Maternal immunization: where are we now and how to move forward?

Abstract

Pregnancy and the postpartum period are associated with elevated risks to both mother and infant from infectious disease. Vaccination of pregnant women, also called maternal immunization, has the potential to protect pregnant women, foetuses and infants from several vaccine-preventable diseases. Maternal immunoglobulin G antibodies are actively transferred through the placenta to provide passive immunity to new-borns during the first months of life, until the time for infant vaccinations or until the period of greatest susceptibility has passed. Currently, inactivated influenza, tetanus, and pertussis vaccines are recommended during pregnancy in many countries, but other vaccines may also be administered to pregnant women when risk factors are present. Several new vaccines with a specific indication for use during pregnancy are under development (e.g. respiratory syncytial virus and group B streptococcus vaccines). Years of experience suggest that maternal immunization against influenza, tetanus or pertussis has an acceptable safety profile, is well tolerated, effective and confers significant benefits to pregnant women and their infants. This review describes the principles of maternal immunization and provides an update of the recent evidence regarding the use and timing of maternal immunization. Finally, the barriers preventing wider vaccination coverage and the current limitations in addressing these are also described (Supplementary Material).

Key messages

• Maternal immunization gives pregnant women greater protection against infectious diseases; induces high levels of maternal antibodies that can be transferred to the foetus; and helps protect new-borns during their first months of life, until they are old enough to be vaccinated.

• Pregnant women and new-borns are more vulnerable to infectious diseases than the overall population; nevertheless, vaccination rates are often low in pregnant women.

• This review provides an update of the recent evidence regarding the use and timing of maternal immunization and describes the barriers preventing wider vaccination uptake and the current limitations in addressing these.

Keywords:

• Maternal immunization
• immunity
• patient safety
• quality of care
• pregnancy
• vaccine

Introduction

Pregnant women and new-borns are more vulnerable to some infections, associated with elevated morbidity and mortality, as illustrated during the 1918 and 2009–2010 influenza A (H1N1) pandemics [1,2]. In addition, although mortality has been greatly reduced in children aged <5 years over the last decade, only minimal reductions have been achieved in new-borns [3]. Of the 5.8 million children who died before 5 years of age in 2015 worldwide, approximately 2.6 million died in the neonatal period (0–27 days of age) [3].

It has been known for more than a century that vaccination during pregnancy, referred to as maternal immunization, can provide protection against vaccine-preventable infections for the mother but also for the developing foetus and the new-born through maternal antibodies transferred via the placenta and subsequently through breast milk [4]. Recommendations for maternal immunization have existed for decades, notably for preventing influenza in industrialized countries and tetanus in developing countries [4], but interest in maternal immunization has been recently raised worldwide, notably after the 2009–2010 H1N1 influenza pandemic and outbreaks of pertussis with associated infant deaths in several countries despite high vaccination coverage. Although wider acceptance of maternal immunization has been hampered by the perception that limited safety and efficacy data are available [5], a growing body of evidence suggests that maternal immunization against tetanus, pertussis and influenza has an acceptable safety profile, is effective, and confers significant benefits on pregnant women and their infants [6]. More proactive communication of these points to the healthcare community and the public could help support the acceptance of maternal immunization as a routine immunization practice [7–9].

This review describes the principles of maternal immunization and the vaccines currently available for use during pregnancy. It also presents differences in recommendations worldwide, and the barriers to wider implementation.

The immune system during pregnancy and the effect of maternal immunization

The immune system during pregnancy

The foetus bears antigens recognized as foreign by the maternal immune system due to the inheritance of 50% of the genome from the father. In immunocompetent pregnant women, a range of complex processes take place to ensure the mother’s body can actively tolerate this semi-allogeneic foetus [10]. Pregnancy is therefore a unique situation where physiological and immunological changes may increase the susceptibility of mothers to certain infectious diseases (e.g. malaria, listeriosis, human immunodeficiency virus-1), the risk of more serious outcomes in other diseases (e.g. influenza, malaria, hepatitis E, measles, herpes simplex virus) and the risk of congenital anomalies for the foetuses (e.g. the “TORCH” pathogens: Toxoplasma gondii, other [syphilis, varicella-zoster virus, parvovirus B19], rubella virus, cytomegalovirus and herpes simplex virus) [1,11]. These changes include modifications to the immune system driven by hormones, cytokines and immune cells as well as structural changes such as remodelling of the endometrium [1,12].

Several hypotheses have been proposed to explain why the foetus is not rejected by the maternal immune system. It was initially proposed in the 1950s that pregnancy induces general immunosuppression to allow tolerance of the semi-allogeneic foetus [13]. However, pregnant women are able to induce immune responses and immune memory similarly to non-pregnant women after natural infection and vaccination, suggesting that this concept was too simplistic [1,13]. Instead, the immune system appears to be modulated during pregnancy rather than actively suppressed, with the consequence that the risk increases only for some infections [6,10].

