Vaccination of Pregnant Women

WHY MATERNAL VACCINATION?

The term “maternal immunization” has been used to describe vaccination of women prior to, during, and after pregnancy. In this chapter, we use the term maternal immunization to refer to vaccination of women during pregnancy and/or in the immediate postpartum period. Maternal vaccination can be used for the benefit of the mother, for the benefit of the infant, or for the benefit of both.

Several infections disproportionally impact pregnant women. While infections such as influenza, herpes simplex virus, and hepatitis E virus are not associated with increased susceptibility during pregnancy, they result in more adverse outcomes among pregnant women compared to nonpregnant women. On the other hand, pregnancy makes women more susceptible to infections such as malaria, listeriosis, and (possibly) human immunodeficiency virus (HIV). In the case of malaria, but not HIV, pregnancy is associated with more severe outcomes after infection.

In addition to maternal benefits, maternal immunization has the potential to impact early childhood morbidity and, in some cases, mortality. Infections such as respiratory syncytial virus (RSV), influenza, and pertussis are associated with adverse outcomes in young infants. Influenza vaccines are generally not recommended for children <6 months of age, and pertussis vaccines are not started during an infant’s most vulnerable period, the first month of life. Similarly, vaccines against Group B streptococcus and influenza could have a protective effect on birth outcomes such as low birth weight and preterm and small-for-gestational-age births.

Gains in reducing global childhood mortality have mostly been outside the neonatal period. Approximately 40% of global childhood deaths occur in the neonatal period. Many of these deaths are due to infections that can be prevented through existing maternal vaccines and those in development.

IMMUNOLOGY OF PREGNANCY

The increased susceptibility to and/or severity of several infections in pregnancy may be explained by immunological changes in pregnancy. Moreover, understanding these immunological changes might provide insights into vaccine responses in pregnancy. While there are several human studies on the immunological changes in pregnancy, a substantial portion of the evidence base comes from animal models.

Conventionally, pregnancy has been perceived as a generalized state of immune suppression with the biological goal of preserving the embryo/fetus by avoiding its potential allogeneic effects. However, emerging evidence suggests that this conventional model may be too simplistic. For example, fetus-specific cytotoxic T cells with broad functional capacity can be detected in approximately half of all normal pregnancies—often as early as the first trimester. These cells are not deleted through the course of pregnancy. These data demonstrate that a fetus-specific adaptive cellular immune response is a part of normal human pregnancy. In fact, a lower number of decidual cytotoxic CD8+ lymphocytes has been associated with development of preeclampsia.

It is more appropriate to consider pregnancy as a physiologically dynamic state in which the immune response is progressively altered—not across the board suppressed. There is an overall increase in the levels of sex hormones during the course of pregnancy ( Fig. 73.1 ). Since most of the changes in the immune responses during pregnancy are mediated by sex hormones, the responses during pregnancy vary by trimester. Low estradiol levels are associated with Th1 type responses and higher cell-mediated immunity. ^, Conversely, high estradiol levels generally result in enhanced Th2 type responses. Increased progesterone levels are associated with overall suppression of maternal immune responses. During pregnancy, the number of T lymphocytes as well as B lymphocytes decline, with a resulting decline in Th1 and Th2 responses. By contrast, phagocytic activity, alpha-defensin expression and the numbers of neutrophils, monocytes, and dendritic cells are maintained and may even increase during the second and third trimesters, representing some enhancement of innate immunity. The altered cell-mediated immunity may be the reason for severe disease in pregnancy after infection with organisms such as influenza virus in which cell-mediated immune responses are important to suppression of pathogen replication. Enhancement of other aspects of the immune system may help explain why pregnancy does not result in overall immune suppression and how pregnant women are able to mount adequate immunologic responses when vaccinated.

Infections that result in more severe clinical outcomes among pregnant women compared to nonpregnant women often vary in severity by stage of pregnancy. For example, compared to early pregnancy, influenza infection results in more severe outcomes in later stages of pregnancy. In contrast, P. falciparum associated malaria is more severe in the first half of pregnancy compared to the second half. ^, These pregnancy-stage-dependent differences in post-infection outcomes may be, in part, a result of the types of immune responses involved in the control of various pathogens and the progressive alteration of the immune system during the course of the pregnancy. For example, during implantation and placentation in the first trimester, extensive tissue remodeling is associated with a local inflammatory reaction. Later in pregnancy when the tissue remodeling substantially diminishes and when there is rapid fetal growth, there is a switch to an anti-inflammatory milieu —ostensibly to ensure fetal survival. As the pregnancy approaches the final phase, fetal development is complete and there is a resurgence of inflammatory processes in the uterus to initiate parturition-related events such as smooth muscle contraction. It has been hypothesized that the increased severe outcomes after parasitic infections (e.g., P. falciparum malaria) may be due to predominantly local inflammatory Th1 and Th17 responses associated with enhancement of local tissue damage. In contrast, the higher severity of influenza virus infections during late pregnancy may reflect the reduced Th1-type response.

