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Maternal Immunization

Munoz, Flor M., MD, MSc; Jamieson, Denise J., MD, MPH

doi: 10.1097/AOG.0000000000003161
Contents: Prenatal Care: Clinical Expert Series
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Vaccines administered to women during pregnancy can provide protection against serious infectious diseases for the mother, for the newborn, or both. Maternal immunization boosts the concentration of maternal antibodies that can be transferred across the placenta to directly protect infants too young to be immunized. In addition, indirect protection through prevention of maternal infection and through breast milk antibodies can be achieved through maternal immunization. In general, inactivated vaccines are considered safe for pregnant women and their fetuses, whereas live vaccines are avoided owing to the theoretical potential risk to the fetus. However, the risks and benefits of vaccination must be carefully weighed and whenever possible, protection to the mother and her infant should be prioritized. Influenza and tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccines are routinely recommended for all pregnant women in the United States. Seasonal inactivated influenza vaccine is recommended for all pregnant women in any trimester of pregnancy, mainly to protect the mother, but there is growing evidence that infants benefit from passive antibody protection against influenza complications. The Tdap vaccine is recommended during the third trimester of each pregnancy to provide optimal protection to infants who are at particularly high risk of pertussis complications and mortality in the first 3 months of life. The effects of maternal immunization on the prevention of maternal and infant disease have been demonstrated in observational and prospective studies of influenza and pertussis disease in the United States and worldwide. Maternal immunization has the potential to improve the health of mothers and young infants and therefore, other diseases of relevance during this period are now targets of active research and vaccine development, including group B streptococcus and respiratory syncytial virus. Similarly, several vaccines can be administered during pregnancy in special circumstances, when maternal health, travel, or other special situations arise. This article reviews the current recommendations for vaccination of women during pregnancy.

Obstetrician–gynecologists play a key role in maternal immunization, a critical public health strategy that may substantially reduce preventable diseases in mothers and infants.

Department of Pediatrics, Baylor College of Medicine, Houston, Texas; and the Department of Gynecology and Obstetrics, Emory University School of Medicine, Atlanta, Georgia.

Corresponding author: Denise Jamieson, MD, MPH, Department of Gynecology and Obstetrics, Emory University School of Medicine, 69 Jesse Hill Jr. Drive, Atlanta, GA 30303; email: djamieson@emory.edu.

Financial Disclosure Dr. Munoz receives funds (paid to her institution) to conduct research on topics related to maternal immunization from the National Institutes of Health, the CDC, the Bill and Melinda Gates Foundation, the National Vaccine Program Office, and industry (Novavax, Inc). The other author did not report any potential conflicts of interest.

Peer reviews and author correspondence are available at http://links.lww.com/AOG/B314.

Received June 01, 2018

Received in revised form August 11, 2018

Accepted August 23, 2018

Obstetrician–gynecologists (ob-gyns) and other obstetric providers have been recommending specific vaccines in pregnancy for many years. For example, the Surgeon General first recommended that pregnant women receive influenza vaccines in the 1960s.1 However, the field of obstetrics and gynecology did not fully embrace maternal immunization as a priority until the 2009 influenza pandemic. From 2005 to 2008, the American College of Obstetricians and Gynecologists (ACOG) formed a small work group that focused on strengthening the role of ob-gyns as vaccinators. After the influenza pandemic in 2010, this group was reinvigorated, expanded, and renamed the Immunization Expert Work Group (https://www.acog.org/About-ACOG/ACOG-Departments/Immunization/About-Us). Recently, after the introduction and rapid spread of Zika in the Americas,2 the scope of this work was again expanded to include the infectious diseases that are not currently vaccine-preventable, and the group was renamed the “Immunization, Infectious Disease and Public Health Preparedness Expert Work Group.” The efforts of this group are largely focused on reducing morbidity and mortality from vaccine-preventable diseases and supporting and promoting the role of ob-gyns as immunizers. As part of these efforts, ACOG maintains a website (http://www.immunizationforwomen.org/) that serves as a valuable resource for up-to-date immunization information relevant to practicing ob-gyns.

In developing immunization recommendations and resources, ACOG works in close collaboration with the Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention (CDC). The Advisory Committee on Immunization Practices, which was established under Section 222 of the Public Health Service Act in 1964, provides advice and guidance about vaccine-preventable diseases to the director of the CDC. The Advisory Committee on Immunization Practices formulates and provides draft recommendations for the use of vaccines in the United States. Once approved, the recommendations are published as official recommendations in the Morbidity and Mortality Weekly report (MMWR) (https://www.cdc.gov/vaccines/acip/committee/charter.html). The recommendations of ACOG and the Advisory Committee on Immunization Practices are summarized in Table 1.

Table 1-a

Table 1-a

Table 1-b

Table 1-b

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EFFICACY AND SAFETY OF VACCINES IN PREGNANCY

Vaccines given during pregnancy can provide maternal protection and protection for the newborn. In general, pregnant women are capable of developing an adequate immune response after vaccination, and although some, but not all, studies have shown a reduction in immunogenicity of vaccines administered to pregnant women compared with nonpregnant women, a clinically relevant reduction in vaccine effectiveness has not been demonstrated.3,4 Because neonates are susceptible to infections at birth and achieving adequate immunity requires repeated doses of childhood vaccines in the first few months of life, maternal vaccination is a feasible option to close this “immunity gap.”4 Maternal antibodies transferred across the placenta can protect infants too young to be immunized.

