Vaccines in pregnancy: The dual benefit for pregnant women and infants

ABSTRACT

Maternal immunization has the potential to reduce the burden of infectious diseases in the pregnant woman and her infant. Many countries now recommend immunization against influenza at any stage of pregnancy and against pertussis in the third trimester. Despite evidence of the safety and effectiveness of these vaccines when administered during pregnancy, uptake generally remains low for influenza and moderate for pertussis vaccine. Enhancing confidence in both immunization providers and pregnant women by increasing the evidence-base for the safety and effectiveness of vaccines during pregnancy, improving communication and access by incorporating immunization into standard models of antenatal care are likely to improve uptake. Developing a framework for implementation of vaccines for pregnant women which is cognizant of local and national cultural, epidemiological, behavioral and societal factors will enable a smooth transition and high uptake for new vaccines currently in development for pregnant women.

KEYWORDS:

• immunization
• influenza
• maternal immunization
• pertussis
• pregnant women
• vaccines

Introduction

In 1988, the World Health Organization (WHO) estimated that 787,000 newborns died of neonatal tetanus. Immunization against tetanus during pregnancy was a key component of the Maternal and Neonatal Tetanus Elimination Program which had led to a 94% reduction in deaths from neonatal tetanus to an estimated 49,000 in 2013.¹ In addition influenza immunization for pregnant women has been recommended in many high resource countries, to protect pregnant women and their infants from influenza infection.^2-5 The recent success of the maternal pertussis immunization program in the United Kingdom in reducing infant pertussis also confirms the role of maternal immunization. More recently pertussis immunization delivered during the last trimester of pregnancy has been adopted in several countries.^2-5 Current data on the safety and effectiveness of influenza and pertussis vaccines in pregnancy provides reassurance that the benefits out-weigh any possible risks in population program delivery.

Immunization of pregnant women affords the opportunity to deliver protective antibody transplacentally to the fetus and conferring protection in those infants too young to have received childhood immunizations at the time of exposure. In the absence of maternally derived pathogen-antigen specific antibody, infants remain vulnerable to severe disease until they have established an adequate protective antibody response to their primary immunizations. Infants under 6 months of age are currently unable to be immunized against influenza, as influenza vaccine is not licensed in this age group, due to a modest immune response.⁶ Pregnant women are also at risk of severe disease and complications from infectious disease.⁷ Immunizing during pregnancy provides the opportunity to protect both the pregnant woman and her infant by transplacental transfer of vaccine-induced antibody during the third trimester of pregnancy with the additional benefit of reduced risk of transmission of infection from mother to infant.

Despite strong recommendations from immunization advisory groups globally, including the WHO,⁸ uptake of influenza vaccine in pregnancy has been low, globally. In contrast, uptake of pertussis vaccination is higher in countries which have implemented a funded program. Estimated influenza vaccine uptake in pregnant women in Australia is 33%,⁹ in the USA it ranges from approximately 40–50%,¹⁰ and in the UK coverage was 44% during the 2014–15 campaign.¹¹ Evidence suggests that the barriers to uptake of vaccines by pregnant women are more complex than the barriers observed for low uptake in infant programs.¹² Pregnant women need to assess the benefits and risks not only for themselves, but additionally for their unborn infant. Importantly, pregnant women have consistently advised they are reliant on health care provider endorsement for pregnancy related interventions, including immunization.¹³ With the uptake of currently recommended maternal influenza and pertussis containing vaccines suboptimal, it is worth noting that the barriers to uptake of vaccines in pregnancy remain an understudied area but are likely to include a complex network of attitudinal, process and program delivery factors.

The aims of this paper are to review 1. maternal-infant disease burden and the safety and effectiveness of vaccination in pregnancy, with a focus on influenza and pertussis and 2. ways to improve implementation of vaccine programs for pregnant women.