Concentrations of steroid hormones such as estrogens and progesterone progressively increase over the course of pregnancy. These increases induce a shift in the balance of pro- and anti-inflammatory responses [1]. Pro-inflammatory responses are prominent during the first trimester of pregnancy (“open wound phase” contributing to morning sickness), whereas anti-inflammatory are prominent in the second and third trimesters to prepare the body for delivery [10]. It also explains why the severity of diseases caused by inflammatory responses (e.g. multiple sclerosis, rheumatoid arthritis) is often reduced during the third trimester of pregnancy, whereas the severity of diseases that are controlled by inflammatory responses (e.g. influenza, malaria, lupus) is increased [6]. The transition is associated with an alteration of the balance between type 1 (Th1) and type 2 (Th2) T helper cells, with a shift from Th1 (i.e. oriented towards cell-mediated immunity) towards Th2 (i.e. oriented towards humoral immunity) responses, which is needed for healthy foetal development [10,14]. This Th2-skewed response can suppress cytotoxic T lymphocytes and stimulate B lymphocytes to increase the production of antibodies that can potentially be transferred to the foetus [1].

Recent findings suggest that the placenta is an active immunological site capable of interacting with and responding to pathogens [10,13]. Local immunological mechanisms at the foeto-maternal interphase contribute to protect the foetus from rejection, with cytokines providing growth factors necessary for implantation of the foetus in the placenta [13]. The signals from the placenta may modulate the maternal immune response to pathogens, leading to a new paradigm in which the immunological responses during pregnancy result from a combination of signals and responses originating both from the maternal and the foeto-placental immune systems [10].

The effect of maternal immunization in infants

In the first months of life, the adaptive immune system of infants is unable to mount a fully protective response to many pathogens. The foetal and neonatal T cells are skewed towards Th2 responses that are ineffective against intracellular pathogens [15]. Antibody responses to bacterial polysaccharides are also ineffective [15]. During this period, infants rely on additional protection acquired during gestation from maternal antibodies passively transferred through the placenta [15]. The levels of antibodies present in infants at birth are correlated to the levels of maternal antibodies, hence the degree of transfer appears to be interconnected to the antibody levels in the mother’s circulation [15]. However, levels of maternal specific antibodies are often suboptimal and therefore may not be sufficient to confer full protective immunity to the infants or may protect them for only a short period of time. In addition, the levels of maternal antibodies wane over a period of approximately 6 months after birth. The aim of maternal immunization is therefore to increase maternal specific antibody concentrations to increase their passive transfer to the foetus, which reduces the window of vulnerability until the appropriate time for infant vaccinations or until the period of greatest susceptibility has passed.

Of the five antibody classes, immunoglobulin G (IgG) is the only isotype able to efficiently cross the human placenta [15]. IgG antibodies are transferred from the mother to the foetus through the syncytiotrophoblast cells of the placenta, which are in contact with maternal blood [15]. Maternal IgG in the circulation are internalized in endosomes and bind to neonatal Fc receptors (FcRn) expressed on the internal endosomal surface [15]. The endosomes then fuse with the membrane on the foetal side of the syncytiotrophoblasts, where IgG are released from FcRn [15]. IgG subsequently pass through the villous stroma and foetal capillary endothelium to enter the foetal circulation, but the mechanisms underlying transport across these two layers are not yet fully understood [15,16].

Placental transfer of IgG increases over time, with the largest proportion transferred during the third trimester, especially within the last 4 weeks of pregnancy [15]. At full term, IgG concentrations in the foetal circulation are usually greater than those in the maternal circulation, consistent with an active transport process [15]. Several factors influence this transfer such as placental integrity, maternal non-infectious diseases, total maternal IgG concentration, IgG subtype, FcRn availability, nature of the antigen and timing of vaccination (or infection) [15,17]. IgG₁ is the subtype of antibodies transferred most efficiently to the foetus, followed by IgG₄, IgG₃ and IgG₂, which is the least efficiently transferred [15]. IgG₁ are induced predominantly by vaccines containing protein antigens, whereas IgG₂ are induced predominantly by vaccines containing polysaccharide antigens [17]. The concentration of specific antibodies starts increasing approximately two weeks after maternal immunization; thus, vaccination between 28 and 32 weeks of pregnancy may optimize the amount of specific IgG present at birth in full-term infants, but may not be optimal for preterm infants [17]. A recent study suggested that vaccination with tetanus toxoid-reduced diphtheria toxoid-acellular pertussis vaccine (Tdap) in the second trimester results in higher neonatal anti-pertussis antibody titers than vaccination in the third trimester, both in term and pre-term neonates [18,19]. This may be due to a longer total transfer time resulting in antibody accumulation in the foetal circulation.

In addition to the protection provided by maternal IgG antibodies transferred through the placenta, high concentrations of maternal IgA and to a lesser extent IgG and IgM, are excreted in the colostrum and breast milk [20]. For instance, vaccination with Tdap in the second or third trimester of pregnancy, or immediately after delivery, increased the levels of pertussis-specific IgA antibodies in breast milk [21]. Breastfeeding therefore represents another mode of transferring antibodies to new-borns. Secreted IgA is an important part of host defence at the mucosal level, notably in the gastrointestinal and respiratory tracts [20]. IgA transferred through breast milk help protect infants against enteric infections and, in infants born to influenza-vaccinated mothers, against respiratory illness with fever for at least 6 months after birth [20,22].

Although much evidence has highlighted the benefits of maternal immunization, some studies have also shown a potential interference between maternally derived IgG antibodies and infant antibody responses [23]. Specifically, maternally derived IgG antibodies can inhibit immune responses against the same or related antigens after primary vaccination series in early infancy, a phenomenon termed “immunological blunting”. This blunting usually dissipates after the booster dose [15,24]. Blunting has been observed for maternal antibodies acquired after natural infection or maternal immunization, notably with measles and polio vaccines, although the effect varies considerably between vaccines and studies [15,25]. The clinical relevance of this blunting is unknown. Indeed, epidemiological data from countries that implemented maternal immunization do not show negative impact on the protection against the targeted diseases, such as for pertussis [26].