According to the Advisory Committee on Immunization Practices, inactivated vaccines can be administered safely during pregnancy, but pregnant women generally should not receive live vaccines owing to the potential, theoretical risk of infection to the fetus. In addition, women should avoid conception for 4 weeks after vaccination with a live vaccine. However, smallpox vaccine is the only vaccine with documented fetal infection resulting from vaccination during pregnancy. No cases of congenital rubella have been documented after inadvertent vaccination with measles–mumps–rubella (MMR) during pregnancy, and no adverse effects in the fetus have occurred after administration of yellow fever vaccine to pregnant women in the context of outbreaks. No evidence exists of risk to the fetus from vaccinating pregnant women with inactivated vaccines (https://www.cdc.gov/vaccines/hcp/acip-recs/general-recs/downloads/general-recs.pdf). However, as with all clinical decisions in obstetrics, the risks and benefits of vaccination must be carefully weighed and there are sometimes substantial risks of avoiding vaccination. For example, although there is some evidence that pregnant women may be at increased risk for severe illness and death when infected with Ebola virus,5 most if not all Ebola vaccine trials have excluded pregnant women.6 An ongoing outbreak of Ebola in the Democratic Republic of the Congo7 highlights the urgent need for vaccines that can be used safely in pregnancy.

The safety of certain adjuvants in pregnancy has also been an area of concern. Adjuvants are substances added to vaccines to boost the immune response. Although influenza vaccines currently licensed and used in the United States do not contain adjuvants, in the event of a future influenza pandemic, adjuvants may be used to provide longer-lasting and broader protection and could allow for use of lower doses of antigen during a public health crisis when demand may outstrip vaccine supply.8 This was the case during the 2009 influenza pandemic, where pandemic vaccines containing adjuvants such as MF59 (an oil in water emulsion), were used for vaccination of pregnant women, mostly outside of the United States, without any associated adverse events.9–11 Additional safety data on adjuvanted vaccines used in pregnancy are needed.

Monitoring vaccine safety in pregnant women is a priority in the United States. Several large systems have been developed to monitor postlicensure vaccine safety. The Vaccine Adverse Event Reporting System is a passive reporting system administered by the U.S. Food and Drug Administration (FDA) and the CDC. After the approval of a vaccine, the FDA and CDC continue to monitor its safety by collecting information on adverse events among vaccinated persons through reports from health care providers and patients.12 The Vaccine Safety Datalink is a collaborative project between the CDC and eight large managed care organizations, which includes approximately 3% of the US population.13 Both the Vaccine Adverse Event Reporting System and Vaccine Safety Datalink were set up in 1990 after the National Childhood Vaccine Injury Act of 1986. Unlike the Vaccine Adverse Event Reporting System and Vaccine Safety Datalink, which collect information on adverse events among the broad U.S. population, the Vaccines and Medications in Pregnancy Surveillance System is specifically designed to assess the safety of vaccines and medications administered in pregnancy. Pregnancy-specific monitoring for adverse events is critically important because pregnant women are often excluded from clinical trials.14 The Vaccines and Medications in Pregnancy Surveillance System incorporates a prospective surveillance component in which pregnant women are prospectively enrolled in the first trimester. In addition, the Vaccines and Medications in Pregnancy Surveillance System incorporates a case–control surveillance component whereby mothers with infants with birth defects and two control groups of mothers are interviewed about vaccine exposure during pregnancy.15 The Clinical Immunization Safety Assessment is a network of vaccine safety experts from the CDC, seven medical research centers and other partners. Established in 2001, Clinical Immunization Safety Assessment conducts a variety of studies to identify adverse events after vaccination.16 In addition to these, vaccine registries are established by vaccine manufacturers to monitor adverse events after a vaccine is introduced, including reporting of pregnancies.

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TRENDS IN VACCINATION COVERAGE

Although ACOG and the Advisory Committee on Immunization Practices have recommended the seasonal influenza vaccine in any trimester of pregnancy since 2004, vaccination rates among pregnant women remained low for many years at less than 25%.17 After the 2009 H1N1 pandemic, influenza coverage rates increased to about 50%18,19 (Fig. 1). Recently however, there is some evidence that coverage rates may have decreased again; as of November 2017, approximately 36% of pregnant women reported being vaccinated (https://www.cdc.gov/flu/fluvaxview/pregnant-women-nov2017.htm). Regardless of whether this represents a recent downturn in vaccination coverage rates, one half or more of pregnant women do not get vaccinated for influenza each year, so there is opportunity for improvement. Because the recommendation and offering of influenza vaccine by health care providers has been consistently shown to increase vaccine uptake,18 it is critical that ob-gyns encourage their pregnant patients to get vaccinated and that their practices provide the vaccine. Health care provider recommendation and offering the vaccine at the time of routine prenatal care visits are the most important factors pregnant women consider when deciding on receiving influenza vaccine every year.

