NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Institute of Medicine (US) Vaccine Safety Committee; Stratton KR, Howe CJ, Johnston RB Jr., editors. Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality. Washington (DC): National Academies Press (US); 1994.

Cover of Adverse Events Associated with Childhood Vaccines

Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality.

Show details

7Polio Vaccines

Background and History

Poliomyelitis is an acute infectious disease caused by an enterovirus. There are three types of this virus: types 1, 2, and 3. Each type is capable of infecting humans; there is no cross-immunity and only those individuals immune to each of the three types are protected against all three types. The virus enters the body by the oral or respiratory route and multiplies in the pharynx and small intestine. Within 24 hours it invades the regional lymph nodes, and after an additional 24 to 48 hours it enters the bloodstream, which carries it to the secondary sites of replication in many organs, and thus, viremia develops and is maintained and enhanced. During the period of viremia, the virus can reach the central nervous system and initiate infection there. Antibodies appear within 1 week to 10 days after the initial infection, and viremia then ceases, probably as a consequence of neutralization by the antibodies. Only 1 to 2 percent of infected individuals develop disease in the central nervous system, and fewer still have residual paralysis. Nevertheless, the portent of these rare consequences is great, because they result in death or lifelong disability.

Although there are currently effective vaccines against poliovirus, even before they became available, Hammon et al. (1953) demonstrated the effectiveness of passive immunization by injections of pooled gamma globulin. Various attempts at developing a vaccine had been thwarted by the absence of an effective in vitro system of virus replication. The establishment in 1949 of the tissue culture technique for supporting virus growth made development of a vaccine possible (Enders et al., 1949). It was for these findings that J.F. Enders, F.C. Robbins, and T.H. Weller received the Nobel Prize in 1954. This development was followed by efforts to generate sufficient quantities of the virus to inactivate it and use it as an inert antigen. An alternative approach was to attenuate the wild-type virus and render it safe as a replicating antigen. Both were successful and today there are two forms of the vaccine: the inactivated polio vaccine (IPV), which is administered by the parenteral route, and the live attenuated vaccine, which is administered orally and hence is known as the oral polio vaccine (OPV).

IPV was developed in 1953 by Jonas Salk (Salk, 1953; Salk et al., 1953); OPV was developed by Koprowski and colleagues (1952), who were the first to use it, and Albert Sabin (1956). An enhanced-potency IPV was developed in the late 1970s and is used today. Currently, IPV and the Sabin strains of OPV are available for use in the United States; however, OPV is the vaccine recommended for general use and is the most prevalent (American Academy of Pediatrics, Committee on Infectious Diseases, 1991).

Shortly after the licensure of IPV in 1955, the vaccine manufactured by Cutter was found to cause paralytic disease. It contained residual infectious virus. The reason was traced to the method of inactivation. At that time the dynamics of the inactivation process were not fully understood, and the U.S. government's requirements for vaccine production were ambiguous. All of these problems have since been corrected.

The first OPV was licensed in 1960 after an extensive trial in the former Soviet Union (Benison, 1982). By then, over 100 million people in the former Soviet Union and Eastern Bloc countries—except Poland—had received the Sabin vaccine (LaForce, 1990). Trials of OPV in the United States followed, and monovalent OPVs were quickly licensed. The trivalent OPV used today was licensed in 1963. In the 1962 recommendations of the U.S. Public Health Service, no preference for one or the other form of the vaccine was expressed (U.S. Public Health Service, 1962), but in 1964 the Committee on Infectious Diseases of the American Academy of Pediatrics recommended the use of OPV.

Polio has been eliminated as an endemic disease in the United States and many developing countries. Outbreaks have occasionally occurred in subsets of unvaccinated susceptible individuals. A persistent concern has been the possibility of the rare complication of paralytic poliomyelitis in vaccinees and their contacts, particularly those with impaired immunity. This is discussed in detail later in this chapter. Some countries, for example, Denmark, use a mixed schedule of IPV followed by OPV. Other nations, such as Finland and Holland, continue to rely on IPV. The debate over the relative efficacy of OPV versus that of IPV continues in the literature, as does debate regarding the use of combined schedules of IPV and OPV (Institute of Medicine, 1977, 1988).

The American Academy of Pediatrics and the Advisory Committee on Immunization Practices recommend that OPV be administered at ages 2, 4, and 15 months and again at ages 4 to 6 years. If IPV is used, it should be given according to the same schedule as OPV.

Biologic Events Following Immunization

Each of the three immunologically distinct types of poliovirus—types 1, 2, and 3—can cause paralytic disease. Both IPV and OPV stimulate immune responses against all three types of virus. OPV induces gastrointestinal mucosal immunity to a greater degree than IPV. The enhanced-potency IPV used today in the United States produces a humoral antibody response superior to that of OPV (Onorato et al., 1991). It is not clear whether either OPV or IPV confers lifelong immunity (Nishio et al., 1984). The mechanism of attenuation of the neurovirulence and that of occasional reversion to neurovirulence have been described in detail in a recent review (Racaniello, 1992). Recipients of OPV shed the virus in their feces, and contacts exposed to the virus can become infected.


Clinical Description

Infection with poliovirus can take several forms: inapparent infection, mild illness, aseptic meningitis (nonparalytic poliomyelitis), and paralytic poliomyelitis. Approximately 4 to 8 percent of all wild-type poliovirus infections result in nonparalytic polio disease. This manifests as fever, malaise, headache, nausea, stiffness of the neck and back, and meningeal signs. Approximately 1 percent of infections results in paralytic disease. In paralytic poliomyelitis, the virus invades the central nervous system, replicating in motor neurons within the anterior horn of the spinal cord, in the brainstem, and in the motor cortex. When viral replication destroys sufficient numbers of neurons, paralysis occurs (Racaniello, 1992). The illness begins with a headache, fever, and stiff neck; this is followed by paralysis of the voluntary muscles previously controlled by the destroyed neurons of either the spinal cord or the brainstem. The muscle paralysis is usually asymmetrical. The spinal fluid contains an increased number of lymphocytes, the protein concentration is elevated, and the glucose concentration is normal.

History of Suspected Association

The association between live attenuated polio vaccine and cases of paralytic poliomyelitis dates back to the time of administration of the first live attenuated polio vaccine tried by Kolmer in the 1930s (Kolmer, 1936). Leake (1935) described nine cases of poliomyelitis that occurred following vaccination with the Kolmer vaccine and that seemed to be caused by the vaccine. The concept that live attenuated polio vaccine causes a small number of poliomyelitis cases thus has a history of at least six decades.