Vaccines available for use in pregnant women

Tetanus

Vaccination against tetanus, pertussis and diphtheria is included in the routine vaccination schedule in many countries, and tetanus and diphtheria are now rare diseases in industrialized countries. Most cases of tetanus occur in developing countries among new-borns or mothers following delivery in poor hygiene conditions [27]. Tetanus cannot realistically be eradicated because the causative agent of tetanus, Clostridium tetani, is widespread in the environment, highly resistant to many antimicrobial measures, and transmitted by open wound contact (as opposed to person-to-person transmission) [28]. Nevertheless, efforts are being made to reduce the burden of tetanus worldwide. These efforts focus on prevention using vaccination, improvement of perinatal care and post-exposure prophylaxis in high-risk areas [28].

Regular booster doses with the tetanus toxoid vaccine are required to provide long-term immunity [27,28]. Infants born to mothers who lack sufficient circulating antibodies may therefore be unprotected against tetanus in the first months of life. For this reason, the World Health Organization (WHO) currently recommends unimmunized pregnant women (or those with unreliable immunization information) to receive two doses of tetanus-containing vaccine during the first pregnancy, one month apart, with the first dose as early in the pregnancy as possible (Table 1) [27].

Table 1. Selected examples of vaccinations recommended during pregnancy by the World Health Organization or national health authorities.

Vaccine	Type of vaccine	Country/organization	Recommendation	Timing of vaccination
Influenza	Inactivated	WHO [67]	Recommended during each pregnancy in the influenza season	At any stage of pregnancy (since 2005)
		US [68]	Recommended during each pregnancy in the influenza season	Pre-conception or at any stage of pregnancy (since 2004)
		UK [7]	Recommended during each pregnancy in the influenza season	At any stage of pregnancy (since 2010)
		Germany [116]	Recommended during each pregnancy in the influenza season	From the second trimester or, for pregnant women with underlying chronic disease, from the first trimester (since 2010)
		France [117]	Recommended during each pregnancy in the influenza season	At any trimester (since 2010)
		Belgium [108]	Recommended during each pregnancy in the influenza season	Second or third trimester (since 2006)
		Argentina [75]	Recommended during each pregnancy in the influenza season	At any trimester (since 2011)
Tetanus	Toxoid	WHO [27]	Pregnant women with inadequate or unknown vaccination history	Two doses of tetanus toxoid-containing vaccine. A total course of five vaccinations should be targeted (at postnatal visits and subsequent pregnancies) (since 2006)
		WHO [27]	All women of childbearing age in high-risk areas for maternal and neonatal tetanus	Three doses, usually over a 12-month period (since 2006)
Tetanus–diphtheria–pertussis (Tdap)	Toxoid/subunit	WHO [30]	In countries or settings with high or increasing infant morbidity/mortality from pertussis, as a strategy additional to routine primary infant pertussis vaccination (since 2015)	Second or third trimester, at least 15 days before the end of pregnancy
		US [44]	Recommended during each pregnancy regardless of previous vaccination (since 2012)	27–36 weeks of pregnancy, but may be administered at any time
		Argentina [75]	Recommended during each pregnancy	Starting at 20 weeks of pregnancy (since 2012)
		Ireland [118]	Recommended during each pregnancy	7–36 weeks of pregnancy (since 2013); 16–36 weeks of pregnancy (since 2016)
		Australia [119]	Recommended during each pregnancy (since 2015)	Third trimester
Reduced diphtheria–tetanus–pertussis–inactivated poliomyelitis (dTaP-IPV)	Toxoid/subunit/inactivated	UK [47,120]	Recommended during each pregnancy	28–38 weeks of pregnancy (preferentially at 28–32 weeks; since 2012); 16–32 weeks of pregnancy (since 2016)
Hepatitis A	Inactivated	WHO [79]	Two doses if risk of infection outweighs theoretical risk of vaccine (since 2012)	Before travel
		US [82]	If risk factors (since 2002)	–
Hepatitis B	Subunit	US [82]	Three doses if previously unvaccinated or at high risk of infection (since 2002)	–
Pneumococcal	23-valent polysaccharide	US [82]	If risk factors (since 2002)	–
Meningococcal (ACWY)	Polysaccharide and conjugate	US [82]	If indicated (since 2013)	–
Yellow fever	Live attenuated	WHO [86]	If travel to endemic regions and risk of infection outweighs risk of vaccine (since 2013)	During epidemics and before travel
Japanese encephalitis	Inactivated	WHO [84]	If travel to endemic regions and risk of infection outweighs risk of vaccine (since 2015)	Before travel
Rabies	Inactivated	US [88]	Post-exposure prophylaxis and pre-exposure prophylaxis if high risk of exposure (since 1991)	–
Anthrax	Adsorbed	US [89]	Post-exposure prophylaxis (since 2009)	–

UK: United Kingdom; US: United States; WHO: World Health Organization.

The start years of the recommendations are shown in parenthesis.

