaccin*, maternal, antenatal and immunisation/immunization. References within included articles were further reviewed for additional articles. Duplicate publications were identified and removed.
We identified 670 potentially relevant studies through database searches (figure 1). Of these, there were 309 duplicates and 314 were excluded on basis of title and abstract screening. The grey literature and national reports were not eligible for inclusion. We, therefore, included 47. The majority of included studies were from the USA and the UK.
Results
Recommendations for antenatal immunisation against pertussis
In 2011, the Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention in the USA recommended the combined tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine (Tdap) vaccination in the third trimester of pregnancy (between 27 and 36 weeks of pregnancy) for women who had never received a Tdap vaccine prior to pregnancy.14 This recommendation was modified in 2012 to include all women, regardless of prior receipt of Tdap and with every pregnancy, following evidence of waning vaccine immunity after vaccination in the first trimester of pregnancy or in a previous pregnancy.15
In the UK, following the national outbreak of pertussis in 2012, a temporary antenatal vaccination programme began in October 2012, offering Tdap to pregnant women, ideally at 28–32 weeks and up to delivery.16–18 In July 2014, the UK Joint Committee on Vaccination and Immunisation (JCVI) recommended that this programme should continue for at least five more years, owing to continuing high levels of pertussis activity.19 In April 2016, the UK’s Department of Health, following JCVI recommendation,20 and reassuring evidence of a Swiss study,21 of adequate immunogenicity earlier on in pregnancy, updated its advice to recommend antenatal vaccination at any time between 16 and 32 weeks of pregnancy,17 in order to provide greater opportunity for pregnant women to access the vaccine, improve protection for premature babies and increase vaccine-induced antibody levels at birth. Moreover, women may be vaccinated after week 32, recognising though that this does not offer optimal passive protection to the baby. However, if it is not possible to immunise earlier then vaccinating later in pregnancy is still advisable because it will directly protect pregnant women against disease, thereby reducing the risk of subsequent exposure to their offspring, and will also provide some protection to the newborn.
In addition to the USA and the UK, antenatal vaccination against pertussis is recommended and government funded in a variety of countries worldwide22 23 including Argentina,24 Belgium,25 Brazil,22 Colombia,22 El Salvador,22 Mexico,22 New Zealand,26 Australia,27 Switzerland,28 Ireland,29 Czech Republic,29 Israel,30 Spain31 and Greece.32
Immunogenicity and interference
Transplacental transfer of vaccine-induced antibodies from the mother to the fetus before birth and through breast feeding after birth is the rationale behind antenatal immunisation.33 The immunogenicity of pertussis-containing vaccines has been studied in various studies where almost a thousand women were vaccinated in pregnancy and compared with unvaccinated pregnant women (table 1). These studies have shown high rates of passive antibody transfer from the mother to the fetus prior to delivery. In one randomised trial, the 33 pregnant women who received Tdap at 30–32 weeks gestation and their infants had higher pertussis antibodies at delivery compared with the 15 women who received the vaccine post partum and their infants.34 In another randomised controlled trial on pneumococcal vaccination schedules, higher pertussis antibody concentrations prior to routine infant immunisation at 2 months of age were reported in 31 premature infants whose mothers had received Tdap at 28–32 weeks gestation, compared with premature infants of unvaccinated mothers.35 Other studies have also reported high concentrations and high antibody avidity of vaccine-induced antibodies in infants of mothers receiving Tdap in the third trimester.25 36–40 A Spanish study reported a high correlation between maternal and infant pertussis toxin (PT) antibody concentrations following Tdap vaccination at ≥20 weeks gestation.41 With regard to the timing of maternal vaccination, a prospective Australian study reported higher pertussis antibody concentrations in the cord blood of infants born to women immunised at 28–32 weeks gestation compared with those vaccinated at 33–36 weeks gestation, suggesting that vaccination early in the third trimester may be more effective than later in pregnancy.40 More recently, a Swiss study found that early second-trimester maternal Tdap immunisation (between 13 and 25 weeks) was associated with significantly higher neonatal pertussis antibody concentrations compared with vaccination after 26 weeks gestation.21