Shortly after licensing of Sabin's OPV, the United States Communicable Diseases Center (CDC; later named the Center for Disease Control, the Centers for Disease Control, and, more recently, the Centers for Disease Control and Prevention) reported its monitoring of vaccine-associated cases of paralytic polio. Henderson et al. (1964) summarized data for the United States collected by the CDC in 1962, 1963, and 1964. They evaluated 123 cases of paralytic polio that had occurred within 30 days of OPV administration and decided that 57 cases were compatible with vaccine-induced disease. Fifteen of the cases occurred after receiving the type 1 vaccine, with an estimated incidence of 0.17 case per 1 million doses. Thirty-six cases occurred following vaccination with the type 3 vaccine, with an incidence of 0.40 case per 1 million doses. Two cases occurred following vaccination with the type 2 vaccine, and four cases occurred following vaccination with the trivalent vaccine. The authors also described three cases of poliomyelitis that occurred in contacts of a recipient of the type 3 vaccine, but it is not clear whether the contact cases were included in the overall counts of vaccine-associated cases. Following publication of the paper by Henderson et al. (1964), case reports documenting vaccine-associated paralytic polio in recipients and contacts of recipients continued to appear. Table 7-1 summarizes the early case reports that described vaccine-associated poliomyelitis. By 1966, Chang et al. described a case of poliomyelitis in a 7-year-old recipient who was then found to have hypogammaglobulinemia. In 1966, Morse et al. documented a case of poliomyelitis in an unimmunized mother of a vaccinated infant. This was similar to the case of polio in an unimmunized father of a recently vaccinated infant reported by Swanson et al. (1967). Two reports provided evidence that contacts other than the parents or household members were also at risk of contracting polio. Balduzzi and Glasgow (1967) and Stolley et al. (1968) described unimmunized children who developed poliomyelitis after contact with recently vaccinated playmates or classmates.

TABLE 7-1. Early Reports of Vaccine-Associated Poliomyelitis, Published Before 1970.


Early Reports of Vaccine-Associated Poliomyelitis, Published Before 1970.

Evidence for Association

Biologic Plausibility

OPV consists of live attenuated viruses that multiply in the intestinal tract and that can revert to a more virulent form, causing disease. A vaccine recipient excretes live virus for several weeks, and recipients or contacts may become infected with the virus.

Case Reports, Case Series, and Uncontrolled Observational Studies

Since the 1960s there have been about 100 studies reporting individual cases, case series, and national surveillances of vaccine-associated cases of paralytic poliomyelitis. Case definitions have been well developed by the CDC and the World Health Organization (WHO); a case of vaccine-associated paralytic poliomyelitis is said to occur in recipients if the onset of the disease begins 7-30 days postvaccination and is said to occur in contacts of vaccine recipients if the onset of the disease begins 7-60 days after a recipient's vaccination. Laboratory tests can identify the strain of the infecting virus as a wild-type or vaccine strain of poliovirus. The cases described above in the section History of Suspected Association are typical of those that followed in the 1970s and 1980s.

WHO and CDC have used standard definitions of cases of paralytic poliomyelitis for almost 30 years, and many nations have implemented polio surveillance systems to monitor their polio immunization programs. Table 7-2 summarizes national data from the United States, England and Wales, Belgium, Spain, Romania, Hungary, Italy, and northern Greece. Despite differences in the ways that data are categorized and reported and the changes in the incidence of polio from 1959 to the present, all the national data show a low incidence of vaccine-associated paralytic polio, on the order of a few cases per 1 million doses given or a few cases per 1 million vaccine recipients. The CDC data for the years 1975 to 1984 show an incidence of 1 case of vaccine-associated paralytic polio per 3.22 million doses of OPV distributed (Centers for Disease Control, 1986; Nkowane et al., 1987). When cases among immunodeficient recipients and contacts and patients with vaccine-like virus are included, the incidence is 1 case per 2.64 million doses of OPV distributed (Centers for Disease Control, 1986; Nkowane et al., 1987). The incidence is greater with the first dose of vaccine. The CDC has estimated that the overall dose-related incidence is 1 case per 520,000 first doses distributed versus 1 case per 12.3 million subsequent doses distributed (Nkowane et al., 1987).

TABLE 7-2. National Surveillance Studies of Polio.


National Surveillance Studies of Polio.

The Monitoring System for Adverse Effects Following Immunization (MSAEFI) does not list poliomyelitis as a separate adverse event, although it may be included under categories such as "other neurologic symptoms," "other reactions," and "serious events.'' The Vaccine Adverse Event Reporting System (VAERS) contains several reports (submitted between November 1990 and July 1992) that may be cases of poliomyelitis, but the data are generally insufficient to state whether a case of vaccine-associated polio has occurred. Of the eight VAERS reports suggestive of vaccine-associated poliomyelitis, six provided insufficient information, one provided enough information to rule out vaccine-associated poliomyelitis (the time interval exceeded WHO guidelines), and one report provided information sufficient to be a well-documented case of vaccine-associated poliomyelitis. The report, which was filled out by a physician, stated, "Vaccine associated paralytic poliomyelitis confirmed by box 12 oligonucleotide sequencing of type III viral isolate. Occurred in an unvaccinated contact of a recently vaccinated eight-month old."

The data regarding OPV-related nonparalytic polio are more scarce than those for paralytic disease. A report of poliomyelitis surveillance in England and Wales from 1969 to 1975 documented 44 cases of nonparalytic poliomyelitis (Smith and Wherry, 1978). (Included in this definition were patients with a clinical diagnosis of nonparalytic poliomyelitis, as well as those with encephalitis or aseptic meningitis who also had cultural or serologic evidence of poliovirus infection.) Twelve of those cases were believed to have been associated with administration of OPV (11 in recipients, 1 in a contact). Poliovirus was isolated from 8 of the 11 recipient cases. All of the viruses were typed as the vaccine strain on the basis of reproductive capacity temperature (RCT) tests. Virus isolated from the one contact case was also typed as the vaccine strain. The authors calculated incidence rates of 0.1 per 1 million population at risk per year for both the paralytic and nonparalytic forms of disease. The authors noted that the definition of nonparalytic disease was, perhaps, broad, and thus, this represents an estimate of the highest possible number of nonparalytic cases. Poliovirus was isolated from recently vaccinated patients in the former West Germany between 1965 and 1970 (Thraenhart and Kuwert, 1972). Of the 34 patients with aseptic meningitis, virus isolated from 17 patients was typed by the RCT test as vaccine strain, from 13 patients as wild-type, and from 4 patients as intermediate. A study of the incidence of aseptic meningitis in Olmsted County, Minnesota, from 1950 to 1981 reported that 2 of the 283 patients with aseptic meningitis had received polio vaccine within 4 weeks prior to the onset of symptoms (Beghi et al., 1984). However, no mention of virus isolation was made, and the disease cannot be ascribed to the vaccine.