While there is an overall decrease in maternal CD4+ and CD8+ T cells and natural killer cells with increasing gestational age, components of the innate immune system are either maintained or enhanced with the progression of pregnancy. It has been suggested that the reduced clearance of pathogens due to the decrease in CD4+ and CD8+ T cells is balanced by increases in the cells of the innate immune system resulting in no change in susceptibility to many infections.

RESPONSE TO VACCINES IN PREGNANCY

The evidence regarding the quality and magnitude of response to vaccines in pregnancy, most frequently measured as immunogenicity, is scant but developing. Most of the evidence base is comprised of studies of inactivated influenza vaccine. These studies paint a mixed picture: studies involving 1962–1963 seasonal vaccine, the monovalent A/New Jersey/8/76 influenza vaccine, and the 2010–2012 seasonal vaccines documented equivalent responses among pregnant versus nonpregnant women.

However, other studies reported lower immunogenicity of influenza vaccine among pregnant women compared to nonpregnant women. Similarly with yellow fever, some evidence suggests that the vaccine is potentially less effective due to decreased immunogenicity in pregnancy ; however, other studies report no difference in response between pregnant and nonpregnant women. Recently, Munoz et al. reported lower titers of anti-PT, anti-FHA, anti-PRN, and anti-FIM-2/3 antibodies in pregnant women who received Tdap vaccine compared to nonpregnant women.

Timing of vaccination during pregnancy may have implications for quality of vaccine responses. In a study evaluating quality of cord blood IgG after Tdap vaccination in pregnancy, there was higher avidity of cord blood anti pertussis toxin antibodies with pertussis immunization at 27­–30 weeks of gestation compared to the group that received Tdap after 31 weeks of gestation. These findings may reflect the effect of additional time available for affinity maturation in mothers vaccinated relatively early in pregnancy, rather than differences in immune response later in pregnancy. On the other hand, two studies conducted in Belgium and Vietnam, respectively, did not find an association between gestational age at pertussis vaccination and avidity of anti-pertussis antibody in cord blood samples. The variable findings in studies evaluating the association between gestational age at maternal vaccination and avidity may be due to their small sample size, prior disease and/or vaccine exposure, composition of any prior pertussis vaccine received (acellular vs whole cell), and underlying differences in study populations and study designs. Moreover, in another relatively small study, women immunized with Tdap during pregnancy had a substantial decline in anti-pertussis IgG levels 9–15 months postpartum.

Co-infections such as HIV and malaria could also potentially impact responses to vaccines in pregnancy. Lower antibody responses to seasonal inactivated influenza vaccine have been observed among HIV-positive pregnant women compared to HIV-infected nonpregnant women in the United States and South Africa. Interestingly, in the South African study, compared with HIV-unexposed infants, HIV-exposed infants had lower antibody levels at birth but similar antibody levels after 8 weeks of life. Moreover, HIV-infected South African pregnant women had similar influenza vaccine efficacy as nonpregnant women —this highlights the limitations of using antibody levels alone as predictors of influenza vaccine efficacy, particularly, in HIV infected pregnant women.

PLACENTAL TRANSFER

Placental transfer of antibodies provides a mechanism to compensate for functional deficiencies in some aspects of the immune responses among newborns and young infants. The mother-to-fetus transfer of IgG may begin as early as 13 weeks of gestation; however, the largest amount of antibodies is transferred in the third trimester. The IgG ₁ subclass is more effectively transferred from the mother to the fetus compared to other IgG subclasses. The quantity of IgG transferred is dependent on maternal IgG levels, gestational age, co-infection, and (possibly) nutritional factors. IgG titers are generally lower in preterm infants compared to term infants. Similarly, low birth weight is associated with reduced transfer of maternal IgG to the infant. However, this transfer is not influenced by parity, maternal age, weight, height, and type of delivery. ^,

There may be differences in transfer for antibodies against polysaccharide versus protein antigens. In a study of paired maternal delivery and cord blood samples, antibodies specific for Neisseria meningitidis serogroup C polysaccharide, Haemophilus influenzae type b (Hib) polysaccharide, diphtheria toxin, tetanus toxin, and multiple antigens from Bordetella pertussis were examined. In this study, antibody concentrations directed toward polysaccharides were equal in maternal and cord blood, whereas antibody concentrations to proteins were 1.6 times higher in cord blood than in maternal blood.