Methods

A literature search of English language publications was performed using Pubmed, Embase, ClinicalTrials.gov, and WHO ICTRP search portal. Key search terms were included; maternal, pregnancy, fetal, immunization, vaccination, influenza, and pertussis effectiveness, efficacy, implementation, safety, and hesitancy. Studies and literature were included that were thought to be important to an overview of maternal pertussis and influenza immunization, and systematic review methodology has not been used. For the safety and effectiveness of pertussis and influenza, controlled experimental and observational studies were considered for inclusion. Animal studies, case studies, reports or studies that contained passive surveillance where a denominator is not able to be accurately established were not considered.

Burden of infection in pregnant women and infants

Influenza in pregnant women

Each year between 4% and 22% of pregnant women will develop a respiratory tract infection, a proportion of which will be influenza.^14,15 A recent randomized control trial (RCT) conducted in Africa undertook active surveillance and reported that 3.6% of HIV-uninfected, and 17% of HIV–infected pregnant women became ill with influenza among those that did not receive the vaccine.¹⁶ The difference is likely to be due to the increased susceptibility of HIV-infected pregnant women to influenza.¹⁶

Immunologic and physiologic changes that occur during pregnancy are thought to result in pregnant women being at increased risk of serious disease, cardiopulmonary complications, and hospitalization from influenza compared with the general population.¹⁷ Influenza-related mortality is uncommon in otherwise healthy pregnant women in high resource settings during non-pandemic influenza seasons.^18,19 However, an increased risk of severe disease and hospitalization is reported, particularly in the second and third trimester of pregnancy.^17,20-23 Studies conducted during seasonal and pandemic periods identified that pregnant women with more than one risk factor, such as asthma, and heart disease were most at risk.^17,20-23

A recent interim report from a review by the WHO Taskforce on Influenza based on a meta-analysis of 148 comparative observational studies concluded that the likelihood of hospitalization (OR 2.9 [95% CI, 1.6 to 5.5]) but not mortality (OR 1.0 [95%CI, 0.81 to 1.3]) with influenza illness was increased during pregnancy compared to the non-pregnant population.²⁴ Ecological studies reported higher rates of mortality, hospital admission rates, and intensive care admission rates. However, outcomes other than hospital admission were judged to be low quality evidence. No associations were reported from the pooled estimates for pneumonia, mechanical ventilator support, and intensive care admission outcomes when pregnant women were compared to non-pregnant women of reproductive age.²⁴ Despite the large number of studies, the level of evidence to support pregnancy as a risk factor for influenza-related complications is low. Further research is required to determine if the increased rate of hospitalization is due to complications following influenza, or for precautionary reasons.²⁴

Influenza – fetal outcomes

Overall the risk of transplacental transmission of influenza virus is thought to be low, despite case reports of in-utero infection confirmed with viral culture.²⁵ However, in the absence of placental transmission, the fetus can be adversely affected by the maternal response to infection.²⁶ A literature review conducted prior to the H1N1 2009 influenza pandemic found no association between pregnant women who have contracted influenza and pre-term delivery, low birth weight, low Apgar scores, and delivery complications.¹⁸ However, interim analysis of 20 studies identified by the WHO Taskforce on Influenza suggest that there is an association between pandemic H1N1 2009 influenza illness and preterm birth and fetal death, particularly from studies assessing severe maternal illness.²⁴ In 2013 a systematic review of 33 studies (15 case control, 10 cohort, and 8 ecological) that investigated congenital anomalies following first trimester influenza/influenza like illness reported an increased risk of some congenital anomalies including neural tube defects (OR 3.33,(95% CI, 2.05 to 5.40)), congenital heart defects (OR 1.56 (95% CI, 1.13 to 2.14)), and cleft lip (OR 3.12, (95% CI, 2.20 to 4.42)).²⁷ Hyperthermia is recognized as a potential cause of some congenital anomalies, although the review authors concluded that there was an equivalent or stronger association for influenza than for fever during the first trimester.²⁷

