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Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy Immunization to protect children and adults from many infectious diseases is one of the greatest achievements of public health. Immunization is not without risks, however. It is well established, for example, that the oral polio vaccine can on rare occasion cause paralytic polio, that some influenza vaccines have been associated with a risk of Guillain-Barre syndrome, and that vaccines sometimes produce anaphylactic shock. Given the widespread use of vaccines, state man- dates requiring vaccination of children for entry into school, college, or day care, and the importance of ensuring that trust in immunization programs is justified, it is essential that safety concerns receive assiduous attention. The Immunization Safety Review Committee was established by the Insti- tute of Medicine (IOM) to evaluate the evidence on possible causal associations between immunizations and certain adverse outcomes, and then to present con- clusions and recommendations. The committee's mandate also includes assess- ing the broader significance for society of these immunization safety issues. In this sixth report in a series, the committee examines the hypothesis that infant vaccination is associated with an increased risk of sudden unexpected death during the first year of life. THE CHARGE TO THE COMMITTEE Challenges to the safety of immunizations are prominent in public and scien- tific debate. Given these persistent and growing concerns about immunization safety, the Centers for Disease Control and Prevention (CDC) and the National Institutes of Health (NIH) recognized the need for an independent, expert group 17

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18 IMMUNIZATION SAFFI Y REVIEW to address immunization safety in a timely and objective manner. The IOM has been involved in such issues since the 1970s. (A brief chronology can be found in Appendix C.) In 1999, because of IOM's previous work and its access to inde- pendent scientific experts, CDC and NIH began a year of discussions with IOM to develop the Immunization Safety Review project, which would address both emerging and existing vaccine safety issues. The Immunization Safety Review Committee is responsible for examining a broad variety of immunization safety concerns. Committee members have exper- tise in pediatrics, neurology, immunology, internal medicine, infectious diseases, genetics, epidemiology, biostatistics, risk perception and communication, deci- sion analysis, public health, nursing, and ethics. While all the committee mem- bers share the view that immunization is generally beneficial, none of them has a vested interest in the specific immunization safety issues that come before the group. Additional discussion of the committee composition can be found in the Foreword written by Dr. Harvey Fineberg, President of the IOM. The committee is charged with examining three immunization safety hy- potheses each year during the three-year study period (2001-2003~. These hy- potheses are selected by the Interagency Vaccine Group (IAVG), whose mem- bers represent several units of the Department of Health and Human Services: the National Vaccine Program Office, the National Immunization Program, and the National Center for Infectious Diseases at CDC; the National Institute for Allergy and Infectious Diseases at NIH; the Food and Drug Administration; the National Vaccine Injury Compensation Program at the Health Resources and Services Administration; and the Centers for Medicare and Medicaid Services (formerly the Health Care Financing Administration). The IAVG includes representation from the Department of Defense and the Agency for International Development as well. For each topic, the Immunization Safety Review Committee reviews rel- evant literature and submissions by interested parties, holds an open scientific meeting, and directly follows the open meeting with a 1- to 2-day closed meeting to formulate its conclusions and recommendations. The committee's findings are released to the public in a brief consensus report 60 to 90 days after its meeting. The committee is charged with assessing both the scientific evidence regard- ing the hypotheses under review and the significance of the issues for society. The scientific assessment has two components: (1) an examination of the epidemiologic and clinical evidence regarding a possible causal relationship between exposure to the vaccine and the adverse event; and (2) an examination of theoretical, experimental, and observational evidence from in vitro, animal, or human studies regarding biological mechanisms that might be relevant to the hypothesis. The significance assessment addresses such considerations as the burden of the health risks associated both with the vaccine-preventable disease and the

