Pediatricians and our teams are the immunization experts. We educate, advocate, and incorporate vaccines into much of our daily routine. As such, we recognize the importance of working with our colleagues in family medicine, internal medicine, and obstetrics to optimize immunization programs for high-risk individuals, including pregnant women. Recent advances in vaccine recommendations during pregnancy are a result of the collaborative efforts of the health care providers for these women, and from systematic evaluation of immunization programs, vaccine pregnancy registries, and disease epidemiology.
Vaccinating women during pregnancy should be considered when a vaccine is known to be safe and when the following apply:
• The risk of severe infection is high during or augmented by pregnancy.
• The specific infection during pregnancy threatens the fetus.
• Maternal protection against infection benefits the newborn.
• Passive transfer of antibody from mother to fetus benefits the newborn.
Examples of safe vaccines immediately come to mind that fulfill one of more of these criteria, yet substantial obstacles exist even where safety and effectiveness data are robust. Because clinical vaccine trials traditionally exclude pregnant women, safety and effectiveness data for this group and their newborns are limited and often must come through experience. In a climate of increased vaccine hesitancy in general, both among providers and patients, vaccine delivery can be fragmented and particularly difficult to streamline. Additional obstacles that exist for any immunization program, including one that targets pregnant women specifically, are immunization delivery logistics and cost.
One of the major success stories of maternal immunization that is easily forgotten or overlooked in developed parts of the world is in the prevention of maternal and neonatal tetanus (MNT). A review of recent history reminds us that between the years 2000 and 2014, 35 countries were finally successful in eliminating MNT, including China, Turkey, Egypt, and South Africa. In addition, 24 of 36 states in the country of India, 30 of 34 provinces of Indonesia, and most of Ethiopia have met with success . This has been accomplished through aggressive tetanus vaccination programs, and through education programs targeted at optimal umbilical cord stump care after delivery.
In the United States, the Advisory Committee on Immunization Practices recommends that all pregnant women should receive inactivated influenza vaccine and Tdap vaccine. In addition, several other vaccines are recommended under certain circumstances. Live attenuated vaccines are considered contraindicated, although yellow fever vaccine is an exception during epidemics, or when travel to a highly endemic area during pregnancy cannot be avoided.
Influenza vaccine administered during pregnancy reduces maternal morbidity and mortality. Moreover, safety and benefits for the fetus are clearly documented. Both retrospective cohort analysis studies and randomized controlled trials have consistently demonstrated lower risk of preterm birth and lower risk for delivering newborns small for gestational age among women who received inactivated influenza vaccine during pregnancy. The benefit extends to term healthy infants who are less likely to be hospitalized during the first months of life if their mother was vaccinated against influenza during pregnancy. Because the mother was immunized during pregnancy, it reduces her risk of infection, thereby reducing the potential that the newborn will be exposed to a mother who is contagious. Perhaps more importantly, infants born at or near term have the benefit of transplacental antibody endowment from their mother, including vaccine induced anti-influenza antibodies. This passive protection is expected to last for several months. Active immunization against influenza during infancy begins at 6 months of age.
Tdap vaccine is also recommended during each pregnancy. In the United States, MNT is eliminated. Here, as in other developed countries, Tdap is administered to reduce infant pertussis morbidity. Pertussis remains endemic to the United States, and infants who develop whooping cough during the first 2-3 months of life are at the highest risk for morbidity and mortality.
Historically, one-third of infants infected with pertussis were infected by their mother, although more recent evidence suggests that older siblings are at least as likely a source. Looking back to the paradigm for protection against influenza infection in the first few months of life, it becomes clear why the Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention has recommended Tdap vaccine for all mothers during each pregnancy.
The first goal is to prevent pertussis in the mother so that she will not transmit the infection to her newborn. The additional goal, and the rationale for vaccinating pregnant women during every pregnancy, is to optimize levels of anti-pertussis antibody in the mother, so that the transplacental endowment to the infant is as robust as possible.
Serologic studies have demonstrated that Tdap vaccine induces high anti-pertussis antibodies when administered during pregnancy, but that the half-life of those antibodies is brief. When Tdap is given during pregnancy, and the infant is born at or near term, the antibody transfer to the infant is expected to provide passive protection for several months. Maternal immunization during pregnancy thereby reduces the risk that the mother will develop pertussis and transmit it to her newborn, while at the same time allows a degree of passive immunoprotection to the infant during the most vulnerable period of life. Active immunization against pertussis in the infant begins between 6-8 weeks of age.
Another infection that is exceedingly common during the first several months of life is respiratory syncytial virus (RSV). RSV remains the most common reason for infant hospitalization in the United States and other developed countries. The source of the virus can be any other person with a mild or moderate respiratory tract infection as the virus is ubiquitous, and can re-infect individuals throughout their lifetime. The first infection, however, is the worst. It is estimated that between 3% and 4% of the U.S. birth cohort is hospitalized with RSV. With a U.S. birth cohort of about 4 million, the result is 120,000-160,000 infant admissions annually.