Controlled Observational Studies


Controlled Clinical Trials


Causality Argument

Vaccination with live virus mimics a natural process of exposure to virus that results in immunity to the disease. Although the vaccine virus is attenuated, approximately 1 in 1 million vaccinations with attenuated virus leads to paralytic disease. Infection in the intestinal tract with the vaccine strain of poliovirus results in virus shedding in the feces and the risk that the contacts of a recipient might become infected. The vaccine virus can revert to a virulent form, and this lends demonstrated biologic plausibility to the finding that occasional contacts of vaccine recipients contract polio.

Paralytic poliomyelitis, as an adverse event associated with OPV vaccination, occurs among OPV recipients and contacts of OPV recipients. The presence of vaccine virus in patients suspected of having vaccine-associated polio is often confirmed by laboratory tests that permit specific identification of the virus as the vaccine or wild-type virus. In countries where wild-type poliovirus has almost been eradicated, there is usually no other means of exposure to poliovirus that could explain a case of polio. The confirmation by laboratory tests, the absence of circulating wild-type virus, and the temporal association of paralytic polio with receipt of OPV (onset of illness within 30 days postvaccination in recipients and 60 days in contacts of vaccine recipients), all of which have been seen in the well-documented cases of vaccine-associated polio, fulfill the criteria of infectious disease causality. Surveillance of nonparalytic polio following OPV administration has been much less rigorous and thus, less well-documented in the literature. The arguments in support of accepting a causal relation between OPV and paralytic poliomyelitis apply, most certainly, to the relation between OPV and nonparalytic polio. The quantitative evidence, however, is less complete.


The evidence establishes a causal relation between OPV and paralytic and nonparalytic polio. The incidence of paralytic polio in OPV recipients has been well documented and is greater with the first dose of vaccine. The CDC has estimated that the overall dose-related incidence of paralytic disease is 1 case per 520,000 first doses administered versus 1 case per 12.3 million subsequent doses administered (Nkowane et al., 1987). It is clear that OPV can lead to vaccine-strain infection in contacts as well. There are no data with which to calculate an incidence, but on the basis of data on wild-type poliovirus infection, the incidence of vaccine-related nonparalytic disease would be expected to be slightly greater than the incidence of paralytic disease.

Risk-Modifying Factors

The immune status of a vaccine recipient or a contact of a vaccine recipient modifies the risk of polio as an adverse event associated with OPV vaccination. Among OPV recipients, various types of immunodeficiency are often diagnosed after a patient develops polio after immunization with OPV. These cases are described in Table 7-3. Nonimmune contacts are at increased risk of developing polio after exposure to a person immunized with OPV. These cases are described in Table 7-4. Most of the case reports describe unimmunized contacts who contracted polio, but two case reports describe immunodeficient contacts who contracted polio. For both vaccine recipients and their contacts, case reports may or may not be representative of the vaccine-associated cases of polio that occur in immunodeficient people. The CDC reports its cases of polio among immunodeficient people without categorizing the case as contacts or recipients (Centers for Disease Control, 1984, 1986). Unimmunized siblings and playmates of recipients continue to be at risk of contracting polio and may constitute a special risk group. With the increasingly younger age of entry into day care, there is a growing group of nonimmunized infants who may be exposed to infants recently immunized with OPV. The committee's review uncovered case reports of two infants, ages 20 days and 4 months (Bergeisen et al., 1986; Wilson and Robinson, 1974), who were unimmunized and who contracted polio from contact with a care giver and other infants.

TABLE 7-3. Cases of Polio Among Immune-Deficient Recipients.


Cases of Polio Among Immune-Deficient Recipients.

TABLE 7-4. Cases of Polio Among Nonimmune Contacts of Polio Recipients.


Cases of Polio Among Nonimmune Contacts of Polio Recipients.

Transverse Myelitis

Clinical Description

Transverse myelitis is characterized by the acute onset of signs of spinal cord disease, usually involving the descending motor tracts and the ascending sensory fibers, suggesting a lesion at one level of the spinal cord. The annual incidence of transverse myelitis in Rochester, Minnesota, from 1970 to 1981 was 0.83 per 100,000 people (Beghi et al., 1982). Chapter 3 contains a more complete discussion of transverse myelitis.

History of Suspected Association

There is no particular history of an association between transverse myelitis and polio vaccines.

Evidence for Association

Biologic Plausibility

Chapter 3 contains a discussion of the biologic plausibility for a causal relation between demyelinating disorders and vaccines in general.

Case Reports, Case Series, and Uncontrolled Observational Studies

Table 7-5 summarizes the three cases of transverse myelitis that have been reported in the literature to occur following vaccination with OPV. Two cases occurred in infants. A seven-month old girl developed symptoms 6 days after receiving OPV and diphtheria and tetanus toxoids (DT) (Whittle and Roberton, 1977). A 20-month girl developed symptoms 1 month after receiving OPV and diphtheria and tetanus toxoids and pertussis vaccine (DPT). She was found to be hypogammaglobulinemic (Douglas and Anolik, 1981). The third case occurred in a 24-year-old woman who was simultaneously vaccinated with OPV and typhoid and cholera vaccines (D'Costa et al., 1990). The woman had a fever at the time of vaccination and had an upper respiratory tract infection and pharyngitis for the 5 weeks preceding vaccination. The committee is aware of a case of transverse myelitis in a child with severe combined immunodeficiency syndrome (Richard B. Johnston, Yale University, New Haven, personal communication, 1993). Vaccine-strain poliovirus was isolated from the myocardium. VAERS listed two cases (submitted between November 1990 and July 1992) of transverse myelitis that occurred in patients after receiving a combination of DPT, OPV, and Haemophilus influenzae type b (Hib) vaccine and a combination of DPT, OPV, measles-mumps-rubella vaccine (MMR), and Hib vaccine, but the temporal and clinical details are insufficient for proper evaluation. Another VAERS report of transverse myelitis was a duplicate of the case report published in 1990 and discussed above (the 24-year-old woman). In addition, at a public meeting held in January 1993, the committee heard about a 4-month-old girl who developed transverse myelitis, diagnosed by neurologists, a few days after her second DPT and OPV immunizations. This was thought by the physicians treating the girl to be related to her immunizations (see Appendix B).