In 2011, the Advisory Committee on Immunization Practices recommended that unvaccinated pregnant women be vaccinated with tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine (Tdap) after 20 weeks of gestation.20 As a result of an increasing trend in the incidence of pertussis morbidity and mortality in infants too young to be vaccinated in the United States, this recommendation was revised in 2012 to recommend Tdap vaccine during the third trimester of each pregnancy.21 In 2012, less than 10% of pregnant women were vaccinated; by 2015 slightly more than one half of pregnant women received the Tdap vaccination in pregnancy.22 Although this represents an improvement in the Tdap vaccination coverage rates of pregnant women in recent years, similar to influenza vaccination rates, there is still substantial opportunity for improvement. The American College of Obstetricians and Gynecologists has developed materials describing how to better integrate influenza and Tdap immunizations into obstetrics practice including designating an immunization coordinator, using prompts in the electronic medical record, and instituting standing orders.23

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VACCINES ROUTINELY RECOMMENDED FOR PREGNANT WOMEN

Influenza Vaccination

Although there is no evidence that pregnant women are more susceptible to influenza infection, they are more likely to have a severe disease.3 Although influenza vaccine was first recommended by the United States Surgeon General in 1960 after recognizing the effect of pandemic and seasonal influenza in pregnancy,1 recommendations were inconsistently implemented and have evolved over time. For example, in the 1990s there was period of time in which vaccination was recommended only for pregnant women with other underlying medical conditions24 and only in the third trimester.25 In 2004, the Advisory Committee on Immunization Practices recommended that all pregnant women be vaccinated regardless of trimester.26 In 2005, the World Health Organization, endorsed the recommendations to administer influenza vaccine during pregnancy, and in 2012, after the pandemic, the Special Advisory Group of Experts advised the World Health Organization to make influenza vaccination a priority worldwide. Since then, more than 30 countries have implemented maternal influenza immunization programs in Latin America, Africa, Asia, and Eastern Europe. Influenza vaccination is considered an essential element of prenatal care in the United States, according to ACOG.

Although the influenza vaccine is primarily given for maternal benefit, there is good evidence of infant benefit as well. Four large randomized, controlled clinical trials conducted outside of the United States (Bangladesh, South Africa, Mali, and Nepal) have demonstrated that influenza vaccination during pregnancy provides protection for women against influenza-like illness (reported vaccine efficacy of 19% [95% CI 1–34%] to 36% [95% CI 3.7–57.2%]), and laboratory-confirmed influenza (reported vaccine efficacy of 50% [95% CI 14.5–71.2%] to 70% [95% CI 42.2–85.8%]); and protection of infants in the first months of life against laboratory-confirmed influenza (reported vaccine efficacy from 30% to 62.8%).27–30 Because infants are not eligible for vaccination until 6 months of age, maternal vaccine can provide protection for the infant by active transfer of anti-influenza antibodies across the placenta.27,31 Several studies have shown that vaccination of pregnant women can also prevent influenza-related hospitalization in their infants.31–37 Furthermore, a recently published pooled analysis of three randomized clinical trials suggests that maternal influenza vaccination may reduce severe pneumonia in infants too young to be vaccinated.38 However, it is important to note that the protection from maternally derived antibodies is limited by the natural decay of immunoglobulins; this passive immunity for the infant wanes over time and may decline substantially before the infant can be vaccinated at 6 months of age.29,39

Various influenza vaccine formulations available in the United States can be administered to pregnant women, including egg- and cell-based inactivated trivalent or quadrivalent influenza vaccines, and more recently, recombinant vaccines. However, the live attenuated influenza vaccine is contraindicated during pregnancy.40 A recent case-control study raised some questions about the safety of influenza vaccine in the first trimester. Among women who had been previously vaccinated with a pH1N1-containing vaccine, vaccination during pregnancy was associated with an increased risk of spontaneous abortion.41 However, there were multiple methodologic issues with this study and a large body of evidence supports the safety of influenza vaccination in pregnancy, including the first trimester.42 Nonetheless, additional safety data, particularly in the first trimester, are needed.

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Tetanus Toxoid, Reduced Diphtheria Toxoid, and Acellular Pertussis Vaccine

Tetanus and diphtheria disease have been well controlled in the United States for many decades through high coverage rates of routine childhood immunization. Pertussis cases declined dramatically in the decades after the introduction of the whole cell pertussis and tetanus, diphtheria toxoid vaccines in the 1940s. However, during the 1980s, reports of pertussis disease began increasing to nearly 50,000 cases in 2012, the largest number of cases reported since the mid-1950s (https://www.cdc.gov/pertussis/surv-reporting/cases-by-year.html). Pertussis is an acute respiratory infection caused by Bordetella pertussis that can be particularly severe and fatal in young infants. Although infants receive the pertussis vaccination, they are not well protected against the pertussis disease until they complete their primary series of vaccines at about 6 months of age.43 Infants who are unvaccinated or too young to be vaccinated (under 2 months of age), are at increased risk of pertussis and of severe disease because they also have little passive protection from maternally derived antibodies, given that women of childbearing age have little residual protection from their own childhood immunizations.44