Influenza in infants

A systematic review of 43 studies (˜8 million children) estimated there were 90 million (95% CI, 49 to 162 million) new cases of influenza and 1 million (95% CI, 1 to 2 million) cases of influenza-associated severe acute lower respiratory tract infections (LRTI) that occurred worldwide in children less than 5 y of age in 2008.²⁸ Approximately 28 000 to 111 500 deaths were estimated to be attributable to influenza-associated respiratory infection in 2008, with 99% of these deaths occurring in developing countries.²⁸ Some 368 000 (95% CI, 254 000 to 532 000) cases of severe influenza associated LRTI, and 2 927 000 (95% CI, 1 244 000 to 7 176 000) cases of influenza associated ALRI were estimated among children less than one year of age globally during 2008.²⁸

Similar to pregnant women, infants aged 0–6 months are more susceptible to complications from influenza if they have an underlying comorbidity such as cardiac, respiratory, neurological, or neuromuscular conditions.^17,29

Pertussis in pregnant women and her fetus

Pertussis in adults is usually not severe and can often go undiagnosed.^30,31 However, it can cause serious complications for those who are symptomatic. Complications of pertussis were reported in 23% of adult patients in one study including otits media (4 patients), pneumonia (2 patients), rib fracture (one patient), and severe weight loss (one patient).³² Limited data are available for pregnant women. Pertussis infection during pregnancy is not known to be a direct risk to the fetus, however mothers are a likely source of pertussis transmission to their infants.^30,33

Pertussis in infants

Many countries, including the United States, Australia, and the United Kingdom with well-established immunization programs are experiencing a resurgence of pertussis, including in young infants less than 6 months of age, despite sustained high vaccine coverage.^34-36 Worldwide WHO estimates that there were 89 000 deaths during 2008,³⁷ with the majority of deaths occurring in low resource countries.³⁸ In the UK there were 48 deaths in infants under one year of age identified between 1 January 2001 and 31 December 2011. Analysis of the age distribution of infants showed a clustering in the first 2 months of life, with 36 deaths during this period.³⁹ An Australian epidemiological review of pertussis was conducted between 2006 and 2012.(40) This included an epidemic period when the rate of hospitalization in infants less than 6 months of age was 1832 per 100 000, with 10 deaths in unvaccinated infants less than 2 months of age.⁴⁰ Adults play an important role in pertussis transmission in households, with new mothers identified as the likely source of transmission to infants in 39% of cases in a review of multiple studies, where a source was identified.^30,33 In contrast, in a recent US study mothers were the source of infection in only 21% of the cases in children less than a year old, while siblings were the most common source in 36% of cases.⁴¹

Infants who are too young to receive 2 or more doses of a pertussis containing vaccine, remain at risk of severe disease (hospitalization). In addition premature infants are at increased risk of severe hospitalized infection.⁴²

Safety of vaccines for pregnant women

Influenza vaccine safety in pregnancy

Worldwide, many countries recommend pregnant women receive inactivated influenza vaccine during any stage of pregnancy.⁴³ This recommendation includes administration during the embryonic phase of pregnancy when the fetus is most susceptible to potential teratogens and maternal inflammatory response to a vaccine.^44,45 Live attenuated influenza vaccines are contraindicated during pregnancy due to a theoretical risk of potential harm to the fetus.⁴⁶

Systematic reviews on the safety of inactivated influenza virus vaccines conclude there is no association between maternal immunization and an increased risk of harm for pregnant women,^47,48 or the fetus.^47-52 The largest study investigating adverse events in pregnant women compared rates of medically attended adverse events in trivalent inactivated influenza-vaccinated and unvaccinated pregnant women.⁵³ Using ICD-9 coded data on inpatient, outpatient, or emergency department visits to assess medically attended visits within 3 and 42 d post-vaccination, respectively there was no evidence of an increase in medical visits in the 3 d post vaccination due to adverse events, using a combined outcome measure that included allergic reactions, fever, malaise, rash, and seizures: adjusted incident rate ratio (IRR) 1.12 (95% CI: 0.81 to 1.55).⁵³ Similarly, there was no increase in the 1 to 42 d post influenza vaccination period of acute neurologic events and thrombocytopenia than during other time periods (IRR 0.92, 95% CI: 0.54 to 1.56 and IRR 0.90, 95% CI: 0.68 to 1.19 respectively). Among vaccinated women there were no cases of Guillain-Barré syndrome, optic neuritis, Bell's palsy, or transverse myelitis. Overall, rates for medically attended events 0–3 d after vaccination were low and did not exceed 2 per 10,000 among both the vaccinated and unvaccinated women.⁵³