Maternally derived antibodies are known to interfere with infant responses to primary immunisation with the same vaccine antigens.42 Immune interference has also been observed after immunisation with DTaP vaccines at birth.43 This phenomenon is defined as ‘blunting’ of vaccine responses.6 Following the introduction of antenatal pertussis vaccination in October 2012, 141 infants in England were followed up with pre-immunisation and post-immunisation blood tests at 2 and 5 months, respectively. This study found higher pertussis antibodies at 2 months compared with a historical cohort of 246 infants born to unvaccinated mothers. However, only PT antibodies increased post-immunisation at 5 months of age, whereas filamentous haemagglutinin (FHA) antibodies fell. Moreover, at 5 months, post-vaccination antibodies were significantly lower for all pertussis antigens compared with infants of unvaccinated mothers. There was also evidence of immune interference between maternally derived diphtheria and tetanus antibodies induced by the maternal Tdap/IPV vaccine and infant responses to some of the tetanus toxoid-carrier and CRM-carrier protein conjugated vaccines.44 In a randomised controlled trial conducted in Vietnam, pregnant women received either a Tdap vaccine or a tetanus-only vaccine between 19 and 35 weeks’ gestational age.45 Significantly higher geometric mean concentrations (GMCs) were observed for all three measured pertussis antigens, that is, PT, FHA and pertactin (PRN) in the offspring of the Tdap group, up to 2 months of age. One month after completion of the primary infant vaccination schedule, anti-PRN GMC, but not anti-PT and anti-FHA GMCs, was significantly higher in the control group.
In a recently published prospective cohort from Belgium, blunting was observed for PT antibody responses following the third dose of the primary immunisation schedule in infants of women receiving a pertussis-containing vaccine in pregnancy compared with those of unvaccinated women.25 After the booster dose of vaccine, anti-PT IgG concentrations in the former group of infants remained significantly lower, while antibody concentrations for the other pertussis antigens increased.46 These findings are slightly different and less reassuring than those reported in the randomised control trial by Munoz et al.34 In this study, after primary immunisation, infants of women who received Tdap during pregnancy achieved equivalent antibody concentrations against PRN, lower but not statistically significant antibody concentrations against PT and FIM and significantly lower antibody concentrations against FHA compared with infants whose mothers received placebo. One month after the booster dose, however, antibody concentrations against all pertussis antigens were not significantly different in the two groups.34 These findings are similar to those of a prospective observational study where the marginally lower antibody concentrations after the primary immunisation series did not persist following the booster.39 These differences could be explained by differences in the timing of booster DTaP, vaccine brands or population demographics. Currently, the clinical significance of blunting and antibody waning is not clear (particularly because of a lack of an established correlate of protection for pertussis), and their impact on disease is likely to depend on country-specific immunisation schedules. In the UK, for example, the pertussis booster is not offered until the pre-school vaccinations at 3 years and 4 months and, therefore, blunting is more of a concern compared with countries that boost in the second year of life. Ongoing surveillance in older, vaccinated infants and toddlers will be critical to understand the longer-term impact and significance of these immunological findings.
Determinants of Tdap vaccine uptake and strategies to increase uptake
In the USA, following the recommendations for antenatal pertussis vaccination, there has been a general trend towards higher vaccine uptake, although vaccine coverage in pregnant women is still considered to be low.47–50 Factors associated with lower vaccine uptake include young maternal age, absence of public insurance, black race and premature delivery.48 51 52 In Mexico, a cross-sectional survey found that recommendation of vaccination by an obstetrician was a strong determinant of vaccine uptake, whereas the most popular reason for refusal was concern about vaccine safety.53 Korean women of childbearing age appeared not to be adequately informed by healthcare providers (HCPs) about the vaccinations recommended in pregnancy.54 In a recent UK survey involving 1013 women of childbearing age, multiparous women were more likely to accept antenatal vaccinations including pertussis and to participate in vaccine trials during pregnancy compared with primiparous.55 In addition, HCPs in the UK were the most important and valuable source of information for pregnant women.55 Similarly, in Australia, new mothers were more likely to be vaccinated if they had heard of the disease and the benefits of vaccination from an HCP.56 In Germany, migration status was associated with lower vaccine uptake in pregnant women.57
