Benefits to mother and child of influenza vaccination during pregnancy

Abstract

Influenza virus infection contributes to substantial morbidity and mortality globally. Included in the list of groups at higher risk of either influenza infection or severe complications following influenza infection are pregnant women and their newborns. Influenza vaccination offers a safe and effective means to prevent or lessen the severity of influenza infections. Recent research has helped elucidate the impact of influenza infection and vaccination on pregnant women and their newborn children and young infants. This review summarizes recent findings in this area and identifies additional gaps in the evidence base that need to be addressed to appropriately inform vaccination policies worldwide, to protect pregnant women and their children from influenza and related complications.

Keywords: :

• infants
• influenza
• pneumonia
• pregnancy
• vaccine

Influenza has been responsible for four pandemics in the last hundred years with an additional global burden of seasonal influenza estimated to be between three and five million cases of severe illness and 250,000 to 500,000 deaths annually.¹

Burden of Influenza in Pregnancy

Pregnant women are among high risk groups for influenza. The incidence of influenza infection among pregnant women is similar compared with the incidence in non-pregnant women of similar age.^2,3 However, pregnant women are at a higher risk of influenza complications.³ Neuzil et al. evaluated the association between influenza and risk of hospitalizations or death from acute cardiopulmonary complications (e.g., pneumonia, influenza, heart failure, myocarditis) in pregnant women.³ The risk of cardiopulmonary events was higher in pregnant women compared with both postpartum women and non-pregnant women of similar age. The odds ratios of complications increased with increases in gestational age. In an analysis of more than 6 million hospitalizations among pregnant women in the US, pregnant women who were hospitalized during the influenza season with a respiratory illness had longer hospital stay and higher likelihood of a complicated delivery compared with hospitalized pregnant women without respiratory illness.⁴ The risk of adverse outcomes associated with influenza in pregnancy is higher for women with underlying co-morbidities such as diabetes, heart disease, immunosuppression, asthma, and chronic obstructive pulmonary disease.^3,5-7

Pregnant women are at high risk of influenza-related complications during pandemics. In a report of outcomes in 1,350 pregnant women during the 1918 pandemic, almost half were identified as having pneumonia and, of these women, more than half died, resulting in an overall case fatality rate of 27%.⁸ A recent examination of birth records from the 1918 pandemic identified live birth rate decreases of approximately 5 to 15% below baseline expectations during the pandemic period, with the greatest depression in birth rate occurring 6 to 7 mo after the pandemic peak, indicating the possibility of increased first term miscarriages due to influenza infection.⁹ The highest influenza-associated mortality in pregnant women was seen in the third trimester. During the 1957 pandemic, approximately 50% of all women of childbearing age who died were pregnant.^10,11 Similarly, during the 2009 influenza A(H1N1) pandemic, pregnant women had a higher rate of hospital and intensive care unit admission than the general population and a high risk of complications—including death.^12-14

Biology of Influenza in Pregnancy

The reasons for the higher risk of adverse consequences of influenza infection in pregnant women are not completely understood. However, several biological changes that occur in pregnancy may play a role. Pregnancy is associated with biochemical, mechanical, hemodynamic, and immunologic changes in the mother that become most pronounced by the third trimester. These changes include increased minute ventilation, reduced tidal volumes, and decreased functional residual capacity which leaves less reserve for stress on pulmonary function.¹⁵ In pregnancy, humoral immunity remains generally intact with augmentation of the T-helper-type 2 (Th2) response.^16,17 On the other hand, there is selective suppression of Th1 cell-mediated immunity. Suppression of cell-mediated immunity is likely meant to protect the developing fetus from maternal cytotoxic T-lymphocyte activity but, as a consequence, impairs maternal response to infection–including viral infections.^18-20 This compromise of cell-mediated immunity continues throughout pregnancy.²¹