In 1989, the WHO, the United Nations Children’s Fund and the United Nations Population Fund launched an initiative to eliminate neonatal tetanus by 1995. Guidelines were later expanded to include maternal tetanus because tetanus also threatens women during pregnancy and delivery [29]. This initiative relied on specifically-designed local programs to increase immunization rates in pregnant women and improve birth hygiene and disease surveillance in high-risk regions [29]. As of 2015, approximately 148 million women of childbearing age (including pregnant women) have received at least two doses of tetanus toxoid vaccine through this initiative [29]. Although this approach has decreased neonatal tetanus by 96% compared to the late 1980s, the WHO estimated that 34,000 new-borns still died from the disease in 2015 [29]. As of June 2017, 16 countries were yet to eliminate maternal and neonatal tetanus (i.e. reach a level of <1 case of neonatal tetanus per 1000 live births) [29].

Pertussis

In contrast to tetanus, pertussis is a highly contagious disease that is still endemic worldwide [30]. Most severe pertussis cases and deaths occur in the first months of life, when infants have not yet started or completed their primary vaccination schedule [30]. Although the introduction of vaccination programs in the 1950s with whole-cell pertussis vaccines was very effective at reducing severe disease and mortality, it has been followed by a resurgence of pertussis in multiple countries despite high immunization rates [31–33]. The reasons for this pertussis resurgence are not clear and probably multifactorial but several hypotheses have been proposed. It may be due to the switch from whole-cell to acellular vaccines, leading to a less effective priming or more rapid waning of immunity following primary vaccinations [30,32]. However, outbreaks have also occurred in countries using whole-cell vaccines [34]. Resurgence may also be attributable to the naturally occurring cyclic patterns of the disease and factors such as suboptimal vaccination coverage, higher disease awareness, improved surveillance or enhanced sensitivity of diagnostic tests [30,34].

The high burden of pertussis still seen in infants, both in developing and industrialized countries, has therefore raised concerns regarding the effectiveness of the current vaccination strategies and prompted some countries to rethink their strategies to control the disease in infants [30]. Alternative strategies include “cocooning” and maternal immunization. Based on observations that most infant infections derive from contact with family member, the cocooning approach involves Tdap vaccination of parents and persons in close contact with the susceptible infants before completing the vaccination schedule of children with diphtheria–tetanus–pertussis vaccine (either acellular or whole-cell) to reduce the risk of pertussis transmission [35,36]. However, the main obstacle to this approach is the need to vaccinate multiple individuals, and it has therefore yielded variable results, ranging from no effects to >80% decrease in infant deaths [30,37]. Vaccination of pregnant women seems more effective than cocooning and is likely the most cost-effective strategy for preventing pertussis in infants too young to be vaccinated [38]. The WHO therefore recommends that national programs consider the vaccination of pregnant women with one dose of Tdap (in the second or third trimester, preferably at least 15 days before the end of pregnancy) as an additional strategy when infant morbidity or mortality from pertussis is high or increasing [30].

More than 20 countries such as the United States (US) and the United Kingdom (UK) have moved towards maternal immunization recommendations in an attempt to reduce the burden of pertussis in infants too young to be vaccinated (Figure 1) [30]. Recent systematic reviews supported the safety, immunogenicity and effectiveness of maternal Tdap immunization to reduce the morbidity and mortality associated with pertussis in infants before they receive their primary immunizations [39,40]. Effectiveness against pertussis infection was 90–93% in infants aged <2 months [26,40]. Furthermore, a 51% relative reduction in pertussis cases has been observed in infants aged <2 months in Argentina in states with high Tdap vaccine coverage (>50%) compared to those with low coverage (≤50%) [41]. Regarding safety, Tdap vaccination was not associated with harms for the foetus or the mother, except for a small increased risk of chorioamnionitis that was observed in one retrospective database analysis [39].

Figure 1. Recommendations for maternal immunization worldwide. (A) Countries with national recommendation for influenza maternal immunization. (B) Countries with national recommendations for tetanus maternal immunization. Countries recommending tetanus–diphtheria–acellular pertussis vaccine are not shown. (C) Countries with national recommendation for pertussis maternal immunization with either tetanus–diphtheria–acellular pertussis or diphtheria–tetanus–acellular pertussis-inactivated poliovirus vaccine. Maps are based on data retrieved from the World Health Organization website in February 2016 [115].

In the US, the Advisory Committee on Immunization Practices first recommended in 2011 that unvaccinated pregnant women receive a dose of Tdap [36]. However, a rapid decline of pertussis antibody levels was observed in adults and postpartum women immunized with Tdap [42,43]. This recommendation was thus updated in October 2012 to extend vaccination to all women during each pregnancy regardless of previous immunization status [44]. Women should be vaccinated preferentially between 27 and 36 weeks of pregnancy, and women not vaccinated during pregnancy should be vaccinated during the postpartum period [44]. Tdap vaccination at 27–36 weeks of pregnancy is 85% more effective than postpartum vaccination at preventing pertussis in infants aged <8 weeks [45]. Furthermore, infants with pertussis whose mothers received Tdap vaccine during pregnancy have significantly lower risk of pertussis-related hospitalization, intensive care-unit admission and shorter hospital stays [46].