Infection with “unrelated” pathogens (i.e., pathogens not specifically targeted by a given vaccine) can potentially impact mother-to-fetus antibody transfer. Studies of the effect of malaria infection during pregnancy on placental antibody transfer, mainly focusing on anti-measles and anti-tetanus toxin antibodies, have produced contrasting results. In mothers immunized against tetanus, malaria infection during pregnancy has been associated with reduced infant antibodies against tetanus antigens. ^, However, malaria during pregnancy was not associated with reduced measles antibodies in neonates using the same set of specimens. Studies in Malawi and the Gambia found no association between placental malaria and tetanus antibody levels in the newborn. It is possible that the differing results relate to variations in prevalence of severe malaria. Nonetheless, these considerations need to be assessed with regard to maternal immunization. HIV infection may also reduce transplacental antibody transfer of measles and tetanus antibodies. However, there is a need for further evaluation of the impact of infection on maternal antibody transfer, particularly in the context of nonparasitic infection.

Kinetics and decay of transferred maternal antibodies in infants may vary by source of antibody. For example, RSV antibodies following maternal vaccination with RSV fusion (F) protein nanoparticle vaccine have a relatively shorter half-life in infants compared to maternally derived RSV antibodies after natural exposure. Moreover, at least for influenza, the half-life of maternal antibody depends on the specific viral antigen (e.g., H3N2 vs H1N1 vs influenza B) included in an (inactivated) vaccine. In a randomized, controlled trial of influenza vaccine in pregnant women the proportion of mothers with a protective antibody titer at the time of delivery was 88% for the A/New Caledonia (H1N1) subtype and 98% for the A/Fujian (H3N2) subtype, as compared with 45% for the B/Hong Kong subtype with similar proportions of infants having a protective antibody titer at birth. At 20 weeks, the percentages of infant vaccinees who had a protective hemagglutination-inhibition titer were 18% for the A/New Caledonia (H1N1) subtype and 46% for the A/Fujian (H3N2) subtype, 2 and 13 times the percentage of infant controls, respectively. Among all the infants of women in the study, the estimated half-life of passively acquired maternal antibody against all subtypes of the influenza vaccine ranged from 42 to 50 days (95% confidence interval, 37–56). However, limited evidence suggests that there may be no difference in antibody decay by study population/location, but this evidence primarily comes from evaluation of measles antibody transfer and may not be generalizable to other antigens.

CLINICAL ISSUES REGARDING VACCINATIONS DURING PREGNANCY

Whereas inactivated vaccines are fairly safe in pregnancy, live vaccines are generally avoided during pregnancy and during the 4 weeks preceding a pregnancy. For many live vaccines, immunization poses a theoretical rather than a documented risk. For example, measles, mumps, rubella vaccine (MMR) has not been linked to fetal infection, congenital anomalies, or other adverse pregnancy outcomes. By contrast, vaccination with live smallpox vaccine has resulted in fetal infection with vaccinia, the virus contained in the vaccine. However, this risk is very low, with a recent systematic review of the worldwide literature having identified only 21 presumed cases from 1809 to 2014.

Some vaccines contain adjuvants that are added to boost the immune response and potentially provide better protection against antigenically drifted viruses. For example, aluminum salts are used in a variety of vaccines such as hepatitis A, hepatitis B, and tetanus vaccines. Data from aluminum-based adjuvanted vaccines in pregnancy are reassuring, with no increased risk of adverse pregnancy outcomes. Newer adjuvants such as oil-in water emulsions (e.g., AS03, MF59) were used in some H1N1 influenza vaccine preparations. These adjuvanted vaccines were administered to pregnant women in several European countries and no increased risk of adverse outcomes was found. Thimerosal is a mercury preservative used in some vaccines (thimerosal has been removed from most vaccines in the United States). Despite speculation about a link between childhood vaccine exposure and autism, extensive epidemiologic investigation does not support such an association. Furthermore, there is no evidence that thimerosal-containing vaccines administered in pregnancy are harmful to offspring, and as such, the Advisory Committee on Immunization Practices (ACIP) does not recommend that pregnant women avoid thimerosal-containing vaccines. However, thimerosal-free formulations of most vaccines, such as seasonal influenza, are available.

Women are vaccinated during pregnancy for variety of reasons. A summary of recommendations and rationale for use of vaccinations in pregnancy is provided in Table 73.1 .

Currently, there are only two vaccines routinely recommended in pregnancy in the United States and many other high- and middle-income countries—the seasonal influenza vaccine and Tdap (several low- and middle-income countries include maternal TT or Td in their immunization programs). For these recommended vaccines, rates of vaccination use in pregnancy remain disappointingly low in the United States. Although there has been a sustained increase in vaccination coverage rates for seasonal influenza among pregnant women since the 2009 H1N1 influenza pandemic, coverage rates in the United States remain at about 50% among pregnant women. When health care providers specifically recommend to their pregnant patients that they receive the influenza vaccine, vaccination rates are higher. Rates of Tdap vaccination during pregnancy are even lower. In addition, COVID vaccine has been recommended by some counties for pregnant women who have not been previously vaccinated. Different countries have various degrees of permissiveness regarding COVID vaccination. In the United States, the CDC and professional organizations such as the American College of Obstetricians and Gynecologists strongly recommend that pregnant persons be vaccinated against COVID.