Influenza Morbidity in Young Infants

Young infants (i.e., <6 mo) have a high risk of influenza infection and associated adverse outcomes.^22-27 Although influenza viruses cause disease in all age groups, children and individuals 65 y or older have the highest incidence of seasonal influenza.^28-31 Moreover, during most pandemics, children and the elderly have had high risk of severe influenza illness.^32,33 Among children, the risk is highest in infants—particularly those younger than six months of age.^34,35 In a population-based surveillance study conducted in 9 states (in the US), the incidence of laboratory confirmed influenza in infants <6 mo of age was more than double that observed in 6 to 23-mo-old children (311 vs. 118 per 100,000 population), with even lower rates in the older age groups.³⁵ In another study in Houston, the annual influenza incidence in infants younger than 6 mo of age was estimated to be 12%.³⁴ In a prospective, population-based active surveillance study conducted in children less than five years of age residing in three US counties, Poehling et al. documented an annual influenza associated hospitalization rate of 0.9 per 1,000 children.²⁷ The annual hospitalization rate was the highest in infants younger than six months of age with 4.5 hospitalizations per 1,000 children.²⁷ During the influenza A(H1N1)2009 pandemic, infants were considered a high risk group for acquiring and developing complications following infection with influenza A(H1N1)2009, with continued elevation of pediatric deaths after the initial 2009 pandemic waves.²⁸ Surveillance of pediatric influenza deaths continues to show a burden of influenza A(H1N1)2009 as well as influenza A(H3N2) as a cause of mortality in children.^36,37

Respiratory Infections in Pregnancy and Fetal Growth and Development

Maternal respiratory infections have an impact on fetal outcomes,^11,38 including preterm birth.³⁹ Respiratory infections, particularly pneumonia, have been associated with low birth weight and increased risk of preterm birth.^11,38 In an examination of pregnancy hospitalizations over four influenza seasons, respiratory illness was associated with a 4-fold increase in odds of preterm delivery, 2.5-fold increase in odds of fetal distress, and nearly 4-fold increase in odds of Cesarean delivery.⁴ In a 13 y population-based cohort study in Canada, pregnant women hospitalized with respiratory symptoms during the influenza season gave birth to newborns of lower mean birth weight and a higher likelihood of being small for gestational age (SGA).⁴⁰

Adverse fetal outcomes have been identified as an important consequence of influenza pandemics. In the 1918 influenza pandemic, high rates of premature births were reported among pregnant women admitted to Cook County Hospital in Chicago and among pregnant women treated by physicians—most of them in Maryland.^8,41 In an analysis of data from the 1957–58 pandemic, infants born to women who had serological evidence of influenza during pregnancy were 50% more likely to be premature compared with infants of uninfected women.³⁸ In a national cohort study conducted in the UK, perinatal mortality and prematurity were higher in newborns of women who were hospitalized with confirmed influenza A(H1N1)2009 infection compared with the control group born during the pre-pandemic comparison period.⁴²

Previously, in a Chinese case-control study, neural-tube defects were associated with history of influenza-like illness, cold, and/or fever in pregnancy.⁴³ A large observational study from Hungary documented an association between history of influenza during the first trimester of pregnancy and cleft lip, neural-tube defects, and cardiovascular malformations.⁴⁴ However, a separate analysis of the same data did not find an association between maternal influenza-like illness and prematurity and low birth weight.⁴⁵ A few other observational studies have also not found an association between influenza infection and birth outcomes.^6,46 The variability in observed effect of influenza on birth outcomes could be due to issues related to data sets based on medical records and administrative data, small and/or difficult to measure effect size, or a true lack of association. Evaluating the association between influenza in pregnancy and birth outcomes in the context of protective effect of maternal influenza immunization in a randomized controlled trial will help resolve the uncertainty around this question.