The Tdap vaccine was licensed in the United States for adolescents and adults in 2005. In 2006, the Advisory Committee on Immunization Practices recommended that Tdap be given to women before becoming pregnant and that those not previously vaccinated should receive Tdap postpartum.45,46 Furthermore, the Advisory Committee on Immunization Practices recommended “cocooning” as a strategy to protect susceptible infants by vaccinating postpartum women and all those who would be in close contact with the neonate.46 However, it rapidly became apparent that this strategy was ineffective for a variety of reasons and the number of pertussis cases in the United States continued to rise.43,47 The Tdap vaccine was first recommended for pregnant women in the second or third trimester of gestation who had not previously been vaccinated with Tdap in 2011.20 After the accumulation of data that pertussis antibodies wane after a year, and taking into consideration the increasing burden of pertussis in infants in the United States, the Advisory Committee on Immunization Practices revised their recommendations in 2012 and since, the Advisory Committee on Immunization Practices recommends the Tdap vaccine be given to pregnant women during each pregnancy at 27–36 weeks of gestation.21 The rationale behind this recommendation is that every infant will benefit from a high concentration of maternally derived antibodies at birth and receive protection during the first few weeks of life, the period of greatest vulnerability.

The safety and effectiveness of maternal immunization with Tdap have been documented in the United States and in the United Kingdom, where the Tdap vaccination has also been recommended for pregnant women at 16–32 weeks of gestation since 2012. In a retrospective study, Winter et al48 evaluated a cohort of infants infected with pertussis from 2011 to 2015 in California, and compared the course of pertussis illness in infants whose mothers received Tdap during pregnancy with infants of unvaccinated mothers. Infants with pertussis born to mothers who received Tdap during pregnancy were significantly less likely to be hospitalized (43% vs 73%, relative risk [RR] 0.5 [95% CI 0.4–0.6]), or admitted to the intensive care unit (RR 0.8, 95% CI 0.7–0.9), when compared with infants of unvaccinated mothers. Furthermore, none of the infants born to mothers who received the Tdap vaccination required mechanical ventilation, developed seizures, or died, whereas these complications occurred in 8%, 4%, and 2%, respectively, of infants of unvaccinated mothers.

The most compelling evidence of the efficacy of maternal Tdap vaccination to prevent infant pertussis and its complications comes from data reported by the Public Health England program established in 2012.49,50 In the United Kingdom, where a 50–60% vaccine coverage has been achieved for Tdap during pregnancy, a marked decrease in infant hospitalizations associated with pertussis has been documented, and since the implementation of the program, the number of pertussis-associated deaths in infants has continued to decrease, with cases occurring almost exclusively in infants born to unvaccinated mothers. For the first time since the re-emergence of the pertussis epidemic, the incidence of pertussis in children younger than 3 months of age has decreased below that of older infants and adolescents in the United Kingdom. Furthermore, Tdap vaccination during pregnancy in the United States and the United Kingdom has not been associated with adverse events for the mother or the infant.51–55 In one retrospective, observational cohort study including more than 120,000 women in the United States, where safety was assessed through the identification of International Classification of Diseases, 9th Revision, Clinical Modification coded diagnoses, chorioamnionitis was diagnosed in 6.1% of vaccinated and 5.5% of unvaccinated women (adjusted RR 1.19; 95% CI 1.13–1.26), but the implication of this finding is unclear, as no biological plausibility exists, and the diagnosis of chorioamnionitis is often nonspecific.55 This finding has not been observed in other studies, or in population-based safety assessments of the Tdap vaccination program in the United Kingdom.

Important lessons have been learned from the Tdap vaccination programs in pregnant women, including the evaluation of the optimal timing of vaccination in pregnancy to achieve long-lasting protection in the newborn, and the assessment of potential effects of maternal antibodies on infant responses to active vaccination with pediatric tetanus, diphtheria and acellular or whole-cell pertussis vaccines (DTaP or DTP). Overall, it appears that vaccination in the second trimester or early third trimester of gestation results in higher antibody levels in infants at birth, and this finding was the basis for the widening of the window of vaccination down to 16 weeks of gestation in the United Kingdom.56,57 Regarding the effect of maternal antibodies on infant responses to active vaccination, it is clear that maternal antibodies do not interfere with the initial priming response of infants to DTaP or DTP vaccines, however, a blunting, or decreased geometric mean concentration of antibodies to various pertussis antigens (Pertussis toxin, filamentous hemagglutinin, and pertactin) or other vaccine antigens (Haemophilus influenzae type b or pneumococcal), have been reported in clinical trials of Tdap vaccines in pregnancy.58–60 Nonetheless, adequate boosting responses are documented in these infants, and the clinical implications of these findings is unknown. At this time, the benefit of preventing pertussis disease and mortality in infants in early life outweigh any potential risks of these observations.