Similarly, in response to a national pertussis outbreak resulting in 14 infant deaths, the UK was the first country in Europe to introduce pertussis vaccination in pregnancy in 2012 [47]. The Joint Committee on Vaccination and Immunisation recommended the introduction of a temporary vaccination program with a combined Tdap-inactivated poliomyelitis vaccine (IPV) targeting pregnant women between 28 and 38 weeks of gestation [47]. The coverage rapidly reached ∼60% of pregnant women, and effectiveness against neonatal pertussis in infants aged <3 months was 91% when vaccination was given at least 7 days before birth [26]. This high effectiveness probably resulted from both passive antibodies during pregnancy and reduced transmission from the mother during early infancy. This vaccination program is still on-going but the recommendation has been recently updated to target pregnant women from 16 weeks of pregnancy after a study showed that early second-trimester maternal Tdap immunization significantly increased neonatal antibodies [18,19]. This change is expected to improve neonatal antibody levels and increase the number of opportunities for vaccination during pregnancy, as illustrated by increased vaccination coverage [48].

Influenza

Pregnant women and new-borns are at increased risk of influenza complications including hospitalization, admission to intensive care units and death [2]. Cardiopulmonary changes occurring during pregnancy (e.g. increased heart rate, stroke volume and oxygen consumption; reduced pulmonary capacity) may increase the risk of hypoxemia and contribute to increased severity of influenza in pregnant women [49]. In addition, new-borns born to mothers with influenza infection during pregnancy are at increased risk of adverse outcomes such as preterm delivery, low birth weight or stillbirth [49]. According to the “Barker Hypothesis”, in utero influenza infections or other perturbations of the foetal conditions may also have persistent pathological consequences through adulthood, which could be explained by epigenetic changes [50]. Immunization during pregnancy might thus improve outcomes for the mother and her baby, from foetal life to adulthood. Infants aged <6 months have the highest rate of influenza-related hospitalizations and deaths among children, yet no influenza vaccine is licensed for this age group because of low immunogenicity of current formulations [49,51].

In the US, given the high risk of influenza disease for mothers and infants and the expected low risk of vaccine complications, inactivated influenza vaccines (IIV) have been used in pregnant women at high risk since the 1950s, recommended in the second or third trimester since 1997 and recommended for all pregnant women during the influenza season since 2004 [52].

The effects of maternal immunization for both seasonal and pandemic influenza have been assessed in many studies. Maternal immunization with the 2010–2011 seasonal influenza vaccine at least 2 weeks before delivery increased antibody titers in cord blood 5–17 times and seroprotection rates in infants 6–34 times, depending on the strain and the interval between vaccination and delivery [53]. Similarly, infants born to influenza-vaccinated women had higher antibody titers than infants of unvaccinated mothers at birth and at 2–3 months of age, but not at 6 months (2002–2005 influenza seasons) [54]. In the US, effectiveness of the vaccine given to pregnant women was 45–92% in preventing seasonal influenza-related hospitalizations in infants aged <6 months [55,56]. In England during the 2013–2014 influenza season, vaccination prevented 71% of influenza infections in infants aged <6 months and 64% of infant hospitalizations due to influenza [57]. Results from a randomized controlled trial in Bangladesh provided a proof of concept that maternal vaccination could reduce infant influenza disease in developing countries, with 36% efficacy against febrile respiratory illness in mothers and 29% in infants and 63% efficacy against confirmed influenza illness in infants, compared to the 23-valent pneumococcal polysaccharide vaccine [58]. Three large, controlled, randomized trials in Nepal, Mali and South Africa then evaluated the efficacy and safety of maternal immunization to prevent influenza disease in pregnant women and their infants aged <6 months [59]. In the South African placebo-controlled trial, vaccine efficacy against confirmed influenza was approximately 50% both in mothers and infants [60]. In Nepal, year-round maternal influenza immunization significantly reduced maternal influenza-like illness, influenza in infants and low birth weight, suggesting that this strategy could be useful in subtropical regions where influenza is present for many months [61]. Regarding safety, IIV did not increase risk of foetal death, spontaneous abortion or congenital malformations [59–62].

During the 2009–2010 H1N1 pandemic, the risk of complications, hospitalizations and death in pregnant women was even greater than with seasonal influenza, consistent with observations from the 1918 and 1957 pandemics [49]. Notably, pregnant women accounted for 5% of the 2009 H1N1 influenza-related deaths in the US, although they only represented ∼1% of the population at risk [49]. Several studies showed that pandemic influenza vaccines (most of them being adjuvanted, in contrast to seasonal influenza vaccines) were effective at preventing influenza in pregnant women during the 2009–2010 H1N1 pandemic [2]. For instance, vaccination decreased the risk of influenza diagnosis by 70% among ∼117,000 pregnancies in Norway [63]. Vaccination was also associated with a decreased risk of preterm birth and low birth weight [64]. No evidence has been found for increased risk of spontaneous abortion, congenital malformations, stillbirth, early neonatal death or later mortality after vaccination with pandemic influenza vaccines (with or without adjuvant) [62,65]. The only exception was an analysis of a US database that suggested a modest association between spontaneous abortion and receipt of pH1N1-containing IIV within the previous 28 days among women who had received vaccine in the previous influenza season [66]. This finding does not support any change in the recommendations to vaccinate against influenza during pregnancy but suggests more research is needed in other datasets.