Since influenza virus rarely crosses the placenta,^2,47,48 the adverse effects of influenza infections on birth outcomes are likely to be associated with inflammation.^39,49 Influenza virus infection induces gene expression of pro-inflammatory cytokines including IL-1β, IL-6, TNF-α, interferon (IFN)-β, IFN-α and granulocyte macrophage colony-stimulating factor (GM-CSF).⁵⁰ Increased levels of pro-inflammatory cytokines such as IL-1, IL-6 and TNF-α and reduced levels of anti-inflammatory cytokines (e.g., IL-10) have been associated with `higher likelihood of preterm labor.^49,51 The pro-inflammatory cytokines stimulate the amnion and the decidual tissue to produce prostaglandins which can induce labor and some cytokines can directly stimulate myometrial contractions.^50-53

Immunogenicity, Efficacy and Effectiveness of Influenza Vaccine in Pregnant Women

Vaccination is the most effective tool for preventing morbidity and mortality due to influenza. The data on clinical efficacy of influenza vaccination—particularly in pregnant women (and their infants)—are limited. Immunogenicity studies of influenza vaccination in pregnancy indicate that the seroresponse in pregnant women is similar to of similar aged, non-pregnant women.^54-61 Englund et al. evaluated the immunogenicity of the trivalent inactivated influenza vaccine in a small randomized controlled trial.⁵⁵ In this trial, 13 pregnant women received influenza vaccine and 13 women received the tetanus toxoid. All 13 women who received the influenza vaccine had 4-fold or higher increase in serum neutralizing antibody titer to at least one of the three influenza antigens included in the vaccine.⁵⁵ Four women had a 4-fold or higher response to all three antigens, 5 to two antigens, and 4 to only one antigen. There were no women in the tetanus toxoid group with 4-fold or higher increases in titer to any of the influenza antigens.⁵⁵ During the 1962 Asian influenza outbreak, pooled serologic analysis of 363 pregnant women and 138 non-pregnant women found little difference in immune response by pregnancy status.⁵⁶ Additionally, evaluations of the 1976 swine flu (influenza A/NJ/8/76) vaccine conducted through two small studies (n = 26 pregnant women and n = 56 pregnant women) found immune responses in pregnant women to be slightly lower, but not statistically significantly different from non-pregnant women and that maternal response and passive antibody transfer occurred in more than 50% of mother-infant pairs.^58,60 More recently, clinical trial data from Bangladesh documented strong antibody responses in pregnant women exposed to trivalent seasonal influenza vaccine, with efficient antibody transfer to their babies, and similar proportion with seroprotective titers in mothers and infants at delivery.⁵⁹ During the 2009 influenza A(H1N1) pandemic, pregnant women who received monovalent influenza A(H1N1)2009 vaccine at doses of 25 μg and 49 μg mounted strong antibody responses, with seroprotective antibody levels in 89% and 97% of women, respectively.⁵⁷ However, these data have primarily looked at HAI responses and not cell-mediated immune responses, which may be important in responding to viral infection.

A limited number of observational studies have evaluated influenza vaccine’s clinical effectiveness among pregnant women.^56,62 Munoz et al. conducted an analysis of an electronic database from a clinic in Houston.⁶² In this observational study, 225 healthy pregnant vaccinated women were compared with 826 healthy pregnant unvaccinated women matched by type of insurance, age, and month of delivery.⁶² Approximately 23% of vaccinated and 19% of unvaccinated women developed medically attended acute respiratory infection (p = 0.18). In an analysis of electronic data from Kaiser Permanente Northern California, Black et al., documented similar rates of outpatient visits due to febrile influenza-like illness among vaccinated vs. unvaccinated pregnant women (45.4 vs. 44.7 per 100,000; p = 0.09).⁶³

In the only randomized controlled trial of maternal immunization that measured clinical (in mother and infant) and virological (in infant) outcomes, the vaccine prevented approximately a third of influenza-like illness episodes in pregnant women.⁶¹ However, this trial was conducted during a single influenza season in Bangladesh and needs to be replicated in other settings. Moreover, the Bangladesh trial did not assess laboratory confirmed influenza episodes in mothers.