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VACCINES RECOMMENDED FOR PREGNANT WOMEN IN SPECIAL CIRCUMSTANCES

Pneumococcal Vaccines

Pneumococcal conjugate and polysaccharide vaccines are recommended for adults at risk for pneumonia, including those who are immunocompromised, or who have chronic lung disease or other conditions that increase the risk for complications of respiratory infections, such as diabetes. Pregnant women with underlying medical conditions can receive pneumococcal vaccines when indicated.61,62

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Meningococcal Vaccine

Meningococcal disease is a bacterial infection caused by Neisseria meningitidis and can present as meningitis, bacteremia, or pneumonia. N meningitidis colonizes the nasopharynx and is transmitted through respiratory tract secretions. The most important N meningitidis serotypes in the United States include serotypes B, C, Y, and W-135. There are several inactivated quadrivalent (serotypes A, C, W, Y), and monovalent (serotype B) meningococcal vaccines. MenACWY are protein-conjugated vaccines, and MenB are recombinant vaccines. The Advisory Committee on Immunization Practices recommends routine administration of MenACWY vaccine for all persons aged 11 through 18 years. MenB vaccines are recommended for adolescents and young adults at risk for meningococcal B infection. Risk factors for meningococcal infection include medical conditions such as complement component deficiencies (eg, C5-C9, properdin, factor H, factor D), use of complement-blocking drugs (such as eculizumab—SolirisR), functional or anatomic asplenia, including sickle cell disease, workplace-related risk, travel, or an outbreak situation. In 2013, the Advisory Committee on Immunization Practices stated that pregnancy should not preclude vaccination with meningococcal vaccines if indicated. Since that time, results from a randomized controlled trial of pregnant women in Mali was published. Pregnant women were given either influenza vaccine or MenACWY and there were no safety concerns noted. Therefore, use of MenACWY may be considered for pregnant women at risk for meningococcal disease.63,64 No studies have been conducted with MenB vaccines in pregnancy; therefore, the Advisory Committee on Immunization Practices suggests that serogroup B meningococcal vaccines should only be given to pregnant women or breastfeeding women who are at increased risk for serogroup B disease, when the benefits outweigh the risks.

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Hepatitis A Vaccine

Hepatitis A is primarily transmitted from person to person through fecal-oral transmission. Adults tend to present with more severe disease than children when infected with hepatitis. Highly effective inactivated hepatitis A vaccines were first licensed by the FDA in 1995. In 2006, routine vaccination was recommended for all children 1 year of age or older in the United States. As such, children receive two doses of hepatitis vaccine before their second birthday, and benefit from lifelong protection. Although the safety of the hepatitis A vaccine in pregnancy has not been formally evaluated, because the hepatitis A vaccine is an inactivated viral vaccine, the theoretical risk in pregnancy is low. In susceptible pregnant women at high risk for hepatitis, the benefits of vaccination may outweigh the theoretical risks.65

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Hepatitis B Vaccine

Hepatitis B virus is transmitted by parenteral and sexual contact, and serum, semen, and saliva are infectious. Routine screening of all pregnant women for HBsAg is recommended. HBsAg is on the surface of the virus and circulates freely in the serum in infected individuals. Without intervention, mother-to-child transmission of hepatitis B occurs in 5–90% of infants born to mothers with HBsAg and is largely dependent on the maternal viral load. Maternal antiviral therapy for pregnant women with high viral loads (ie, more than 200,000 international units/mL) is now more routinely recommended. In addition, immunoprophylaxis at birth is highly effective (great than 95%) in preventing vertical transmission of hepatitis and therefore, hepatitis B vaccine and hepatitis immunoglobulin within 12 hours is recommended for all infants born to mothers with hepatitis B.66

The hepatitis B vaccine is a recombinant inactivated viral vaccine. Susceptible pregnant women who are at risk for hepatitis B virus infection should be vaccinated for hepatitis B. Risk factors for infection include having more than one sexual partner during the previous 6 months, been evaluated or treated for a sexually transmitted infection, recent or current infection drug use, or having had an HBsAg-positive sexual partner. In November 2017, a single-antigen hepatitis vaccine with a novel adjuvant (HepB-CpG) was approved by the FDA for prevention of hepatitis B and in February 2018, the Advisory Committee on Immunization Practices recommended the HepB-CpG for persons aged 18 years or older. However, because there is insufficient information about the safety of HepB-CpG vaccine in pregnant women, it should not be used in pregnancy. An alternative hepatitis B vaccine should be used, when indicated, in pregnancy.67

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VACCINES FOR PREGNANT WOMEN IN OUTBREAK OR HIGH-RISK EXPOSURE SITUATIONS

Polio Vaccine

Poliovirus, an enterovirus, can cause poliomyelitis, a highly contagious infectious disease. Although most polio virus infections are asymptomatic, symptomatic infections are typically characterized by a nonspecific febrile illness that can progress to paralysis. Pregnancy is a risk factor for paralytic disease.

Inactivated poliovirus vaccine became available in the 1950s followed by oral poliovirus vaccine in the 1960s. Although there are sporadic cases of polio infection caused by vaccination with live oral polio vaccine, the last case of indigenously acquired case of polio caused by wild poliovirus was in 1979. To decrease the risk of polio infection after vaccination, in 2000, the Advisory Committee on Immunization Practices recommended that only inactivated polio vaccine be used for routine immunization. Although children in the United States are routinely immunized, there is generally no need for routine vaccination of adults living in the United States. However, vaccination is recommended for adults at increased risk such as those traveling to polio-endemic countries or laboratory workers handling poliovirus. Although no adverse effects of inactivated polio vaccine have been documented in pregnancy, vaccination should generally be avoided. However, if a pregnant woman is at risk for infection, vaccination can be considered.68