Birthing outcomes following influenza vaccination during pregnancy have been a major focus of research since 2009. Analyses of stillbirth or spontaneous abortion, premature birth, low birth weight, small for gestational age (SGA) infant outcomes, and congenital anomalies have indicated that there is no increased association following maternal influenza vaccination.^47-52 Findings are generalizable to monovalent influenza A (H1N1) vaccines, with the majority of evidence for women immunized during their 2^nd or 3^rd trimester of pregnancy. Studies published since these reviews have been consistent with these findings.^54-57

Studies that investigated outcomes for women immunized during their first trimester generally had lower statistical power due to the smaller number of women immunized during this period. Only a small number of studies have investigated the most important first trimester outcomes of spontaneous abortion and congenital anomalies.⁵² For congenital anomalies most studies report combined outcomes such as ‘all major anomalies’, which does not enable a more discrete analysis of individual conditions. Discrete outcomes according to different causal pathways will provide more informative analysis.

Pertussis vaccine safety in pregnancy

The composition of pertussis-containing vaccines differ: they may contain tetanus toxoid, diphtheria toxoid, acellular pertussis, and inactivated poliomyelitis antigens (Tdap or Tdap-IPV). In pregnant women, administration of Tdap is recommended during the third trimester of pregnancy, (or earlier in some countries such as the USA) to ensure maximal and timely protection for newborns.^2–4

A phase 1 placebo randomized controlled trial has been conducted to investigate the safety and immunogenicity of Tdap administered during pregnancy.⁵⁸ The trial was conducted from 2008 to 2012 and included 33 pregnant women vaccinated during pregnancy with Tdap and 15 with placebo between 30 to 32 weeks' gestation, with crossover immunization postpartum. No Tdap-associated serious adverse events occurred in women or infants.⁵⁸

Recently, large retrospective studies investigating the safety of pertussis vaccines have been completed in the USA and the UK,^3,59,60 while several other studies are in progress.^2,37,61-65 In the UK, 20 074 pregnant women who received the pertussis vaccine in the first 6 months of the immunization campaign were compared to historical data on unvaccinated pregnant women. The risk of stillbirth (intrauterine death after 24 weeks gestation) within 2 weeks of immunization was not increased (IRR 1.02, 95% CI, 0.96 to 1.08)).³ The overall stillbirth rate was estimated as (IRR 0.85 (95% CI, 0.45 to 1.61)).³ The authors also reported no evidence of an increased risk of other serious events that may occur in pregnancy, including maternal or neonatal death, pre-eclampsia or eclampsia, and low birth weight infants.³

In the US, women in a prenatal care system who were immunized during pregnancy with Tdap were compared with a group who declined immunization over a 12-month period. Stillbirth rates were 25/7152 (0.3%) in the vaccinated cohort and 1/226 (0.4%) in the unvaccinated cohort.⁵⁹ There was also no increase in crude rates of major malformations, birth weight, small for gestational age infant, or neonatal complications.⁵⁹

A retrospective observational cohort study using health care database data of 123 494 pregnant women (21% vaccinated) between 2010–12 found no association with premature birth, small-for-gestational-age (SGA) births, and hypertensive disorders.⁶⁰ A small but statistically significant increased risk of chorioamnionitis (adjusted RR, 1.19; (95% CI, 1.13 to 1.26)) was observed. This was despite no increased risk of preterm birth, a major sequela of chorioamnionitis, which indicates the strong possibility of residual confounding.⁶⁰ Data were unavailable to adjust for prolonged rupture of membranes, prolonged labor, and genital tract pathogens. Ongoing surveillance is required for this outcome.