Fetal Outcomes

There is recent evidence of protective effect of influenza vaccine in pregnancy on fetal outcomes. In a retrospective cohort study in Georgia (US), Omer et al. reported a reduced likelihood of prematurity among infant born during the influenza season to women who received TIV in pregnancy (adjusted odds ratio = 0.60; 95% CI, 0.38–0.94).⁶⁴ The impact of maternal influenza vaccine on reducing prematurity increased with the increase in influenza circulation in the study area, with the highest impact during the period of widespread activity (OR = 0.28; 95% CI, 0.11–0.74).⁶⁴ The protective effect of maternal influenza vaccination on SGA was limited to the period of widespread circulation in which there was approximately 70% reduction in the odds of being SGA among newborns of vaccinated women compared with the newborns of unvaccinated women (adjusted OR = 0.31; 95% CI, 0.13–0.75).⁶⁴ A long-term cohort study in Nova Scotia, Canada, over 13 y, reported increased levels of adverse fetal outcomes (i.e., SGA, low birth weight) among women who were hospitalized for respiratory infections while pregnant. Findings included a 66% increase in small for gestational age and mean birth weight 100 g less among children whose mothers were hospitalized for respiratory illness.⁴⁰ A recent examination of pregnant women infected with influenza A(H1N1)2009 in the UK identified increases in perinatal mortality, stillbirth, and preterm birth.⁴² While Pierce et al. did not find significant decreases in birth weight, after adjusting for gestational age, additional analyses found a non-significant increase in small for gestational age.⁴²

Infant Outcomes

Infants, particularly those younger than 6 mo, are at a high risk of acquiring influenza and developing influenza related complications.^22-27 However, there is no influenza vaccine currently approved for use in infants younger than 6 mo. A recent evaluation of an adjuvanted influenza vaccine in children aged 6 to less than 72 mo of age documented both increased immunogenicity and efficacy relative to standard trivalent inactivated influenza vaccine.⁶⁵ While this vaccine has not been evaluated in infants younger than 6 mo, the increased immune response shown in young children may indicate the possibility of provoking a sufficient immune response in children younger than 6 mo.

Maternal influenza immunization could potentially play a role in protecting newborns and young infants. There are limited data on immunological and clinical outcomes related to infant protection against influenza through immunization during pregnancy.

In the randomized, controlled immunogenicity trial by Englund et al., infants born to women in the influenza vaccine arm had significantly higher levels of vaccine specific IgG antibody both at birth and at two months of age than control women who received tetanus toxoid.⁵⁵ Sumaya et al. conducted a non-randomized observational study that included data from 40 mother-infant pairs.⁶⁰ In this study, evidence of protective levels of antibody titers was present in only 42% newborns.⁶⁰

In a retrospective matched cohort study using data from four managed care organizations, France et al. evaluated the association between maternal influenza immunization and acute respiratory illness in infants.⁴⁶ In this non-randomized study, there was no reduction in respiratory illness in infants (incidence rate ratio during peak influenza season, 0.96; 95% confidence interval, 0.86–1.07).⁴⁶ In the retrospective matched cohort study by Munoz et al., the rate of hospitalization for respiratory illness among infants of women who received influenza vaccine in pregnancy was similar to the hospitalization rate among infants of unvaccinated women.⁶² In a retrospective cohort study by Black et al., infants of vaccinated and unvaccinated women had similar risk of influenza or pneumonia admissions and outpatient visits for influenza-like illness.⁶³ On the other hand, in a recent case-control study, maternal influenza immunization was 85% effective in preventing hospitalization due to laboratory confirmed influenza in infants younger than six months. Maternal influenza vaccine remained 79% effective in preventing influenza-related immunization through 12 mo of age.⁶⁶ Another case-control study of infants less than 6 mo of age, based on an existing active surveillance system in three US counties found that, compared with infants of unvaccinated mothers, those whose mothers received influenza vaccine were 45% to 48% less likely to have been hospitalized for influenza.⁶⁷ The randomized clinical trial in Bangladesh demonstrated that vaccination of pregnant women with the inactivated influenza vaccine was 63% effective in reducing laboratory-confirmed influenza in their infants, while also reducing all respiratory illness with fever by 29%.⁶¹ While Eick et al. documented little difference in infant ILI incidence between mothers who received influenza vaccine and those who did not, they did identify a 41% reduction in laboratory-confirmed influenza infection and a 39% reduction in hospitalization for ILI among infants whose mothers were vaccinated.⁶⁸ The discrepancies between the observational studies argue for more randomized trials of maternal influenza immunization to assess the respiratory burden prevented in their infants.