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Yellow Fever Vaccine

Yellow fever is a mosquito-borne flavivirus present in tropical areas of sub-Saharan Africa and South America. The severity of disease can vary widely, resulting in asymptomatic infection or result in severe hemorrhagic disease with a high case-fatality rate. Yellow fever vaccine, which is a live vaccine, is recommended for those traveling to or living in an area with risk for yellow fever. Some countries require proof of vaccination for entry. However, waivers may be issued if a vaccination is contraindicated and pregnancy may be considered such a condition.69

Although the data are limited, pregnant women do not appear to be at increased risk for acquiring yellow fever nor at increased risk for severe disease compared with nonpregnant persons. From reports of large yellow fever outbreaks involving thousands of cases, vertical transmission has not been reported. Fetal infection resulting from maternal vaccination with live attenuated vaccine has also not been generally reported. During a large epidemic in Trinidad, approximately 100–200 pregnant women were likely inadvertently vaccinated. A retrospective study of 41 of these infants born to vaccinated mothers identified only one infant who had the yellow fever immunoglobulin M antibody. Because immunoglobulin M does not generally cross the placenta, this suggests that fetal exposure through vertical transmission may have occurred in this otherwise healthy infant.70 In terms of safety of the vaccine in pregnancy, several small, underpowered studies did not identify an increased risk of adverse pregnancy outcomes, including congenital malformations, preterm birth, stillbirth, and spontaneous abortion.71–73 In a case-control study of 39 women who had a spontaneous abortion and 74 pregnant women, the odds of being vaccinated during pregnancy were increased, but not statistically significant among the cases (2.3; 95% CI 0.65–8.03).71

Based on limited data, pregnant women should avoid vaccination with live yellow fever vaccine. However, if they are at substantial risk for yellow fever infection, the benefits and risks of infection should be weighed; vaccination may be a reasonable approach.69

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Japanese Encephalitis Vaccine

Japanese encephalitis virus is a mosquito-borne flavivirus that occurs throughout Asia and parts of the western Pacific. Although the number of cases of Japanese encephalitis has decreased markedly over the past 30 years, U.S. travelers can still be at risk depending on where they travel, how long they stay, what season it is, and what type of activity they participate in. For example, travel outside an urban area, travel to areas with an ongoing outbreak, and staying in an endemic area more than one month all increase the risk of Japanese encephalitis. There are two licensed inactivated vaccines available in the United States. An inactivated mouse-brain derived vaccine has been available since 1992 and is licensed for persons aged older than 1 year. Supplies of this vaccine are limited because it is no longer manufactured and is therefore reserved for use in children. A new inactivated vaccine derived from Vero cell culture was licensed in 2009 for use in persons aged 17 years or older. Owing to limited safety data and a theoretical risk to the fetus, pregnant women should not routinely be immunized. However, for pregnant women at substantial risk for Japanese encephalitis, the benefits of vaccination for Japanese encephalitis may outweigh the risks.74

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Rabies Vaccine

Rabies is a zoonotic disease caused by Rhabdoviridae lyssavirus. It is transmitted through the bite of an infected animal and disease in humans is almost always fatal. Owing to improved domestic animal vaccination and canine control programs, there has been a dramatic decline in rabies cases due to domestic animals. The few cases of rabies in the United States are mostly from wild animals, most commonly from bats. Postexposure prophylaxis, which includes wound cleansing, passive immunization with rabies immunoglobulin, and vaccination with inactivated rabies vaccine, is recommended in cases where a person is at relatively high risk for acquiring rabies. Because determining risk is relatively complex and must be individualized, the decision should be made in consultation with local, state, or federal public health officials.

Preexposure prophylaxis with inactivated rabies vaccine is recommended for persons in high-risk groups such as veterinarians and certain international travelers. If international travelers will be in contact with animals in areas where rabies is endemic, particularly if access to medical care, including rabies vaccination will be delayed, preexposure vaccination is recommended. Although safety data in pregnancy are limited, pregnant women at high risk for rabies infection should be promptly vaccinated.75

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Anthrax Vaccination

Concern about the potential for anthrax to be used as a bioterror agent was heightened after the 2001 event involving Bacillus anthracis spores being disseminated through the U.S. postal system. Because the threat of B anthracis to national security remains, it is critical that response plans be in place for how to respond to another event involving B anthracis, including how pregnant women would be managed. Although there is no evidence that pregnant women are more susceptible to anthrax nor more likely to develop severe disease when compared with nonpregnant individuals, there is evidence that anthrax infection in pregnancy can be severe and can result in maternal and fetal death.76

From 1998 to 2004, the Department of Defense routinely vaccinated all nonpregnant military personnel for anthrax. Even though pregnant women were exempt from vaccination, more than 3,400 infants were born to women inadvertently vaccinated in the first trimester of pregnancy. Although not statistically significant, birth defects were slightly more common in infants born to mothers vaccinated in the first trimester when compared with infants born to women vaccinated outside of the first trimester (odds ratio 1.18; 95% CI 0.997–1.41).77

Based on a review of all available data including the Department of Defense data, the Advisory Committee on Immunization Practices recommends that pregnant women not be vaccinated in a preevent setting when the risk of anthrax exposure is low. However, in the setting of an anthrax event, pregnant women who are at risk for inhalational anthrax should be vaccinated.78

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Smallpox Vaccine

The last smallpox outbreak in the United States was in 1949 and routine childhood vaccination was discontinued in 1971. Currently, vaccination is recommended only for specific populations at risk for occupational exposure such as some laboratory workers. However, there is concern that smallpox could be used as a bioterrorist weapon and preparedness plans include postevent vaccination for persons who are at high risk for smallpox infection during an intentional or accidental release of the smallpox virus.79 Plans specifically tailored for pregnant women must be included in these planning efforts.