Effectiveness of maternal immunization for pregnant women

Here, we use the term ‘efficacy’ to describe the outcome for a vaccine when compared in a controlled clinical trial using laboratory confirmed disease as an outcome and ‘effectiveness’ when the vaccine is evaluated in a non-experimental design often without laboratory confirmed disease or what might typically be described as a “real-world situation”.

Maternal influenza immunization for pregnant women

There are 2 published randomized controlled trials of influenza vaccine efficacy in pregnancy, one (South Africa) assessed efficacy against laboratory confirmed influenza in pregnancy¹⁶ whereas the other (Bangladesh) assessed self-reported respiratory illness with fever over 38°C during pregnancy.⁶⁶ The former compared a trivalent influenza vaccine against a placebo control group among 2116 pregnant women without HIV and 194 pregnant women with HIV. Among HIV-uninfected women vaccine efficacy against influenza virus infection was 50.4% (95% CI: 14.5 to 71.2) Among HIV-infected women, vaccine efficacy against influenza virus infection was 57.7% (95% CI: 0.2 to 82.1).¹⁶ The study in Bangladesh was a double blind RCT conducted over a single year (2004–05) investigating a split-virion seasonal vaccine among healthy pregnant women enrolled in their third trimester of pregnancy with a comparator group receiving a pneumococcal vaccine.⁶⁶ While suggestive of benefit, the study was unable to demonstrate efficacy of influenza vaccination in pregnancy against self-reported respiratory illness with fever over 38°C during pregnancy.⁶⁶ Two other RCTs are currently in progress in Nepal and Mali.⁶⁷

A test negative case-control design over 2 influenza seasons from 2010 to 2012 on trivalent influenza vaccines in metropolitan areas in the USA estimated adjusted vaccine effectiveness in pregnancy to be 51% (95% CI, 8 to 74).⁶⁸ Other observational studies on influenza A (H1N1) monovalent vaccines,^69,70 and trivalent vaccines in pregnancy,^71,72 have similarly found modest influenza vaccine effectiveness, similar to the effectiveness of the vaccine in the general adult population.

Maternal influenza immunization for infants

The aforementioned RCT in South Africa,¹⁶ estimated influenza vaccine efficacy in pregnancy of 48.8% (95% CI, 11.6 to 70.4) against laboratory confirmed influenza in infants up to 24 weeks of age in the HIV-uninfected cohort, and 26.7% (−132.0 to 76.8) in the HIV-infected cohort.

The RCT in Bangladesh, which used 23-valent pneumococcal polysaccharide vaccine as the comparator rather than a placebo, estimated vaccine efficacy to be 62.8% (95% CI: 5.0 to 85.4) against laboratory-confirmed influenza in infants.⁶⁶ The number needed to be vaccinated to prevent one test positive case was estimated at 16 (95% CI: 8.2 to 200) in these infants up to 6 months of age.

Case-control and observational cohort studies on the trivalent seasonal influenza vaccine have also indicated a clinically and statistically significant reduction in influenza related hospitalization of infants less than 6 months of age following vaccination of their mothers during their second or third trimester of pregnancy.^73-75 Vaccine effectiveness in the studies that used a laboratory confirmed end point ranged from 48% to 91.5%.^73,74 These demonstrate the importance of the vaccine in reducing severe disease and hospitalization in children too young to be vaccinated.