In 2012, due to the high risk of complications observed during the H1N1 pandemic, the WHO recommended that all pregnant women receive influenza vaccination regardless of the stage of pregnancy and, for the first time, showed a preference and identified pregnant women as the highest priority group in countries considering to initiate or expand seasonal influenza vaccination programs [67]. From this recommendation on, a growing number of countries recommend that all women who are (or plan to become) pregnant receive seasonal IIV, at any stage of pregnancy, during the influenza season [68,69]. In contrast, live-attenuated influenza vaccines are contraindicated in pregnancy, although inadvertent vaccination in the first trimester has not been associated with adverse foetal outcomes [70]. In 2014, 115 (59%) of the 194 WHO member states reported having a national influenza immunization policy, among which 81 (42%) had a national policy targeting pregnant women [69]. In Europe, the number of countries recommending seasonal influenza vaccination for some or all pregnant women increased from 10 in 2008/09 to 22 in 2010/11 and 28 in 2012/13 [71,72].

Despite these recommendations to prioritize pregnant women in national influenza vaccination programs, vaccination rates in this population often remain much lower than national targets (e.g. 50% in the US, 40−65% in the UK, <25% in other European countries or <2% in Hong Kong), with some exceptions such as in Argentina and Brazil (∼95%) [71,73–76]. These low coverage rates are due to multiple reasons such as concerns about vaccine safety, low perceived risk of influenza infection and lack of awareness and of recommendations by healthcare professionals [77,78].

In conclusion, seasonal and pandemic influenza vaccines have been administered to pregnant women with no evidence of harm to the women or their foetuses but with scientific evidence of benefits for both populations.

Other available vaccines

In addition to influenza, tetanus and pertussis vaccines that are routinely recommended for pregnant women in many countries, other vaccines may be administered to pregnant women depending on the presence of risk factors, as described in Table 1. These include hepatitis A and B, yellow fever and meningococcal vaccines.

Hepatitis A virus is transmitted through the faecal oral route by contaminated food or drink or close contact with infected individuals [79]. The safety of hepatitis A vaccine during pregnancy has not been evaluated, but the risk for the mother and the foetus is thought to be low because it is prepared from inactivated viruses [79]. Therefore, in pregnant women who might be at high risk of exposure to hepatitis A, the risk associated with vaccination should be weighed against the risk of disease [79].

Most cases of vertical (mother-to-child) transmission of hepatitis B virus occur during delivery but some can also occur during the prolonged viremic phase, which can persist for months [80]. Hepatitis B infection of mothers before or during pregnancy leads to a high risk of chronic infection in their infants. Indeed, 70–90% of infants and 30% of young children with acute hepatitis B infection develop chronic infection compared to <5% of adult patients [80]. Chronic hepatitis B infection is associated with greatly elevated risk of the long-term development of liver cirrhosis and hepatocellular carcinoma [81]. Therefore, pregnant women who are at high risk of hepatitis B virus infection should be vaccinated [82], although safety data derived from cohort studies are limited [4].

Pregnant women may also be vaccinated against meningococcal disease, cholera, Japanese encephalitis or tick-borne encephalitis during outbreaks, in endemic regions or if the risk of infection is high [83–85]. Although live-attenuated vaccines are not recommended for pregnant women, women who live in or must travel to areas where the risk of yellow fever is high should be vaccinated since the risk of yellow fever infection during pregnancy substantially outweighs the limited theoretical risk from vaccination [86]. However, some cases of yellow fever infection in infants acquired through breast milk have been reported with the live-attenuated vaccine strain, hence nursing mothers should be counselled regarding the benefits and potential risks of vaccination [87]. The rabies vaccine is recommended as post-exposure prophylaxis or even as pre-exposure prophylaxis if the risk of exposure to rabies is substantial [88]. Similarly, the adsorbed anthrax vaccine is recommended as a component of post-exposure prophylaxis in pregnant women exposed to aerosolized Bacillus anthracis spores [89]. Finally, results from pneumococcal maternal immunization studies are encouraging so far but insufficient to determine whether infections are reduced in infants born to vaccinated women [90].

Development of new vaccines for maternal immunization

Beyond the vaccines currently available for use during pregnancy, several new vaccines are being specifically developed to prevent neonatal infectious diseases through maternal immunization and address unmet needs. These potential future vaccines for maternal immunization include those against respiratory syncytial virus (RSV), group B streptococcus (GBS), herpes simplex virus and cytomegalovirus, for which no vaccines are currently available [17].

Respiratory syncytial virus

RSV is the leading cause of viral lower respiratory tract infections in infants and young children [91]. RSV infections are likely to be more severe in the first months of life than in older age groups. No vaccines are currently available to prevent RSV infections [92]. The first formalin-inactivated candidate vaccine was associated with enhanced disease in children subsequently infected naturally with RSV [91]. After these observations, boosting natural antibodies from previous RSV infections in women has acquired greater interest because these maternal antibodies are immediately present at birth and are likely to have high affinity [17,93]. Also, higher concentrations of maternal neutralizing antibodies are associated with less severe disease in infants [17]. Finally, maternal immunization could also reduce virus spread within the household [93]. Several candidate vaccines are currently under clinical development, one of them being in Phase 3 development [92].

Group B Streptococcus

GBS (Streptococcus agalactiae) is a leading cause of pneumonia, meningitis and sepsis in new-borns. Because of the early onset of disease, administration of a GBS vaccine to infants at birth cannot generate immune responses rapidly enough to prevent neonatal disease [94]. Thus, maternal immunization has been identified as a potential strategy to prevent invasive GBS disease in new-borns, in conjunction with existing intrapartum antibiotic prophylaxis given to women who are GBS-positive at prenatal screening [94]. Several vaccine candidates have been tested in pregnant women in Phase 1 and 2 clinical trials but none have yet entered Phase 3 development [94].