TABLE 7-5. Reports Associating Transverse Myelitis with Polio Vaccine.


Reports Associating Transverse Myelitis with Polio Vaccine.

Controlled Observational Studies


Controlled Clinical Trials


Causality Argument

There is biologic plausibility that viral vaccines can cause demyelinating disorders. Vaccine-strain poliovirus can enter the central nervous system and has been associated with a peripheral nerve demyelinating disorder, Guillain-Barré syndrome (see next section). The three cases of transverse myelitis following receipt of OPV reported in the literature, the two cases reported in VAERS, and the case identified by the committee in a personal communication are inadequate to indicate an association between OPV and transverse myelitis beyond that due to chance alone. At least five of the cases occurred following multiple immunizations, which complicates an assessment of a causal relation between OPV and transverse myelitis. No cases of transverse myelitis following receipt of IPV have been reported.


The evidence is inadequate to accept or reject a causal relation between OPV and transverse myelitis.

There is no evidence bearing on a causal relation between IPV and transverse myelitis.

Guillain-Barré Syndrome

Clinical Description

Guillain-Barré syndrome (GBS) is characterized by the rapid onset of flaccid motor weakness with depression of tendon reflexes and inflammatory demyelination of peripheral nerves. The annual incidence of GBS appears to be approximately 1 per 100,000 for adults. The data are not definitive, but the annual incidence of GBS in children under age 5 years appears to be approximately the same. The annual incidence of GBS in children over age 5 years and teenagers appears to be lower. Chapter 3 contains a detailed discussion of GBS.

History of Suspected Association

A relation between attenuated viral vaccines and demyelinating disease has been investigated for many years, as described in Chapter 3. Specific interest in the relation between GBS and polio vaccine was triggered by a report in 1976 of 10 cases of GBS in patients who had received IPV (Andersen and Eeg-Olofsson, 1976).

Evidence for Association

Biologic Plausibility

Chapter 3 contains a detailed discussion of the arguments that vaccines can cause demyelination, including GBS. There are no additional data demonstrating the biologic plausibility of a specific relation between polio vaccines and GBS.

Case Reports, Case Series, and Uncontrolled Observational Studies

Grose and Spigland (1976) describe a 10-month-old girl who developed GBS 4 to 7 days after receiving measles vaccine, DPT, and OPV. Poliovirus type 1 was isolated from a throat swab. The authors attributed the disease to the measles vaccine.

Leneman (1966) reviewed the literature prior to 1966 and described 1,100 case reports of GBS published between 1949 and 1966. In five cases, vaccination with IPV was mentioned, although the time interval between vaccination and the onset of GBS was not described. Changes in diagnostic procedures since 1949 might also disqualify some of the cases included in that summary. This secondhand summary of case reports does not supply sufficient information to determine whether IPV is associated with GBS.

In a study in Sweden, which utilized IPV exclusively, Andersen and Eeg-Olofsson (1976) discussed 10 cases of GBS that occurred in 1971 in individuals less than 60 years of age. In nine of the individuals, the onset of GBS occurred more than 1 year after a vaccination with IPV. The authors concluded that there was no association between IPV and GBS.

Data from the MSAEFI noted 14 cases of GBS following OPV administration from 1979 to 1990. In most cases OPV was given in combination with DPT, or MMR, or both. VAERS listed two cases of GBS (submitted between November 1990 and July 1992) following administration of OPV in combination with DPT and either MMR or Hib vaccine.

Controlled Observational Studies

Two controlled studies examined the association between GBS and polio vaccine (Table 7-6).

TABLE 7-6. Reports Associating Guillain-Barré Syndrome with Polio Vaccines.


Reports Associating Guillain-Barré Syndrome with Polio Vaccines.

The first study took place in a southern province of Finland (Uusimaa), where continuing surveillance of GBS from 1981 to 1986 uncovered an increase in the incidence of GBS following a nationwide program of immunizing children and adults against polio (Kinnunen et al., 1989). At that time, Finland generally used IPV, but an outbreak of 10 cases of poliomyelitis between August 1984 and January 1985 led to the decision to carry out a mass immunization with OPV. Ninety-four percent of the Finnish population was vaccinated with OPV during a 5-week period between February 10 and March 15, 1985. During and shortly after the immunization campaign, hospitals in the southern province, Uusimaa (population, approximately 1.17 million), received an unexpectedly high number of patients with GBS. The first and second quarters of 1985 showed a statistically significant higher number of cases of GBS than were found in the other quarters of the observational period. Over the 6-year period from 1981 to 1986 (including the period of OPV immunization), the mean number of cases of GBS per quarter was 3, and Kinnunen estimated a crude annual incidence of 1 case per 100,000 population. This is significantly higher than the mean for the 6-year period. Ten cases occurred in the first quarter and 6 cases occurred in the second quarter of 1985, the times corresponding to the immunization campaign. Ten patients were diagnosed with GBS within 10 weeks after vaccination with OPV, with the mean time of onset occurring at 31 days postvaccination. Six of the cases occurred within 6 weeks of vaccination. All patients with suspected GBS were evaluated separately by two neurologists, and consensus on the diagnosis was reached in every case. The patients' ages ranged from 15 to 73 years.

The study in Finland took advantage of two unique phenomena: a continuing surveillance of GBS that identified cases in the population over a 6-year period and a national program of immunizing adults in a 5-week period. The data showed an increase in the number of cases of GBS temporally associated with the immunization program, and the increase was statistically significant. The diagnosis of GBS was made by using consistent criteria throughout the observation period because of the prospective study on GBS that was in place well before the polio epidemic and immunization against polio occurred.