An area of investigation that has to date received little attention is the potential benefit of maternal influenza immunization on the acquisition of bacterial pathogens during early infancy. Much of the respiratory burden of young infants is thought to be due to the synergistic lethality of influenza and other respiratory viruses with the bacteria acquired during infancy such as the pneumococcus.⁶⁹ Influenza may also play a role in the acquisition and transmission of the pneumococcus.⁷⁰ It is possible that among the potential benefits of maternal influenza vaccination may be a reduction in pneumococcal acquisition during exposure to influenza.

Maternal Influenza Immunization Recommendations

Pregnant women comprised approximately 50% of deaths in women of reproductive age during the 1956–58 influenza pandemic.¹⁰ Following the pandemic, more than 100,000 women in the US were immunized against influenza.⁷¹ However, in the early 1960s there was lack of data on serious complications of seasonal influenza in pregnant women. As a result, after 1965, the Advisory Committee on Immunization Practices (ACIP) discontinued the recommendation for immunizing pregnant women with the exception of women with certain co-morbidities.^72,73 In the 1990s, the recommendations were expanded to include all women in their second and third trimester of pregnancy.⁷⁴ Since 2004, influenza immunization is recommended in all trimesters for women who are pregnant during the influenza season.^75,76 More recently, pregnant women were included as a high priority group for receiving the pandemic influenza A(H1N1)2009 vaccine.²⁸ Starting with the 2010–2011 influenza season, influenza vaccination in the US is recommended for everyone 6 mo of age and older, and pregnant women remain in the high-priority list in the event of vaccine shortages.⁷⁷

In 2005, the World Health Organization issued a position paper that included the recommendation that all pregnant women should be immunized during the influenza season.⁷⁸ Starting with the 2007–2008 season, Canada’s national advisory committee expanded its recommendations to include all pregnant women in all trimesters of pregnancy.⁷⁹ The Australian national guidelines recommend influenza vaccine for all women who will be in their second or third trimester of pregnancy during the influenza season -even if they are in the first trimester when they receive the vaccine.⁸⁰ In the UK, pregnant women with certain co-morbidities and high risk conditions are encouraged to vaccinate against influenza in all trimesters of pregnancy; however, the recommendations do not include routine influenza immunization for healthy pregnant women.⁸¹ In addition to the US, Canada, Australia and the UK, we identified 24 other countries (Argentina, Austria, Bahamas, Belgium, Bermuda, Cayman Islands, Chile, Cyprus, Denmark, Estonia, Finland, France, Germany, Hungary, Ireland, Italy, Malta, Netherlands, Norway, Portugal, Slovakia, Spain, Sweden Switzerland) that have recommendations directly calling for influenza vaccination of pregnant women, as reported for either seasonal influenza or the influenza A(H1N1)2009 pandemic. Additionally, 27 countries (Algeria, Bahrain, Barbados, Belarus, Bolivia, Bulgaria, Congo, Cuba, Iraq, Israel, Jamaica, Jordan, Kazakhstan, Kuwait, Libya, Marshall Islands, New Zealand, Nicaragua, Palau, Panama, Paraguay, South Africa, South Korea, St. Lucia, Turkey, United Arab Emirates, and Venezuela) include “high-risk” individuals in their influenza immunization recommendations, but do not specifically reference pregnant women as a high risk group. Despite the WHO recommendations, most countries do not have national recommendations for influenza vaccines in pregnancy (www.who.int/immunization_monitoring/en/globalsummary/countryprofileresult.cfm, apps.who.int//immunization_monitoring/en/globalsummary/scheduleselect.cfm) (Fig. 1).^82,83 However, this list may be incomplete, based on the lack of availability of a systematic examination of policies on influenza vaccination of pregnant women in all countries. The authors request that representatives of any countries not properly identified here provide documentation of their country’s policies on influenza vaccination of pregnant women.

Figure 1. Countries with recommendations for provision of influenza vaccine to pregnant women.^82,83 Additional data sources: (www.who.int/immunization_monitoring/en/globalsummary/countryprofileresult.cfm, apps.who.int/immunization_monitoring/en/globalsummary/scheduleselect.cfm.