Herpes simplex virus and cytomegalovirus

Because the risk of neonatal herpes and congenital cytomegalovirus infection is higher in women with primary infection during pregnancy, vaccines would provide high levels of protection if administered in seronegative women, ideally before pregnancy [17]. Several herpes simplex virus and cytomegalovirus vaccine candidates are being evaluated in clinical trials but none has been licensed [95,96].

Implementation of maternal immunization programs

Overview of recommendations at supranational and national levels

As described in previous sections, the WHO and an increasing number of national health authorities now recommend maternal immunization for several diseases, based on clear benefits for both mothers and infants. Influenza, tetanus and pertussis are the key focus of these recommendations worldwide (Figure 1 and Table 1).

Safety considerations about maternal immunization

Vaccine safety is a key consideration during development and after licensure, particularly in pregnant women [97]. Historically, pregnant women were typically excluded from clinical trials due to general concerns about medical interventions in a vulnerable population, leading to misconceptions about vaccine safety [98]. For this reason, most information on safety of the vaccines currently used in pregnant women comes from observational studies and post-licensure surveillance systems [97]. Passive surveillance systems, such as the Vaccine Adverse Event Reporting System in the US, are used in most countries to monitor post-licensure safety of vaccines in the general population including pregnant women, whereas active surveillance systems have been less frequently implemented to directly collect post-vaccination events from recently immunized pregnant women [99]. Nowadays, pregnant women are increasingly included in clinical development plans for candidate vaccines to evaluate their impact on mother, foetus and infant immune responses and to ensure they are well tolerated and effective before licensure.

Due to the physiologic changes in pregnancy, clinical and laboratory assessments may be different in pregnant women compared to non-pregnant women or men; thus, normal ranges of these parameters need to be established first. Indeed, the absence of global standard definitions for adverse events following immunization in pregnant women limits comparisons between safety data across studies and regions and, therefore, the performance of meta-analyses [100,101]. To facilitate comparison of data across clinical trials and observational studies, the Global Alignment of Immunization Safety Assessment in Pregnancy (GAIA) initiative was launched by the Brighton Collaboration Foundation and the WHO [102]. This project aims at harmonizing terms, disease concepts and standardizing case definitions to monitor adverse events following immunization in pregnancy, with particular focus on the requirements of low- and middle-income countries [102].

Regulatory requirements and labelling considerations

Regulatory authorities require that pre-licensure trials evaluate the safety and efficacy of vaccine administration in pregnant women before allowing an indication and usage statement in the prescribing information that specifically addresses use in pregnancy [103]. Until recently, no vaccine has had a specific indication during pregnancy because no licensed vaccine has been studied in pregnant women in pre-licensure trials [103]. This is beginning to change; many post-licensure studies have been conducted to evaluate vaccine safety and effectiveness in pregnant women. Based on available post-licensure safety data and after discussions with the European regulatory authorities [104], the posology and the pregnancy sections of the European summary of product characteristics of one of the commercially available Tdap vaccines (Boostrix, GSK) were recently updated to reflect that the use of this vaccine may be considered during the third trimester of pregnancy. However, it should be noted that the absence of a specific statement in the indication section of the vaccine label does not preclude vaccine use in pregnant women [103].

The WHO produces global recommendations but each country adapts its vaccination recommendations based on local information about risk groups, disease burden and cost-effectiveness. This epidemiological information is important to help advisory groups and policy makers in establishing informed decisions about target groups and vaccination schedule, but in many countries, these data are missing, especially in low- or middle-income countries. Contradictions between national guidelines and recommendations (based on post-marketing experience) and vaccine labels (based on pre-licensure clinical studies) make the messages on maternal vaccination appear ambiguous for healthcare providers and the public [97]. For instance, the Scottish health authority strongly recommends the reduced Tdap-IPV vaccine (Boostrix-IPV) during pregnancy, whereas the UK summary of product characteristics provides only a modest recommendation [104,105]. In an attempt to reduce these barriers, regulatory agencies in the US are working with the vaccine industry to delineate the processes to develop and approve vaccines for use during pregnancy [103].

Overcoming barriers to maternal immunization

Although the WHO and many national health authorities recommend maternal immunization, based on clear benefits for both mothers and infants, major challenges in implementation still need to be addressed. Global vaccination coverage rates remain low in pregnant women, even in countries where national immunization programs are in place. Acceptance of vaccination during pregnancy is mostly affected by concerns about maternal and foetal safety [106]. Other common barriers to maternal immunization reported by pregnant women and healthcare providers are concerns about the vaccine efficacy, belief that the vaccine is not necessary, poor awareness of the vaccines or the diseases, contradictory precautionary language in the labelling information, lack of recommendations from healthcare providers and issues relating to delivery of vaccinations [106,107].