The RSV epidemic is seasonal, fairly predictable, and dreaded by primary care pediatricians and hospitalists alike. Lower respiratory tract infection with RSV, in the form of RSV bronchiolitis, presents all too commonly in the young infant with cough, coryza, tachypnea, and wheezing. When the work of breathing increases, and the cough symptoms predominate, the infant is unable to feed efficiently. Hospitalizations may be for dehydration, concerns for impending respiratory failure, or for the administration of supplemental oxygen or other respiratory support. No specific therapeutic interventions reliably reduce the symptoms or the length of hospital stay, nor do they reduce the possibility that intensive care with mechanical ventilation may be required. Treatments are only supportive. An effective vaccine remains elusive.
All other common infections that once resulted in high rates of hospitalization in the first year of life are now substantially reduced through vaccination. Why not this one? The development of a safe and effective vaccine to prevent infant RSV infection or to reduce RSV-associated hospitalizations is especially challenging for multiple reasons.
Some of these reasons have met with substantial advances quite recently, including the discovery of antigen structures needed to induce neutralizing antibody responses. There also are challenges specific to the infant group we need most to protect. Infant RSV infection itself confers only modest protection against subsequent infection. Repeated infections over time are necessary for protection against illness when re-exposed. A vaccine that is able to induce a response similar to natural infection would therefore require multiple doses, presumably over time (the so called ‘primary series’) before a substantial clinical benefit would be expected. This is particularly important because most RSV-associated hospitalizations occur during the first several months of life, reducing the timeline for which a protective vaccine series could be administered.
The challenges are parallel to the issues described earlier for protection against both influenza and pertussis. Infant protection against both of these infections are now addressed, at least to start with, by vaccinating the mother during her pregnancy. In the infant, the pertussis vaccine primary series is then initiated between 6 and 8 weeks of age, and the influenza series initiated at 6 months of age. It is the passive protection, in the form of transplacental maternal antibody, that offers the interim protection during the highest-risk first months of life.
For infants at very high risk of serious RSV infection, passive antibody protection is already administered in the form of the pharmacobiologic medication palivizumab. Its half-life dictates monthly injections for those eligible, and its cost precludes its use for any but the highest risk infants (those born prematurely, and those with chronic lung disease and/or congenital heart disease). This strategy, however, has proven effective in preventing RSV-associated hospitalization in every group in which it has been studied. This “proof of concept” strongly suggests that if the right RSV vaccine is given to women during pregnancy to induce a robust neutralizing anti-RSV antibody response, and that antibody is transferred to the fetus prior to birth, the newborn will benefit from protection against RSV for a period of time.
Several questions emerge. If RSV is ubiquitous, and can re-infect individuals throughout their lifetime, then some women will be infected during their pregnancy. Do their infants benefit? As a re-infection, the maternal symptoms would be expected to be mild, but the infection could boost the women’s natural immunity with a robust anamnestic antibody response. This possibility has not been studied systematically, but might help to explain why some healthy term infants exposed to RSV develop little or no symptoms, while others (mothers who have not recently had a natural RSV infection) develop severe illness requiring hospitalization.
There are data to support the contention that term infants born to mothers with higher naturally occurring anti-RSV neutralizing antibodies benefit from those antibodies. In a large prospective cohort study performed in Kenya, cord blood anti-RSV antibody concentrations correlated directly with the length of time before the infant’s first RSV infection. It’s therefore logical to conclude that administering an effective RSV vaccine during pregnancy could augment that natural antibody response, be transferred to the infant at birth, and offer protection against RSV when exposed.
Several candidate vaccines for study already exist and have undergone phase I testing in nonpregnant adults. Once safety is demonstrated, the next step is to identify the vaccine formulation resulting in the most robust anti-RSV neutralizing antibody concentrations. Such a candidate vaccine will be chosen for future phase III trials during pregnancy. Safety, and maternal/cord blood RSV antibody titers will be of interest during that clinical trial, but the rates and timing of RSV infection and RSV-associated hospitalizations among the infants born to those mothers will be the most instructive.
Ideally, a candidate RSV vaccine shown to be as safe and as effective during pregnancy as inactivated influenza vaccines and/or Tdap vaccines would be implemented immediately and universally. Unfortunately, substantial vaccine hesitancy for the use of influenza and Tdap vaccines continues among pregnant patients and their providers. Acceptance of an RSV vaccine for use during pregnancy will not come easily, or immediately. As with all of our successful vaccine programs, launching such an effort will require education, patience, and careful post-licensure documentation of the impact that the intervention has in the real world.
Dr. Domachowske is professor of pediatrics and professor of microbiology and immunology at the State University of New York Upstate Medical University, Syracuse, N.Y.