The study in Finland presents evidence that OPV may be associated with GBS and raises the question of why there have not been other reports of GBS associated with OPV. One explanation may be that the rarity of GBS, the usual predominance of GBS in adults, and the rarity of administration of OPV to adults have not produced any recognized cases of OPV-associated GBS. Kinnunen et al. (1989) estimated a crude annual incidence of 1 case of GBS per 100,000 population. The 10 cases that were considered vaccine associated occurred in patients ages 15 to 73 years. Six of the patients were in their 50s and two were in their 30s. If GBS mainly occurs in adults and relatively few adults receive OPV, the probability of uncovering a case of OPV-associated GBS without a surveillance system is low.

At the same time that Kinnunen et al. (1989) published the results of their study, Uhari et al. (1989) published a letter describing a cluster of GBS cases in children in Finland. They identified 27 cases of GBS in children ages 0.4 to 14.3 years over the 7-year period from 1980 to 1986, with an average incidence of 3.9 cases per year. They also noted a peak of 10 cases in 1985, which was different from the number of cases noted in other years, and the difference was statistically significant (P = 0.0042). Unlike Kinnunen et al. (1989), Uhari and colleagues did not confirm that the children with GBS had actually received OPV within the 6 weeks prior to the onset of GBS. They demonstrated an ecologic and temporal association between the OPV campaign and the cluster of GBS cases.

Controlled Clinical Trials


Causality Argument

Other viruses and vaccines have been found to be associated with GBS (see Chapter 3), and it is biologically plausible that OPV may also be associated with GBS. Of the two controlled studies examining the relation between OPV and GBS, one study provided evidence that there may be an effect in adults, and the second study suggested that there may be an effect in children (Table 7-6). The absence of other reports is consistent with the low incidence of GBS (roughly estimated to have an annual incidence rate of 1 case per 100,000 people). The observation of an increased incidence of GBS in Finland temporally associated with a mass immunization with OPV provided a special opportunity to study the association between GBS and OPV. The consistency of diagnostic criteria and statistically significant differences in the incidence of GBS suggest that the increase was not due to chance variation or biased case reporting.

The committee estimated relative risks and risk differences for GBS following OPV based on the studies of Kinnunen et al. (1989) and Uhari et al. (1989). The expected number of cases was calculated by eliminating from the background incidence data the period in which OPV was given (which the authors did not do in their calculations). This led to relative risk (RR) estimates of 3.8 for the study by Kinnunen et al. (1989) and 3.6 for the study by Uhari et al. (1989). The risk difference (calculated as [RR - 1] x background incidence) for GBS in adults on the basis of the relative risk and background incidence derived from Kinnunen et al. is 2.5 per 100,000 per year. Since OPV-induced GBS occurs within 6 weeks of vaccination. the 6-week excess risk is 0.3 per 100,000. By using the background rates and relative risks from Uhari et al., the risk difference for GBS within 6 weeks of OPV in children under 15 years of age is about 0.1 per 100,000.

However, data provided by Winner and Evans (1990) and Hankey (1987) suggest the background incidence rate for children varies by age interval. Based on the latter data, the risk difference in young children could be significantly greater than that based on the background incidence described by Uhari et al. and could approach that in adults. Relatively few adults in the United States receive OPV; thus, the proportion of GBS cases in adults attributable to OPV would be small.


The evidence favors acceptance of a causal relation between OPV and GBS. The relative risk on the basis of studies done in Finland is on the order of 3.5 for adults, and the risk difference is approximately 2.5 per 100,000 people. Estimates of background incidence rates for GBS in children vary. It is not clear what the relative risk and risk difference are for children in the United States (see Chapter 3).

The evidence is inadequate to accept or reject a causal relation between IPV and GBS.

Risk-Modifying Factors

GBS, as a separate discrete attack, recurs in a small percentage of those previously afflicted, perhaps 2 to 3 percent, and some individuals have been known to have three or four separate episodes. Other than the patient described by Pollard and Selby (1978), who experienced three attacks, each within 10-21 days of receipt of tetanus toxoid, cases of recurrence after vaccination are not documented. Nevertheless, if GBS occurs within 5 days to 6 weeks of a vaccination, subsequent vaccinations with either OPV or different immunogens could be associated with a greater risk of GBS than if the person had never had GBS. A previous history of GBS unrelated to vaccination as an antecedent event is even more uncertain as a risk factor.

Anaphylaxis and Thrombocytopenia

Clinical Description

Anaphylaxis is a sudden, potentially life-threatening systemic condition mediated by highly reactive molecules from mast cells and basophils. The clinical manifestations of anaphylaxis include pallor and then diffuse erythema, urticaria and itching, subcutaneous edema, edema and spasm of the larynx, wheezing, tachycardia, hypotension, and hypovolemic shock, usually occurring within minutes of intramuscular or subcutaneous exposure to antigen. See Chapter 4 for a more detailed discussion of anaphylaxis.

Thrombocytopenia is a decrease in the number Of platelets that are involved in blood clotting. Thrombocytopenia can stem from the failure of platelet production, a shortened platelet life span, or an abnormal distribution of platelets within the body. In most cases, thrombocytopenia in children is mild and transient, and it is often discovered only incidentally when a complete blood count is performed. Severe thrombocytopenia associated with spontaneous bleeding, including bleeding into the skin, is called thrombocytopenic purpura. No population-based incidence rates for either condition were identified.

The committee was asked to evaluate the data regarding a possible causal relation between IPV only and anaphylaxis and thrombocytopenia.

Evidence for Association

There are no published reports of anaphylaxis or thrombocytopenic purpura associated with IPV.


There is no evidence bearing on a causal relation between IPV and anaphylaxis.

There is no evidence bearing on a causal relation between IPV and thrombocytopenia.


A detailed discussion of the evidence regarding death following immunization can be found in Chapter 10. Only the causality argument and conclusion follow. See Chapter 10 for details.

Causality Argument

The evidence favors acceptance of a causal relation between OPV and GBS. The evidence establishes a causal relation between OPV and paralytic poliomyelitis in recipients or contacts. GBS and paralytic poliomyelitis can be fatal. Although there is no direct evidence of death as a consequence of OPV-induced GBS, in the committee's judgment OPV could cause fatal GBS. There are data regarding death from vaccine-strain poliovirus infection; the data derive primarily from immunocompromised individuals. There is no evidence or reason to believe that the case fatality rate for GBS or vaccine-associated poliovirus infection (including that resulting in paralytic poliomyelitis) is greater than that for these adverse events associated with any other cause.

The possible causal relation between polio vaccines and sudden infant death syndrome (SIDS) has rarely been studied. The evidence is inadequate to accept or reject a causal relation between polio vaccines and SIDS.