A number of strategies to increase uptake have been proposed, such as electronic antenatal alerts reminding HCPs to vaccinate pregnant women under their care from 32 weeks gestation and at each subsequent encounter up to delivery until vaccination is performed and recorded.58 Vaccine coverage using such a best-practice alert increased from 48% to 97% and this intervention nearly halved the incidence of neonatal pertussis, although the reduction was not significant, possibly because of small numbers of cases.58 In other studies, mobile phone text alert messages have been successfully used to improve antenatal care provision in Africa, including maternal vaccination uptake.59 In Ohio, USA, the implementation of a hospital-based outpatient pertussis prevention clinic improved Tdap vaccination rates in pregnant women and family members (cocooning strategy).60
A questionnaire-based study involving 133 obstetric providers in New York State found that, although 92% of them were aware of the national recommendations for antenatal Tdap vaccination, only 67% provided vaccine in their office. Moreover, 11% and 13% of them expressed concern about vaccine safety and efficacy, respectively, despite the growing body of literature against these beliefs.61 Concerns raised included vaccine price, the need to vaccinate in each pregnancy, vaccine safety and low incidence of pertussis in the area. The authors concluded that educational programmes were needed to improve provider vaccine confidence and recommendation. A recent review highlighted the difficulties, relating mainly to financial barriers, in achieving high antenatal pertussis vaccination coverage in the USA (such as the cost of ordering and storing vaccines, maintaining vaccine inventory and mainly inadequate reimbursement) compared with the UK, where antenatal care and vaccination is provided mainly by general practitioners in primary care.62
In summary, in order to achieve high vaccination coverage in countries with national recommendations for antenatal vaccination, better education of the public and HCPs is essential as well as overcoming financial and logistical barriers.
Safety
During the time frame of this systematic review, no excess in adverse events over background rates was demonstrated among 138 277 pregnancies assessed (table 2). In the UK, following the introduction of antenatal pertussis vaccination in 2012, an observational study of more than 20 000 pregnant women found no evidence of an increased risk of stillbirth in the 14 days after vaccination (incidence rate ratio, 0.69; 95% CI 0.23 to 1.62) or later in pregnancy compared with historical national rates. There was also no association with any of a wide range of maternal, perinatal and neonatal outcomes assessed.63
Equally reassuring are the findings of other well-designed observational studies,50 51 64–66 including a US retrospective observational cohort study using data from two California Vaccine Safety datalinks,64 a more recent analysis from seven US Vaccine Safety Datalinks in the year following ACIP recommendations for antenatal Tdap vaccination,50 a retrospective review of medical records of 1759 women who delivered a singleton infant in Texas during 2012–201465 and a prospective follow-up study of 403 infants in New Zealand whose mothers had received Tdap antenatally following a pertussis epidemic in 2012.67
Following recent national recommendations to vaccinate pregnant women in each pregnancy in the USA, the UK and elsewhere, irrespectively of previous history of vaccine uptake, recent studies have attempted to assess the safety of repeated doses of antenatal Tdap vaccination. An observational cohort study using data from seven Vaccine Safety Datalink sites in the USA evaluated acute adverse events and adverse birth outcomes in 29 155 women over a 5-year period.68 Women who were vaccinated in pregnancy with Tdap were divided into three groups according to the timing of prior receipt of Tdap: <2 years, 2–5 years and >5 years (the control group). Overall, no differences were found in vaccine-associated (fever, allergy or local reactions) or pregnancy-associated (preterm delivery, low birthweight rate or SGA) adverse events. It should, however, be noted that one of the exclusion criteria was pregnancies with non-live birth outcomes (stillbirth, spontaneous abortion and ectopic pregnancy).