Maternal pertussis immunization for infants

Evidence of the effectiveness of pertussis vaccine administered during pregnancy and protection provided to infants has recently emerged following the introduction of population wide immunization campaigns. In the UK, an analysis of laboratory-confirmed cases and hospital admissions for pertussis in infants between Jan 1, 2008, and Sept 30, 2013 was conducted following the introduction of the pertussis maternal vaccination program. Vaccine effectiveness was calculated using the ‘screening method’ that compares vaccination status for mothers of confirmed infant cases with estimates of vaccine coverage for the national population of pregnant women. Vaccine effectiveness based on 82 confirmed cases in infants born from Oct 1, 2012 was 90% (95% CI: 82 to 95) in the analysis restricted to cases of less than 2 months of age.⁷⁶ These results were replicated in a case control study, with adjusted vaccine effectiveness of 93% (95% CI, 81% to 97%).⁷⁷

Timing of maternal pertussis and influenza immunization

Studies investigating the transfer of maternal pertussis antibodies to the infant following immunization during the third trimester have shown high concentrations in cord blood, maternal sera, and infant sera that can last until the infant is 2 months of age. ^58,78,79 Pertussis antibodies were significantly higher in the sera of infants of mothers who were immunized during pregnancy, than those mothers immunized post-partum at 2 months of age.⁵⁸ The optimal time for maternal pertussis immunization is thought to be later in pregnancy to facilitate maximal transfer of maternal antibodies to the infant, but early enough to allow an adequate immune response prior to delivery. A recent study that investigated the relative activity index of IgG to pertussis toxin in cord blood found it was significantly higher following immunization between 27 to 30⁺⁶ weeks gestation, when compared to 31 to 36 weeks gestation, and 36 to delivery.⁸⁰ There is no serologic correlate of protection determined for pertussis, however.

Maternal influenza immunization is most commonly recommended as early as possible during pregnancy to protect the pregnant woman, as well as the newborn infant. However the timing for vaccination that would provide the greatest benefit for mother, fetus and infant in providing optimal protection against severe influenza is not yet established. A study is currently underway in the USA to determine the optimal timing for influenza vaccine in pregnancy.

Implementation of maternal immunization

In 2012, the WHO Strategic Advisory Group of Experts (SAGE) on immunization recommended pregnant women as the highest priority for seasonal influenza vaccination in countries considering the initiation or expansion of influenza immunization programs.⁸ The Advisory Committee on Immunization Practices (ACIP) in the USA officially recommended the influenza vaccine for all pregnant women in 1997.⁸¹ Originally, this recommendation was for vaccination in the second and third trimester only, but was changed in 2004 to include any trimester.²⁵ The April 2015 SAGE meeting noted major gaps in the evidence base that is required to broaden the recommendation for all pregnant women in all countries, although they are expecting substantial data becoming available late 2015 to early 2016.⁸²

In the UK, high rates of pertussis in infants resulted in 14 infant deaths in 2012 and prompted a funded immunization campaign for all pregnant women.⁷⁶ Following the UK campaign, pertussis vaccination has also been funded for women in the third trimester of pregnancy in NZ, and in all States and Territories of Australia.³ Despite such recommendations in a number of high income countries, maternal influenza immunization has not been incorporated into routine immunization programs in many low-resource settings.²⁴

Seasonal influenza uptake in the UK for pregnant women as a percentage of those registered as seeing a GP was 27.4% in the 2011/12 season,40.3% in 2012/13 and 44% in 2014/15.^11,83 Following the introduction of the funded pertussis campaign, maternal coverage of pertussis in the UK peaked at 78% and dropped to 60%.⁷⁶ During the 2014/15 period uptake averaged 56.%, with the lowest monthly uptake at 52%, and a peak of 62%.⁸⁴ The ongoing “FluMum” study,¹⁵ in Australia has recruited 10,150 mother infant pairs and found low levels of uptake in pregnancy (33% for influenza vaccine for 2012–2014 and 18% during the early stages of a 2015 program roll-out for pertussis vaccine in pregnancy).⁹ In the USA, influenza vaccine uptake has ranged from approximately 38–50% over recent influenza seasons.^10,85 These levels are a marked improvement post the 2009 influenza pandemic, but are still well short of efforts to reach an 80% target set in the USA.⁸⁶ A study of 40,054 pregnant women in the US found that Tdap receipt during pregnancy increased from 13.8% among women delivering during January 2013 to 51.0% among women delivering during March 2014.⁸⁵