Vaccine Coverage in Pregnancy

Despite ACIP’s strong recommendations for influenza immunization in pregnancy, the coverage of the seasonal vaccine in the US has been consistently low, though increases in coverage in recent years offer some hope that additional increases are possible. In 1997, the coverage of influenza vaccine in pregnant women was approximately 11% which only rose to 19% by 2008 (Fig. 2). Limited data from other countries where influenza vaccine is recommended in pregnancy (to at least some women e.g., with co-morbidities) suggests similar levels of vaccine uptake.^82,84,85 Following identification of the influenza A(H1N1)2009 virus and the related impact on pregnant women, there was increased outreach to pregnant women, encouraging influenza vaccination. This resulted in a substantial increase in maternal influenza immunization coverage during the 2009–2010 influenza season that was maintained through the 2010–2011 influenza season (Fig. 2).^77,86,87

Figure 2. Self reported influenza vaccine coverage in pregnant women, US 1997–2011. Note: earlier estimates (1997–2005) were based on calendar year surveys of influenza vaccine receipt in the past year. Starting with the 2006–2007 influenza season, more comprehensive seasonal estimates were available. Data sources: www.cdc.gov/flu/professionals/pdf/NHIS89_08fluvaxtrendtab.pdf; www.cdc.gov/mmwr/preview/mmwrhtml/mm5947a1.htm?s_cid-mm5947a1_w, Fiore MMWR Recomm Rep 2010, www.cdc.gov/mmwr/preview/mmwrhtml/mm6032a2.htm?s_cid=mm6032a2_w

Low influenza vaccine coverage in pregnancy is due to multiple individual and health system-related factors and a multifaceted approach will be required to significantly increase the coverage.⁸⁸ However, women’s and clinicians’ beliefs regarding maternal influenza vaccine’s impact on infants are among the factors that play a role in vaccine-related decisions.⁸⁹ In a survey conducted in Los Angeles, Silverman and Greif found that obstetricians who considered the maternal influenza vaccine to protective for infants were more likely to offer influenza vaccine to their patients.⁸⁹ Development of robust evidence base regarding infant and fetal protection due to maternal influenza vaccination will inform clinical decision-making and help increase vaccine acceptance.

Future of Maternal Influenza Immunization

From a programmatic and operational standpoint, the increase in maternal influenza immunization coverage in response to the H1N1 pandemic in the US was encouraging. While only approximately 50% of pregnant women were vaccinated with seasonal influenza vaccine and H1N1 influenza vaccine during the 2009–2010 influenza season, this was more than double the coverage seen in the US in prior years. It was reassuring to not see immunization coverage levels in pregnant women drop in the year following the pandemic, however they did not increase. In the US, to continue to improve influenza vaccination of pregnant women and ultimately reach the Healthy People 2020 goal of 80% influenza vaccination of pregnant women will take a concerted effort firmly grounded in science.

Recent clinical trials and observational studies have identified that influenza immunization of pregnant women is safe and effective in preventing influenza infections in both mother and infant. These have been bolstered by additional recent studies indicating other benefits, such as reductions in prematurity and low birth weight. It is important to note that thus far, the majority of the benefits of vaccinating pregnant women have been identified as benefits to the health of the mother. The recent focus on examining the impact among children too young to be vaccinated have produced promising results, but these studies currently consist of a minority of the literature in this area. Additional studies are needed to continue to develop this evidence base, including examinations of the benefit/cost ratio of maternal influenza vaccination, to ensure that the economics of this strategy are properly understood. While there are clinical trials of influenza vaccination of pregnant women currently scheduled or underway in South Africa (clinicaltrials.gov/ct2/show/NCT01306669), Nepal (clinicaltrials.gov/ct2/show/NCT01034254), and Mali (clinicaltrials.gov/ct2/show/NCT01430689), that will add to the knowledge on infant outcomes of maternal influenza vaccination, other studies, in other parts of the world are needed to ensure a robust evidence base, as influenza viruses are variable.