A study analysing the attitude of healthcare providers towards maternal influenza and pertussis immunizations conducted in Belgium showed that vaccination coverage during pregnancy was 64% for pertussis and 45% for influenza [108]. In this country, pertussis vaccination is recommended for each pregnancy and influenza vaccination during the influenza season. Overall, 78% of gynaecologists and general practitioners recommended both maternal vaccinations but only 24% of midwives did. One of the main reasons for not getting vaccinated was because vaccination was not offered or was even discouraged by healthcare providers, suggesting that the attitude of the healthcare provider towards the vaccination was crucial to achieve high vaccination coverage in pregnant women. Another study conducted among midwives in England showed that, although 76% of respondents agreed that influenza vaccination should be routinely recommended to pregnant women, only 25% of them felt well prepared for discussing this topic [109]. Also, 67% of the midwives reported that they would welcome better access to evidence of effectiveness. Similar findings were reported by other studies [110]. Lack of knowledge about disease risks and vaccine safety and efficacy was also frequently cited as barriers by pregnant women, which underscores the need for clearer education in this area [110].

Recommendations from healthcare providers are essential to increase vaccination coverage during pregnancy [106]. Healthcare providers responsible for pregnant women should understand the main aspects of maternal immunization and be convinced about its clear benefits for pregnant women and infants but, traditionally, they have had little experience in this area and often do not offer any vaccination to pregnant women [37]. Therefore, effective communication strategies are needed to improve awareness of maternal immunization among obstetricians-gynaecologists, midwives and general practitioners. However, education of healthcare providers alone is unlikely to be sufficient; parental vaccine hesitancy should also be addressed through specific public awareness campaigns [37]. Tailored communication strategies for pregnant women should focus on improving perceptions related to personal benefits and risks of vaccination compared to the disease. An example of a successful campaign comes from Stockport, a town in the UK that used a multi-channel approach, including a community awareness campaign, a pharmacy program and a general practitioner incentive scheme [7]. Through this campaign, Stockport obtained the highest rates of influenza vaccine coverage in pregnant women in England during the 2011–2012 influenza season [7].

As noted above, data regarding efficacy or safety from clinical trials are lacking in pregnant women. One of the consequences is that vaccine manufacturers typically refrain from promoting maternal vaccination due to the concerns that this might be seen as “off-label” promotion, despite existing recommendations from public health authorities and supporting data. Whereas the existence of recommendations for maternal immunization is a pre-requisite, it is not sufficient to ensure that healthcare professionals feel confident to recommend vaccination to pregnant women and that pregnant women are aware of the value of such vaccination. To improve confidence, further progress in generating data acceptable for label updates would require collaboration between manufacturers, regulators and other public health actors. Using existing post-licensure safety data available from pregnancy registries and post-licensure safety analyses of claim databases is an option, as outlined in the new US Food and Drug Administration (FDA) pregnancy lactation and labelling rule [111]. This is in line with the guidance currently prepared by the FDA on “medicinal product communications that are consistent with FDA-required labelling”, and the WHO’s addendum to the recommendations for production and control of IIVs indicating that IIVs may be administered to pregnant women, unless there are clear contraindications and the risks outweigh the benefit of such vaccination [112,113].

Discussion

A growing body of evidence suggests maternal immunization is a well-tolerated and efficient approach to provide protection to pregnant women, foetuses and new-borns against vaccine-preventable diseases. Effective immune responses to vaccines and transmission of specific antibodies to infants through the placenta are observed when pregnant women are vaccinated. Over the last decade, substantial progress has been made regarding maternal immunization programs. In addition to the widely used tetanus maternal immunization, inactivated influenza and diphtheria–tetanus–pertussis vaccines are now also recommended for all pregnant women in many countries. Other vaccines, such as meningococcal, pneumococcal or hepatitis A and B vaccines, are also recommended for specific subpopulations of pregnant women depending on risk factors. Despite these recommendations, the concept of maternal immunization has not been widely accepted by the general public or healthcare providers. Vaccination rates in pregnant women remain suboptimal in many countries and are still much lower than those in children [71,73,74,114]. One of the key reasons is that clinical trial data on efficacy or safety during pregnancy are limited for most vaccines. It is therefore crucial that clinical trials, observational studies and safety surveillance are systematically performed in pregnant women and their infants to evaluate vaccine effectiveness and safety. When available, these data should be included in the labels to help guide the healthcare providers in making an informed decision about the benefits and risks of vaccination for a specific woman. Finally, efforts should be made to improve awareness of the benefits of vaccination during pregnancy among healthcare providers and parents for currently recommended vaccines, as the current perceptions of maternal immunization value is likely to impact those of the new vaccines in development such as those against RSV and GBS.

Acknowledgements

The authors thank Alberta Di Pasquale (GSK, Belgium) for her critical review of the manuscript. Writing assistance was provided by Dr. Julie Harriague (4Clinics, France), on behalf of GSK. Authors would like to thank Business & Decision Life Sciences platform for editorial assistance and manuscript coordination, on behalf of GSK. Carole Desiron coordinated manuscript development and editorial support. The authors would like to apologize to the many authors whose work could not be cited due to space constraints.

Disclosure statement

I. V., I. D., T. M. D., V. F., J. M., R. B-B., W. K. and D. P-C. are employees of the GSK group of companies. L. H. and A. V. were employees of the GSK group of companies at the time of the study. I. V., I. D., R. B-B., V. F., L. H., J. M., T. M. D. and A. V. hold shares in the GSK group of companies. A. V. is a current employee of Pfizer Ltd.

Additional information

Funding

GlaxoSmithKline Biologicals S.A. funded all costs related to the development of this publication.