Improving confidence in immunization providers and pregnant women

Attempts to increase the uptake of maternal vaccines have so far been largely unsuccessful in improving the overall rates of maternal influenza immunization

Reasons behind low uptake are likely to be multi-factorial. Systematic reviews conducted in the area of vaccine hesitancy in pregnant women have mostly involved studies that were conducted during periods when the pandemic influenza vaccine was available.^87-89 The most recent review on vaccine acceptance in pregnant women conducted by Wilson et al. included 113 articles on pandemic and/or seasonal influenza vaccines, as well as 16 on tetanus, 7 on dTaP/IPV, 2 on Group B streptococcal (GBS) vaccine, and 17 on any maternal vaccine.⁸⁹ The primary reasons identified for hesitancy in vaccination in these studies were the safety of vaccines in pregnancy (64/155, 41% of studies), belief that the vaccine is not necessary (28/155, 18% of studies), poor knowledge about the vaccines and/or disease (22/155, 14% of studies), no recommendations from HCW (17/155, 10% of studies), and access/availability issues (6/155, 4% of studies). The main barriers identified by healthcare workers were reported as inadequate reimbursement, training, and increased workload (6/155, 4% of studies). Over half the papers that investigated ethnicity as a factor reported reduced coverage in ethnic minorities (27/46, 59% of studies).⁸⁹ The review authors concluded that barriers are complex and vary depending on context in population.

Ongoing work is required to help inform vaccine hesitancy in pregnant women in multiple different locales and cultures. The introduction of funded pertussis containing vaccines for pregnant women in some countries provides an opportunity for comparisons and further analysis. With the uptake of pertussis vaccine in pregnant women significantly higher than that of influenza vaccines, it is likely that the emphasis on protection for the infant as opposed to protection for the mother is a key factor. This will be important to elucidate in further research.

Overcoming barriers to vaccines for pregnant women

Improving uptake through communication, better access and integrating maternal immunization into standard care are all aspects of the multifaceted approach that is required, to improve maternal vaccine uptake.^82,90

Strategies that have been found to be most effective at improving uptake in a wide range of population groups involve increasing knowledge and awareness, improving convenience and access, targeting specific groups in the community, mandating vaccinations or penalty for non-vaccination, reminders and follow-up, and engaging religious leaders.⁹¹ Strategies that were found to be most successful at shifting attitudes and increasing knowledge included the introduction of education initiatives that embed new knowledge in to process e.g., new hospital procedures and individual plans.⁹¹

Recent research on the attitudes of obstetricians, shared care family physicians and midwives has indicated strong support for immunization of pregnant women.⁹² However, structures to embed immunization into maternal healthcare have been lacking, with many tertiary obstetric services not providing ready access to recommended vaccines for pregnant women.⁹³

Introduction of measures such as midwife delivery of immunizations eliminates the barrier of difficulty accessing vaccines, and confusion among vaccine providers of responsibility for immunization (the family physician expecting the midwife or obstetrician to deliver the vaccines whereas the obstetrician expecting the family physician to vaccinate the pregnant woman). Pregnant women can then receive vaccines at the point of care contact for antenatal care.

Combined with other approaches, incorporating immunization into routine maternal care through measures such as inclusion in pregnancy records held by pregnant women, incorporation into perinatal guidelines, documentation in the medical notes, and recalls and reminders is likely to be an important component to increase the uptake of maternal immunization especially in high resource settings.^82,94-96 Importantly, the WHO SAGE working group identified that interventions should focus on meaningful engagement through dialog and social mobilization. Contextual influences should be considered in planning of new interventions with evaluation of interventions being crucial.⁹¹