Pregnant women infected with smallpox are more likely to have a severe disease, including the hemorrhagic form of smallpox and an increased risk of death compared with nonpregnant persons. The vaccine contains the smallpox vaccine, which is a live vaccine containing vaccinia, can rarely result in fetal infection. In a recent systematic review, 21 cases of fetal vaccinia were reported, dating as far back as 1809. Although there was no association between vaccination in pregnancy and adverse events such as spontaneous abortion, preterm birth or stillbirth, there was a small increased risk of congenital birth defects among women vaccinated in the first trimester.80 Overall, given the devastating effects of smallpox infection, the CDC recommends that pregnant women exposed to smallpox or at high risk for smallpox infection should be vaccinated.79

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VACCINES THAT ARE CONTRAINDICATED DURING PREGNANCY

Measles–Mumps–Rubella and Varicella Vaccines

Live vaccines, including MMR and varicella vaccines, are contraindicated during pregnancy. However, these infections can be serious in pregnant women, and may be transmitted to the newborn infant. Therefore, women who are seronegative, or known to be unvaccinated, should be immunized with MMR and varicella vaccines in the postpartum period, or before becoming pregnant.81,82

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VACCINES IN DEVELOPMENT FOR MATERNAL IMMUNIZATION

Respiratory Syncytial Virus Vaccine

Respiratory syncytial virus (RSV) is a leading cause of morbidity and mortality among young infants.83 Although the search for a safe and effective RSV vaccine for children has been ongoing since the 1960s, challenges with the development of sufficiently immunogenic infant vaccines, safety concerns associated with previous candidate vaccines, and the need to protect infants in early life, maternal immunization strategies have been actively explored in the past 2 decades.84 For example, a small clinical trial evaluated the safety and immunogenicity of a purified fusion protein-2 RSV vaccine with adjuvant administered to 35 pregnant women in the third trimester. Although no safety concerns were raised, the vaccine failed to induce a robust antibody response.85 Since then, multiple RSV vaccine candidates are in various phases of development.84 A nanoparticle vaccine based on the fusion protein of RSV was safe and well tolerated, eliciting a significant immune response in the mothers and efficient antibody transfer to the infants, in phase II clinical trials. This promising vaccine candidate is currently being evaluated in a global phase III randomized, placebo-controlled clinical trial seeking to enroll approximately 8,000 pregnant women and their infants to demonstrate efficacy in the protection of severe lower respiratory tract RSV disease in infants in the first 6 months of life. Other RSV vaccine candidates based on the fusion protein, gene-vectors, and live attenuated formulations are also in active development and expected to enter clinical trials in target populations that include pregnant women, children, and the elderly. It is likely that to effectively prevent RSV disease in infants and young children, a combined approach that uses maternal immunization followed by vaccination of infants in the first year of life would be most effective. Given that infants who are born prematurely would not benefit from transplacentally transferred antibodies after maternal immunization, administration of passive antibodies for protection against RSV in early life remains a necessary strategy for preterm infants at risk.

Other important outcomes from studies of RSV vaccines in pregnancy include an evaluation of the effect of RSV in pregnancy and potential for protection of the mother. A few observational studies have shown that RSV can cause acute upper and lower respiratory tract disease in pregnant women, particularly in the third trimester of gestation.86–88 In a small case series, two of three pregnant women with confirmed RSV lower respiratory tract disease required mechanical ventilation and delivered early, at 34 weeks of gestation, owing to the severity of their RSV illness.86 In an observational study recently conducted in Houston, Texas, among 155 pregnant women followed during the winter respiratory viral season, one third (36%) developed acute lower respiratory tract illness, with a viral etiology identified in most, and RSV accounted for 10% of the cases. Only one woman was hospitalized, but women with lower respiratory tract illness often reported substantial morbidity including symptoms of wheezing, shortness of breath, chest pain, and use of prescription medications, suggesting that morbidity from RSV and other viral infections in pregnancy is substantial.89

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Group B Streptococcus Vaccine

Group B streptococcus (GBS) is a common cause of neonatal sepsis in the United States despite considerable efforts to prevent GBS disease. In 1996–1997, ACOG, the American Academy of Pediatrics, and CDC issued recommendations for the prevention of early-onset GBS disease through screening of high-risk populations and intrapartum antibiotic prophylaxis. In 2002, universal screening at 35–37 weeks of gestation for all pregnant women was recommended. After the implementation of these prevention efforts, early-onset disease incidence markedly declined. However, the incidence of late-onset disease (after the first week of life) was not substantially reduced.90 A GBS vaccine administered during pregnancy could have the potential to protect infants after the first week of life and potentially to decrease the need for extensive prenatal screening and intrapartum prophylaxis programs. Several promising vaccine candidates are being evaluated in clinical trials and have been found to be safe and immunogenic.91,92