In a retrospective, cohort study of 7378 women offered antenatal Tdap at 32 weeks gestation at a single institution in Texas,69 there was no difference in the risk of stillbirths, major malformations, chorioamnionitis, Apgar scores, cord blood pH or neonatal complications such as ventilation requirement, sepsis, intraventricular haemorrhage or death. Interestingly, however, preterm birth before 37 weeks gestation (6% vs 12%, p<0.001), SGA (10% vs 15%, p=0.03) and duration of hospitalisation (3.9 vs 4.7 days, p<0.001) were all significantly higher in the unvaccinated cohort. Notably, though, adverse neonatal outcomes were not significantly different between the 1229 women receiving >1 Tdap vaccine in the previous 5 years and the 4159 women who received only a single dose.69 There are also some safety data for Tdap administered in early pregnancy. In a single-centre, retrospective study assessing pregnancy and birth outcomes in infants born to 138 women during 2005–2009, 63% of whom had received Tdap in the first trimester, mainly as vaccination against tetanus following trauma (many of the women were not aware that they were pregnant at the time), there were no significant differences in maternal (spontaneous or elective abortion) or infant (preterm delivery, gestational age, birth weight, congenital anomalies or complex chronic conditions) outcomes when compared with infants of 552 unvaccinated pregnant women.70
Effectiveness
The impact and effectiveness of antenatal pertussis immunisation has been reported for the UK. In England and Wales, a 78% and 68% reduction in pertussis cases and hospital admissions, respectively, was noted in infants younger than 3 months of age during the first 9 months of 2013 compared with the same period in 2012. The antenatal vaccine coverage before delivery was 64%. Vaccine effectiveness based on 82 confirmed cases in infants born from October the 1st, 2012, and younger than 3 months was 91% (95% CI 84% to 95%). When the analysis was restricted to cases in those younger than 2 months, vaccine effectiveness was 90% (95% CI 82% to 95%).71 Similar vaccine effectiveness rates (93%; 95% CI 81% to 97%) were reported in a subsequent case control study conducted for infants aged <8 weeks with confirmed pertussis.72
Cost-effectiveness
A number of studies have assessed the cost-effectiveness of maternal pertussis vaccination in different countries. Antenatal vaccination against pertussis is considered an effective strategy in preventing severe infant disease and deaths, but cost-effectiveness depends—among other factors—highly on disease incidence, which is difficult to predict. In the UK, if the incidence remained at the level of the 2012 epidemic, then antenatal immunisation would be a cost-effective intervention.73 A recent US study found antenatal vaccination to be cost-effective, in contrast to vaccinating a second parent or vaccinating either parent post partum.74 Economic analysis in New Zealand also found that the addition of pertussis vaccination to the New Zealand national antenatal immunisation programme was a cost-effective or even a cost-saving decision.75 In Spain, it was estimated that 4752 parents would need to be vaccinated as part of a cocoon strategy to prevent one pertussis hospitalisation; >900 000, to prevent one death.12 For antenatal immunisation, the numbers were 1331 and 200 000, respectively, highlighting the cost-benefit compared with cocooning. In Brazil, antenatal immunisation of one annual cohort had the potential to avoid 661 cases and 24 infant deaths, saving 1800 years of life.76 Economic analysis indicated that universal antenatal Tdap immunisation would be a cost-effective intervention for preventing pertussis cases and deaths in infants in Brazil.
Conlusions
There is now an increasing body of evidence to support the safety, immunogenicity and effectiveness of antenatal vaccination to reduce the morbidity and mortality associated with pertussis in neonates and young infants before they receive their primary immunisations. Pregnant women produce high concentrations of vaccine-induced antibodies and can offer protection to their offspring through efficient transplacental antibody transfer. The introduction of antenatal vaccination against pertussis into a national immunisation programme will depend on a range of local factors, especially disease incidence, vaccine costs, implementation barriers and cost-effectiveness analyses. Narrowing the gap between scientific evidence and public health policies is critical in order to protect the most vulnerable as quickly as possible.
Given the initial safety and efficacy concerns of off-license antenatal immunisation, the rapid and sustained 60% coverage achieved in the UK is commendable. There are, however, opportunities to improve vaccine coverage in all countries that currently recommend antenatal immunisation against pertussis, through education of the public, vaccine givers and all primary and secondary healthcare professionals who have any contact with pregnant women and improvements in access to vaccine to ensure timely immunisation. There is also a need for on-going surveillance to monitor disease activity, safety and long-term vaccine impact. The lessons learnt will be vital for the introduction of new antenatal vaccines, including those against respiratory syncytial virus and group B streptococcus, which are currently under development and will further reduce neonatal morbidity and mortality in the near future.
References
Footnotes
Contributors DG: writing the first version of manuscript, literature search, study design, data analysis.
PK: reviewed and edited the first version of manuscript, literature search, study design, data analysis.
YH: literature search, figures. MM,
GA,
PTH: reviewed and edited the first version of manuscript.
SL: reviewed and edited the first version of manuscript, literature search, study design, data analysis.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.