The evidence establishes a causal relation between OPV and death from vaccine-strain poliovirus infection, including infection that results in paralytic poliomyelitis. The conclusion is based on case reports and not on controlled studies. No relative risk can be calculated. However, the risk of death from OPV-related polio infection would seem to be extraordinarily low.

The evidence favors acceptance of a causal relation between OPV and death from GBS. There is no direct evidence for this; the conclusion is based on the potential of GBS to be fatal. The risk appears to be extraordinarily low.

The evidence is inadequate to accept or reject a causal relation between polio vaccines and SIDS.

The evidence is inadequate to accept or reject a causal relation between OPV and death from causes other than those listed above.


  • Adams J. Francke E, Lillestol M. Poliomyelitis vaccination (letter). New England Journal of Medicine 1977; 297:1290-1291. [PubMed: 917078]
  • American Academy of Pediatrics, Committee on Infectious Diseases. Report of the Committee on Infectious Diseases. Elk Grove Village, IL: American Academy of Pediatrics; 1964.
  • American Academy of Pediatrics, Committee on Infectious Diseases. Report of the Committee on Infectious Diseases: 22nd edition. Elk Grove Village. IL: American Academy of Pediatrics; 1991.
  • Andersen O, Eeg-Olofsson E. A prospective study of parapareses in western Sweden. Acta Neurologica Scandinavica 1976; 54:312-320. [PubMed: 973553]
  • Andre FE. Poliomyelitis vaccines in Belgium: 20 years of experience. Developments in Biological Standardization 1979; 43:187-193. [PubMed: 230109]
  • Arlazoroff A, Bleicher Z, Klein C, Vure E, Lahat E, Gross B, et al. Vaccine-associated contact paralytic poliomyelitis with atypical neurological presentation. Acta Neurologica Scandinavica 1987; 76:210-214. [PubMed: 3687370]
  • Balduzzi P, Glasgow LA. Paralytic poliomyelitis in a contact of a vaccinated child. New England Journal of Medicine 1967; 276:796-797. [PubMed: 6023641]
  • Basillico FC, Bernat JL. Vaccine-associated poliomyelitis in a contact. Journal of the American Medical Association 1978; 239:2275. [PubMed: 650811]
  • Bateman DE, Elrington G, Kennedy P, Saunders M. Vaccine related poliomyelitis in nonimmunised relatives and household contacts. British Medical Journal 1987; 294:170-171. [PMC free article: PMC1245171] [PubMed: 3109551]
  • Beghi E, Kurland LT, Mulder DW. Incidence of acute transverse myelitis in Rochester, Minnesota, 1970-1980, and implications with respect to influenza vaccine. Neuroepidemiology 1982; 1:176-188.
  • Beghi E, Nicolosi A, Kurland LT, Mulder DW, Hauser WA, Shuster L. Encephalitis and aseptic meningitis, Olmsted County, Minnesota, 1950-1981. I. Epidemiology. Annals of Neurology 1984; 16:283-294. [PubMed: 6148911]
  • Bell EJ, Riding MH, Grist NR. Paralytic poliomyelitis: a forgotten diagnosis? British Medical Journal 1986; 293:193-194. [PMC free article: PMC1340919] [PubMed: 3015321]
  • Benison S. International medical cooperation: Dr. Albert Sabin, live poliovirus vaccine and the Soviets. Bulletin of the History of Medicine 1982; 56:460-483. [PubMed: 6760938]
  • Bergeisen GH, Bauman RJ, Gilmore RL. Neonatal paralytic poliomyelitis: a case report. Archives of Neurology 1986; 43:192-194. [PubMed: 3947264]
  • Bernal A, Garcia-Saiz A, Liacer A, De Ory F, Tello O, Najera R. Poliomyelitis in Spain, 1982-1984: virologic and epidemiologic studies. American Journal of Epidemiology 1987; 126:69-76. [PubMed: 3035919]
  • Biberi-Moroeanu S, Muntiu A. Commentary on the oral poliomyelitis vaccine (Sabin):associated cases of acute persisting spinal paralysis. Archives Roumaines de Pathologie Experimentale et de Microbiologie 1978; 37:355-368. [PubMed: 757664]
  • British Medical Journal. Report from the PHLS Communicable Disease Surveillance Centre. British Medical Journal 1986; 293:195-196. [PMC free article: PMC1340920] [PubMed: 3089445]
  • Canadian Medical Association Journal. Vaccine-associated poliomyelitis in Quebec. Canadian Medical Association Journal 1987; 137:418-419. [PMC free article: PMC1492781] [PubMed: 3621100]
  • Centers for Disease Control. Paralytic poliomyelitis—United States, 1982 and 1983. Morbidity and Mortality Weekly Report 1984; 33:635-638. [PubMed: 6436667]
  • Centers for Disease Control. Poliomyelitis—United States, 1975-1984. Morbidity and Mortality Weekly Report 1986; 35:180-182. [PubMed: 3081788]
  • Centers for Disease Control. Epidemiologic classification of reported cases of paralytic poliomyelitis, U.S.A., 1975-1986. Unpublished. Atlanta: Centers for Disease Control; 1987.
  • Cesario TC, Nakano JH, Caldwell GG, Youmans RA. Paralytic poliomyelitis in an unimmunized child: apparent result of a vaccine-derived poliovirus. American Journal of Diseases of Children 1969; 118:895-898. [PubMed: 4311013]
  • Chang TW, Weinstein L, MacMahon HE. Paralytic poliomyelitis in a child with hypogammaglobulinemia: probable implication of type I vaccine strain. Pediatrics 1966; 37:630-636. [PubMed: 5930025]
  • Collingham KE, Pollock TM, Roebuck MO. Paralytic poliomyelitis in England and Wales, 1976-1977. Lancet 1978; 1:976-977. [PubMed: 76901]
  • Daneault N, Albert G, Girouard Y, Remillard G, Furesz J. Postvaccinal poliomyelitis: a case report. Canadian Journal of Neurological Science 1986; 12:202.
  • Davis LE, Bodian D, Price D, Butler IJ, Vickers JH. Chronic progressive poliomyelitis secondary to vaccination of an immunodeficient child. New England Journal of Medicine 1977; 297:241-245. [PubMed: 195206]