Developing an effective strategy for the prevention of GBS disease in mothers and infants is currently a priority, and studies are being conducted to better understand the epidemiology of GBS and its effect worldwide. Obstetric outcomes and fetal and neonatal morbidity, including stillbirths and neonatal deaths, could be prevented with an effective GBS vaccine administered during pregnancy.93 The World Health Organization, along with global stakeholders, have therefore proposed priority research and development pathways, as well as preferred product characteristics for GBS vaccines, to facilitate and accelerate the licensure of a GBS vaccine, as well as policy recommendations for its wide-scale use and implementation.94 One important goal of this effort is to conduct a pivotal efficacy trial with a vaccine that includes the most relevant GBS serotypes and specific, measurable, priority endpoints, such as the prevention of stillbirth, neonatal deaths, and late-onset GBS disease and its complications. Studies of GBS vaccines in pregnancy have been successfully conducted with monovalent (serotype III) and trivalent (serotypes Ia, Ib, III) conjugate vaccines, demonstrating their safety and tolerability, as well as efficient transplacental antibody transfer to the infant, but it is clear that multivalent vaccines are necessary to better protect mothers and infants against GBS.92,95–98 Furthermore, many research questions remain, including understanding the effect of maternal immunization on GBS colonization and disease in women; vaccine efficacy, correlates of protection, duration of protection in infant; potential protection through breastmilk antibodies; and the effect of maternal comorbidities on vaccine efficacy, among others. As with RSV, there is a real potential for a GBS vaccine to be available for maternal immunization in the near future.

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DISCUSSION

In 2011, the CDC published 10 noteworthy public health achievements in the United States over the first 10 years of the 21st century (2001–2010).99 Declines in vaccine-preventable disease largely due to childhood vaccination programs were highlighted as one of the 10 success stories. During the second decade of the 21st century (2011–2020), maternal immunization may represent the next major public health success story. During this decade, influenza vaccination coverage rates among pregnant women have increased substantially and Tdap was newly recommended and implemented for use and in pregnancy. There is tremendous potential for maternal immunization to further improve the health of mothers and their young infants and some exciting developments in the field of vaccine research and development. Other diseases of relevance during this period are now targets of active research and vaccine development, including RSV and GBS. Overall, maternal immunization as a public health strategy supported by antenatal care programs, is a platform that may be used to substantially reduce the effect of infectious diseases in mothers and infants.

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CME FOR THE CLINICAL EXPERT SERIES Learning Objectives for “Maternal Immunization”

After completing this learning experience, the involved learner should be able to:

  • List common infectious diseases for which maternal immunization can provide passive immunization to the fetus and young infant;
  • Discuss diseases for which maternal immunization is recommended for the protection of the mother and newborn infant;
  • Know the potential risks of inadvertent immunization with a live vaccine during gestation; and
  • Implement a comprehensive plan to ensure appropriate immunizations are given during pregnancy in the health care provider's practice.
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Instructions for Obtaining AMA PRA Category 1 Credits TM

Continuing Medical Education credit is provided through joint providership with The American College of Obstetricians and Gynecologists.

Obstetrics & Gynecology includes CME-certified content that is designed to meet the educational needs of its readers. This article is certified for 2 AMA PRA Category 1 Credits TM. This activity is available for credit through April 30, 2022.

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Accreditation Statement

ACCME Accreditation

The American College of Obstetricians and Gynecologists is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

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AMA PRA Category 1 Credit(s) TM

The American College of Obstetricians and Gynecologists designates this journal-based CME activity for a maximum of 2 AMA PRA Category 1 Credits TM. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

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College Cognate Credit(s)

The American College of Obstetricians and Gynecologists designates this journal-based CME activity for a maximum of 2 Category 1 College Cognate Credits. The College has a reciprocity agreement with the AMA that allows AMA PRA Category 1 Credits TM to be equivalent to College Cognate Credits.

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Disclosure of Faculty and Planning Committee Industry Relationships

In accordance with the College policy, all faculty and planning committee members have signed a conflict of interest statement in which they have disclosed any financial interests or other relationships with industry relative to article topics. Such disclosures allow the participant to evaluate better the objectivity of the information presented in the articles.

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How to Earn CME Credit

To earn CME credit, you must read the article in Obstetrics & Gynecology and complete the quiz, answering at least 70 percent of the questions correctly. For more information on this CME educational offering, visit the Lippincott CMEConnection portal at https://cme.lww.com/browse/sources/196 to register and to complete the CME activity online. ACOG Fellows will receive 50% off by using coupon code, ONG50.

Hardware/software requirements are a desktop or laptop computer (Mac or PC) and an Internet browser. This activity is available for credit through April 30, 2022. To receive proper credits for this activity, each participant will need to make sure that the information on their profile for the CME platform (where this activity is located) is updated with 1) their date of birth (month and day only) and 2) their ACOG ID. In addition, participants should select that they are board-certified in obstetrics and gynecology.

The privacy policies for the Obstetrics & Gynecology website and the Lippincott CMEConnection portal are available at http://www.greenjournal.org and https://cme.lww.com/browse/sources/196, respectively.

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Contact Information

Questions related to transcripts may be directed to educationcme@acog.org. For other queries, please contact the Obstetrics & Gynecology Editorial Office, 202-314-2317 or obgyn@greenjournal.org. For queries related to the CME test online, please contact ceconnection@wolterskluwer.com or 1-800-787-8985.

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