Improving maternal immunisation research

New interventions to improve the health of pregnant women and their infants present major ethical challenges for researchers, clinicians and ethics committees. Pregnant women are usually an automatic exclusion from clinical research studies, even when the risks are negligible and they are seldom included in initial safety and efficacy trials.⁹⁷ Against the backdrop of thalidomide, there is a tendency during pregnancy to value risk more highly than benefit; unfortunately this superimposes another risk, that the benefits of a new intervention will not be realized. Some argue that even though pregnant women are excluded from the research agenda in the spirit of “protection,” this comes at a profound cost for women and children alike.⁹⁸

Regulators are recognizing the need to work with clinical trialists to conduct RCTs in pregnant women, and this will be important as new vaccines, such as respiratory syncytial virus vaccine and Group B streptococcus vaccine, are targeted to pregnant women.⁹⁹ Other steps are also being taken to address the variable methodology used in vaccine safety studies. Heterogeneity of safety outcomes has made valid comparison of vaccines' safety difficult. Work is currently being conducted by the Brighton Collaboration to develop case definitions and improve comparability between trials.

Remaining gaps in evidence

Further research on the burden of disease for mothers and infants and the safety and effectiveness of vaccines in pregnancy continues to be a priority. Evidence gaps include outcomes for pregnant women with mild influenza disease, populations in low resource countries, and exposures during non-pandemic influenza seasons. Additional research questions remain with the respect to understanding the impact of vaccines delivered in pregnancy on disease burden and identifying the optimal time for administration of individual vaccine.

Even though the evidence for safety following maternal influenza immunization is reassuring, ongoing evaluation of the safety of specific vaccine products is required. Most influenza studies are powered to evaluate composite congenital anomaly outcomes. Discrete outcomes according to different causal pathways will assist to move this body of evidence forward.⁴⁴ This will also facilitate meta-analysis and help define the risk of less frequent congenital anomaly outcomes.⁵⁶ Further data on the safety of immunization during the first trimester is also required to provide greater statistical precision for congenital anomalies and spontaneous abortion outcomes.

In addition, the effect of infant responses to primary pertussis immunizations following exposure to pertussis antibodies from maternal pertussis immunization remains an important area of research. Early data from the UK suggests there may be some blunting of infant responses in infants born to women who received pertussis vaccine in pregnancy compared to historical controls, although the clinical significance of this is unknown.¹⁰⁰

Further implementation research is also required to establish the best methods of improving uptake in pregnant women. These methods are likely to be different within and between high and low resource countries.

Conclusion

Immunization of pregnant women has been shown to be safe and effective in reducing disease burden in pregnant women and their infants. Optimizing the protection afforded by maternal immunization is likely to lead to significant reduction in disease, particularly for influenza and pertussis which are both still poorly controlled infectious diseases. The increased benefit is likely to be seen during pandemics and epidemics, which still occur despite funded pertussis and influenza immunization programs. Other vaccines against infections such as respiratory syncytial virus and group B streptococcus are in development for pregnant women and provide the first opportunity to potentially deliver protection against additional severe infections in infants. Development of a framework approach to implementation including education of pregnant women and health care providers, immunization provider endorsement, direct access to vaccines for pregnant women and incorporating immunization into standard antenatal care will be necessary to ensure successful uptake of future vaccines for pregnant women.

Disclosure of potential conflicts of interest

HSM is supported by an NHMRC Career Development Fellowship (1016272). HSM's institution has received research grants from vaccine manufacturers CSL, GSK, Pfizer, Novartis and Sanofi Pasteur for investigator-led research. HSM has been an investigator for studies funded by pharmaceutical companies including Pfizer, GSK Sanofi-Pasteur, Novartis. Travel support has been provided to HSM and MM's institution by GSK and/or Sanofi-Pasteur for HSM and MM to present scientific data at scientific meetings. RMA and HSM are members of the Australian Government ATAGI (Australian Technical Advisory Group on Immunisation). KM and KE have no potential competing interests to declare.

Acknowledgment

We gratefully acknowledge Annette Braunack-Mayer who assisted with review of the draft manuscript.