  • D'Costa DF, Cooper A, Pye IF. Transverse myelitis following cholera, typhoid and polio vaccination. Journal of the Royal Society of Medicine 1990; 83:653. [PMC free article: PMC1292867] [PubMed: 2286971]
  • Derenne F, Vanderheyden JE, Bain H, Jocquet P, Jacquy J, Yane F, et al. Poliomyelite anterieure aigue maternelle en zone nonendemique. [Acute maternal anterior poliomyelitis in a nonendemic zone.] Acta Neurologica Belgica 1989; 89:358-365. [PubMed: 2561040]
  • Domok I. Experiences associated with the use of live poliovirus vaccine in Hungary, 1959-1982. Reviews of Infectious Diseases 1984; 6(Suppl. 2):S413-S418. [PubMed: 6740083]
  • Douglas SD, Anolik R. Postvaccination paralysis in a 20-month-old child. Hospital Practice 1981; 16:40A. [PubMed: 6792042]
  • Enders JF, Weller TH, Robbins, FC. Cultivation of the Lansing strain of poliomyelitis virus in cultures of various human embryonic tissues. Science 1949; 109:85-87. [PubMed: 17794160]
  • Frantzidou-Adamopoulou F. Poliomyelitis cases in northern Greece during 1976-1990. European Journal of Epidemiology 1992; 8:112-113. [PubMed: 1315292]
  • Grose C, Spigland I. Guillain-Barré syndrome following administration of live measles vaccine. American Journal of Medicine 1976; 60:441-443. [PubMed: 1258890]
  • Gross TP, Khurana RK, Higgins T, Nkowane BS, Hirsch RL. Vaccine-associated poliomyelitis in a household contact with Netherton's syndrome receiving long-term steroid therapy. American Journal of Medicine 1987; 83:797-800. [PubMed: 3674066]
  • Hammon WM, Coriell LL, Wehrle PF, Stokes J. Evaluation of Red Cross gamma globulin as a prophylactic agent for poliomyelitis. 4. Final report of results based on clinical diagnoses. Journal of the American Medical Association 1953; 151:1272-1285. [PubMed: 13034471]
  • Haneberg B, Orstavik I. Poliomyelitis associated with oral poliovaccine: report on two cases. Acta Paediatrica Scandinavica 1972; 61:105-108. [PubMed: 5018571]
  • Hankey GJ. Guillain-Barré syndrome in Western Australia, 1980-1985. Medical Journal of Australia 1987; 146:130-133. [PubMed: 3574191]
  • Henderson DA, Witte JJ, Morris L, Langmuir AD. Paralytic disease associated with oral polio vaccines. Journal of the American Medical Association 1964: 190:41-48. [PubMed: 14197143]
  • Institute of Medicine. Evaluation of Poliomyelitis Vaccines. Washington, DC: National Academy of Sciences; 1977.
  • Institute of Medicine. An Evaluation of Poliomyelitis Vaccine Policy Options. Washington, DC: National Academy Press; 1988.
  • Ishizaki A, Noda Y. [Neurological complications of immunization]. No To Hattatsu 1986; 18:105-113. [PubMed: 2871848]
  • Kinnunen E, Farkkila M, Hovi T, Juntunen J, Weckstrom P. Incidence of Guillain-Barré syndrome during a nationwide oral poliovirus vaccine campaign. Neurology 1989; 39:1034-1036. [PubMed: 2788248]
  • Kolmer JA. Vaccination against acute anterior poliomyelitis. American Journal of Public Health and the Nations Health 1936; 26:126-135. [PMC free article: PMC1562616] [PubMed: 18014365]
  • Koprowski H, Jervis GA, Norton TW. Immune responses in human volunteers upon oral administration of a rodent-adapted strain of poliomyelitis virus. American Journal of Hygiene 1952; 55:108-126. [PubMed: 14885170]
  • Kostrzewski JM. Zachorowania na poliomyelitis w otoczeniu szczepionych wirusem atenuowanym. [Case of poliomyelitis in unvaccinated children in contact with persons vaccinated with attenuated virus.] Przeglad Epidemiologiczny 1973; 27:259-265. [PubMed: 4720593]
  • Kruppenbacher JP, Mertens T, Adrian M, Smolenski S, Leidel J, Eggers HJ. Die Impfpoliomyelitis als Komplikation der Oralvakzination. [Vaccine poliomyelitis as a complication of oral vaccination.] Offentliche Gesundheitswesen 1983; 45:528-531. [PubMed: 6227849]
  • Kuwert E, Thraenhart O, Hoher PG, Dorndorf W, Voit D, Blumenthal W. Spinale Kinderlahmung nach Kontakt mit Polioimpfvirus. [Spinal poliomyelitis due to contact with polio vaccine virus.] Deutsche Medizinische Wochenschrift 1971 ; 96:1562-1568. [PubMed: 4328539]
  • LaForce FM. Poliomyelitis vaccines: success and controversy. Infectious Disease Clinics of North America 1990; 4:75-83. [PubMed: 2407779]
  • Leake JP. Poliomyelitis following vaccination against this disease. Journal of the American Medical Association 1935; 105:2152.
  • Leneman F. The Guillain-Barré syndrome. Archives of Internal Medicine 1966; 118:139-144. [PubMed: 5945962]
  • Loffel M, Meienberg O, Diem P, Mombelli G. Impfpoliomyelitis bei einem Erwachsenen unter Chemotherapie wegen Non-Hodgkin-Lymphoms. [Vaccine poliomyelitis in an adult undergoing chemotherapy for non-Hodgkin lymphoma.] Schweiz Medizinische Wochenschrift 1982; 112:419-421. [PubMed: 7071564]
  • Maass G, Quast U. Acute spinal paralysis after the administration of oral poliomyelitis vaccine in the Federal Republic of Germany (1963-1984). Journal of Biological Standardization 1987; 15:185-191. [PubMed: 3597450]
  • Mathias RG, Routley JV. Paralysis in an immunocompromised adult following oral polio vaccination (letter). Canadian Medical Association Journal 1985; 132:738-739. [PMC free article: PMC1345860] [PubMed: 3978497]
  • Morse LJ, Rubin HE, Blount RE Jr. Vaccine-acquired paralytic poliomyelitis in an unvaccinated mother. Journal of the American Medical Association 1966; 197:1034-1035. [PubMed: 5953205]
