August 1996
WASHINGTON, D.C. — "In considering maternal interventions that would improve fetal and infant outcome, I can think of none more straightforward than maternal immunization," said Carol J. Baker, MD, at the Pediatric Academic Societies' annual meeting here.
The Advisory Committee on Immunization Practice (ACIP) in 1989 looked into the risks of maternal-fetal immunization. "There is no convincing evidence of risk to the fetus by immunizing the pregnant woman with inactivated virus, or bacterial vaccines or toxoids," the Committee wrote. Yet, today only two vaccines — tetanus toxoid and inactivated influenza — are recommended for use in pregnant Americans, and influenza vaccine is recommended only for pregnant women with underlying conditions, such as chronic pulmonary disease.
Baker said this should change. The professor of pediatrics, microbiology and immunology at Baylor College of Medicine in Houston said that immunizing pregnant women can be an effective strategy to protect newborns from infectious diseases, while also protecting the mother. There is evidence to validate the scientific rationale of passive immunization.
"The barriers that exist are found in realms other than science or medicine," she said. "Between 1930 and 1965, the vaccines for tetanus, diphtheria and polio became available, and even pregnant women were routinely immunized. This practice probably reflected a perception by medicine and society that the anticipated benefit far outweighed concerns for potential but unlikely adverse effects for mother and fetus."
Current medical thinking seems to no longer share this risk-benefit ratio, and barriers to researching and developing vaccines for this population have developed. Research funding is restricted. The Food and Drug Administration's requirements for maternal immunization studies turn them into slow, arduous and expensive exercises. Liability issues plague the FDA, the pharmaceutical industry and the physician. Baker said an indemnification policy is needed before any substantial progress is made. "Failure to address the legal aspects of maternal immunization has impeded progress to date," she said.
Yet, maternal immunization has been practiced successfully for more than a century. Baker provided several examples beginning in 1879, when infants born to mothers who received smallpox vaccine during pregnancy were protected from smallpox during the first few weeks of life. A study of whole cell pertussis vaccine in 1945 showed the vaccine was safe, and there was transplacental passage of antibody in 57 immunized pregnant women. In the late 50s, inactivated or live polio vaccine was given to nearly 16,000 pregnant women, and their children were followed for up to 10 years. The rate of fetal abnormalities did not increase due to the vaccines.
Tetanus neonatorum decreased from per 1,000 infants to six per 1,000 infants in 1961 when pregnant women in New Guinea were vaccinated with tetanus toxoid. "Numerous other studies have shown the efficacy of maternal immunization in protecting both mothers and neonates from tetanus," said Baker, who is also head of the section of pediatric infectious diseases at Baylor.
Maternal vaccination is a safe and cost-effective method to prevent tetanus neonatorum, she said, and in the developing world has become the standard of care. "It is not practiced in the U.S. however, because of the low incidence of tetanus infection and the success of our childhood immunization program that results in a population of young women who enter their pregnant years with pre-existing protective levels of antibody available for fetal transport," she said.
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Although tetanus and polio are not major concerns to U.S. mothers, respiratory syncytial virus (RSV) can be a serious problem. RSV in infants could be prevented by passive immunization of infants via active immunization of the pregnant mother, Baker said. RSV, which causes yearly outbreaks of pneumonia and bronchiolitis, leads to an estimated 22 cases of lower respiratory tract infection in 100 infants a year, with hospitalization rates at five per 1,000 live births per year, according to Baker.
A study done in 1994 at Baylor showed a high rate of very young infants were hospitalized due to RSV. Seventy-five percent of all infants hospitalized for RSV were younger than 5 months old; 45% were younger than 2 months old. "This age distribution illustrates the need for passive immunizations since active immunization, even if effective, would provide protection too late," she said.
Studies have examined passive immunization of the infant with RSV. High maternal IgG antibody levels of RSV appear to protect the infant against infection during the first few months of life. A prospective, controlled study done in 1993 showed that hospitalizations for RSV were reduced in infants who received monthly infusions of a specific high-titer IVIG. A study of immunization of pregnant women with the fusion (F) protein of RSV has been initiated.
Group B streptococcus (GBS) is another area that could be addressed by maternal immunization, Baker said. The need is there. GBS in newborns accounts for nearly 8,000 cases per year. According to the Centers for Disease Control and Prevention, GBS has lead to substantial mortality and the potential for lasting brain damage in some survivors. It also causes about 50,000 cases in pregnant women whose illness is typically one of febrile morbidity immediately before or after delivery with or without accompanying bacteremia. "This is a bad disease that has been around since my pediatric career began 27 years ago," she said.
In 1988, a group at Baylor reported immunizing 40 pregnant women at a mean gestation of 31 weeks with a purified capsular polysaccharide vaccine. IgG antibody was produced and delivery levels were comparable to cord blood levels, she said, showing that there was sufficient transport of IgG class of antibody from mother to fetus. Protective antibody levels remained until 3 months of age in the infants.
However, while the polysaccharide vaccine was well-tolerated and induced IgG antibodies that could be passed to the infant, immunogenicity results for this vaccine were variable. Thus, improved vaccines are needed, and researchers are developing conjugate GBS vaccines. So far, the conjugates have been well tolerated with no systemic signs or symptoms, and injection site reactions have been mild.
Baker made several suggestions to help promote the vaccination of pregnant women. First, multivalent conjugate vaccines representing the currently prevalent serotypes of perinatal GBS disease need to be tested in healthy women as a prelude to testing in pregnant women. Industry must make a commitment to develop and test these vaccines, and standards must be set to determine how efficacy will be determined in the clinical setting.
"Worldwide maternal immunization as a method to prevent infectious diseases is a feasible and inexpensive method when compared with other prevention strategies," she said.
She said physicians should become advocates for the health of pregnant women and their infants by arming themselves with the available data and speaking up for these two groups. The strategy of passively immunizing infants by actively immunizing the mother early in the third trimester would use vaccines for those pathogens with higher attack rates of younger infants and for those infectious diseases with substantial mortality, morbidity and economic burden.
Ed. note: The main deterrent to this strategy is the fear of lawsuits if an immunized mother has a problem during pregnancy or her infant has a malformation. These events are common enough to keep lawyers working overtime. Unfortunately, we will not be able to implement this strategy until this problem is addressed. I am not optimistic that this can be done successfully. — P. Brunell
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