  • Nishio O, Ishihara Y, Sakae K, Nonomura Y, Kuno A, Yasukawa W, et al. The trend of acquired immunity with live poliovirus vaccine and the effect of revaccination: follow-up of vaccinees for ten years. Journal of Biological Standardization 1984; 12:1-10. [PubMed: 6699021]
  • Nkowane BM, Wassilak SG, Orenstein WA, Bart KJ, Schonberger LB, Hinman AR, et al. Vaccine-associated paralytic poliomyelitis, United States: 1973 through 1984. Journal of the American Medical Association 1987; 257:1335-1340. [PubMed: 3029445]
  • Novello F, Lombardi F, Amato C, Santoro R, Fiore L, Grandolfo ME, Pasquini. P. Paralytic poliomyelitis in Italy (1981-85). European Journal of Epidemiology 1987; 3:54-60. [PubMed: 3582600]
  • Onorato IM, Modlin JF, McBean AM, Thoms ML, Losonsky GA, Bernier RH. Mucosal immunity induced by enhanced-potency inactivated and oral polio vaccines. Journal of Infectious Diseases 1991; 163:1-6. [PubMed: 1845806]
  • Openshaw H, Lieberman JS. Vaccine-related poliomyelitis: serum IgM and cerebrospinal fluid antibodies. Western Journal of Medicine 1983; 138:420-422. [PMC free article: PMC1021499] [PubMed: 6305036]
  • Orzechowska-Wolczyk M, Szulc-Kuberska J, Zawadzki Z. Przypadek zapalenia rogow przednich rdzenia kregowego u matki dziecka szczepionego przeciw polio. [Case of poliomyelitis in the mother of a child vaccinated against poliomyelitis.] Wiadomosci Lekarskie 1976; 29:1007-1010. [PubMed: 180696]
  • Pollard JD, Selby G. Relapsing neuropathy due to tetanus toxoid: report of a case. Journal of Neurological Science 1978; 37:113-125. [PubMed: 308529]
  • Racaniello VR. Poliovirus vaccines. Biotechnology 1992; 20:205-222. [PubMed: 1318134]
  • Riker JB, Brandt CD, Chandra R, Arrobio JO, Nakano JH. Vaccine-associated poliomyelitis in a child with thymic abnormality. Pediatrics 1971; 48:923-929. [PubMed: 4331606]
  • Sabin AB. Immunization of chimpanzees and human beings with avirulent strains of poliomyelitis virus. Annals of the New York Academy Sciences 1956; 61:1050-1056. [PubMed: 13340614]
  • Sakano T, Kittaka E, Tanaka Y, Yamaoka H, Kobayashi Y, Usui T. Vaccine-associated poliomyelitis in an infant with agammaglobulinemia. Acta Paediatrica Scandinavica 1980; 69:549-551. [PubMed: 6255734]
  • Salk JE. Recent studies in immunization against poliomyelitis. Pediatrics 1953; 12: 471-482. [PubMed: 13111847]
  • Salk JE, Bennett BL, Lewis LJ, Ward EN, Youngner JS. Studies in human subjects on active immunization against poliomyelitis. 1. A preliminary report of experiments in progress. Journal of the American Medical Association 1953; 151:1081-1098. [PubMed: 13034436]
  • Saulsbury FT, Winkelstein JA, Davis LE, Hsu SH, D'Souza B J, Gutcher GR, Butler, IJ. Combined immunodeficiency and vaccine-related poliomyelitis in a child with cartilage-hair hypoplasia. Journal of Pediatrics 1975; 86:868-872. [PubMed: 165279]
  • Smith JW, Wherry PJ. Poliomyelitis surveillance in England and Wales, 1969-1975. Journal of Hygiene 1978; 80:155-167. [PMC free article: PMC2129973] [PubMed: 563892]
  • Stolley PD, Joseph JM, Allen JC, Deane G, Janney JH. Poliomyelitis associated with type-2 poliovirus vaccine strain: possible transmission from an immunised child to a nonimmunised child. Lancet 1968; 1:661-663. [PubMed: 4170650]
  • Swanson PD, McAlister R, Peterson DR. Poliomyelitis associated with type 2 virus: paralytic disease in the father of a recently immunized child. Journal of the American Medical Association 1967; 201:771-773. [PubMed: 6071888]
  • Thraenhart O, Kuwert E. Intratypische charakterisierung von poliovirussammen unter besonderer Berucksichtigung der impfreaktion nach schluckimpfung. [Intratypic differentiation of poliovirus strains with special regard to complication after oral vaccination in West-Germany.] Sentralblatt fur Bakteriologic, Parasitunkunde, Infektionskrankheiten und Hygiene. 1972; 221:143-156. [PubMed: 4146494]
  • Uhari M, Rantala H, Niemela M. Cluster of childhood Guillain-Barré cases after an oral poliovaccine campaign (letter). Lancet 1989; 2:440-441. [PubMed: 2569613]
  • U.S. Public Health Service. Interim document gives advice on use of Salk and Sabin vaccines. Journal of the American Medical Association 1962; 180:23-26.
  • Whittle E, Roberton NR. Transverse myelitis after diphtheria, tetanus, and polio immunization. British Medical Journal 1977; 1:1450. [PMC free article: PMC1607668] [PubMed: 861686]
  • Wiechers DO. New concepts of the reinnervated motor unit revealed by vaccine-associated poliomyelitis. Muscle Nerve 1988; 11:356-364. [PubMed: 3398882]
  • Wilson J, Robinson R. Poliomyelitis after contact with recently vaccinated infant (letter). British Medical Journal 1974; 2:53. [PMC free article: PMC1610140] [PubMed: 4362453]
  • Winner SJ, Evans G. Age-specific incidence of Guillain-Barré syndrome in Oxfordshire. Quarterly Journal of Medicine (New Series) 1990; 77:1297-1304. [PubMed: 2290923]
  • World Health Organization Consultative Group. The relation between acute persisting spinal paralysis and poliomyelitis vaccine: results of a ten-year enquiry. Bulletin of the World Health Organization 1982; 60:231-242. [PMC free article: PMC2535960] [PubMed: 6980734]
  • Wright PF, Hatch MH, Kasselberg AG, Lowry SP, Wadlington WB, Karzon DT. Vaccine-associated poliomyelitis in a child with sex-linked agammaglobulinemia. Journal of Pediatrics 1977; 91:408-412. [PubMed: 197220]
Copyright 1994 by the National Academy of Sciences. All rights reserved.
Bookshelf ID: NBK236293


Related information

  • PMC
    PubMed Central citations
  • PubMed
    Links to PubMed

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...