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VACCINATIONS AND SUDDEN UNEXPECTED DEATH IN INFANCY 19 adverse event. Other considerations may include the perceived intensity of public or professional concern, or the feasibility of additional research to help resolve scientific uncertainty regarding causality. The findings of the scientific and significance assessments provide the basis for the committee's recommendations regarding the public health response to the issue. In particular, the committee addresses needs for a review of immunization policy, for current and future research, and for effective communication strate- gies. See Figure 1 for a schematic representation of the committee's charge. THE STUDY PROCESS The committee held an initial organizational meeting in January 2001. CDC and NIH presented the committee's charge at the meeting, and the committee then conducted a general review of immunization safety concerns. At this initial meeting, the committee also determined the basic methodology to be used for assessing causality in the hypotheses to be considered at subsequent meetings. A website (www.iom.edu/imsafety) and a listserv were created to provide public access to information about the committee's work and to facilitate communica- tion with the committee. The conclusions and recommendations of the committee's reports thus far (see Box 1) are summarized in Appendix A. For its evaluation of the potential role of vaccination in sudden unexpected death in infancy, the committee held an open scientific meeting in October 2002 (see Appendix B) to hear presentations on issues germane to the topic. These presentations are available in electronic form (audio files and slides) on the project website (www.iom.edu/imsafety). In addition, the committee reviewed an extensive collection of material, primarily from the published, peer-reviewed scientific and medical literature. A list of the materials reviewed by the commit-

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VACCINATIONS AND SUDDEN UNEXPECTED DEATH IN INFANCY 21 tee, including many items not cited in this report, can be found on the project's website. THE FRAMEWORK FOR SCIENTIFIC ASSESSMENT Causality The Immunization Safety Review Committee has adopted the framework for assessing causality developed by previous IOM committees (IOM, 1991; 1994a,b), convened under the congressional mandate of P.L. 99-660 to address questions of immunization safety. The categories of causal conclusions used by the committee are as follows: 1. No evidence 2. Evidence is inadequate to accept or reject a causal relationship 3. Evidence favors rejection of a causal relationship 4. Evidence favors acceptance of a causal relationship 5. Evidence establishes a causal relationship. Assessments begin from a position of neutrality regarding the specific vac- cine safety hypothesis under review. That is, there is no presumption that a specific vaccine (or vaccine component) does or does not cause the adverse event in question. The weight of the available clinical and epidemiologic evidence determines whether it is possible to shift from that neutral position to a finding for causality ("the evidence favors acceptance of a causal relationship") or against causality ("the evidence favors rejection of a causal relationship"~. The commit- tee does not conclude that the vaccine does not cause the adverse event merely if the evidence is inadequate to support causality. Instead, it maintains a neutral position, concluding that the "evidence is inadequate to accept or reject a causal relationship." Although no firm rules establish the amount of evidence or the quality of the evidence required to support a specific category of causality conclusion, the committee uses standard epidemiologic criteria to guide its decisions. The most definitive category is "establishes causality," which is reserved for those relation- ships in which the causal link is unequivocal, as with the oral polio vaccine and vaccine-associated paralytic polio or with anaphylactic reactions to vaccine ad- ministration (IOM, 1991; 1994a). The next category, "favors acceptance" of a causal relationship, reflects evidence that is strong and generally convincing, although not firm enough to be described as unequivocal or established. "Favors rejection" is the strongest category in the negative direction. (The category of "establishes no causal relationship" is not used because it is virtually impossible to prove the absence of a relationship with the same surety that is possible in establishing the presence of one.)

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22 IMMUNIZATION SAFFI Y REVIEW If the evidence is not reasonably convincing either in support of or against causality, the category "inadequate to accept or reject a causal relationship" is used. Evidence that is sparse, conflicting, of weak quality, or merely sugges- tive whether toward or away from causality falls into this category. Under these circumstances, some authors of similar assessments use phrases such as "the evidence does not presently support a causal association." The committee believes, however, that such language does not make the important distinction between evidence indicating that a relationship does not exist (category 3) and evidence that is indeterminate with regard to causality (category 2~. The category of "no evidence" is reserved for those cases in which there is a complete absence of clinical or epidemiologic evidence. The sources of evidence considered by the committee in its scientific assess- ment of causality include epidemiologic and clinical studies directly addressing the question at hand. That is, the data are specifically related to the effects of the vaccines under review and the adverse health outcomes) under review in this report, the effects of vaccination on the risk for sudden unexpected death in infancy. Epidemiologic studies carry the most weight in a causality assessment. These studies measure health-related exposures and outcomes in a defined set of sub- jects and then make inferences about the nature and strength of associations between exposures and outcomes in the overall population from which the study sample was drawn. Epidemiologic studies can be categorized as observational or experimental (clinical trial), and as uncontrolled (descriptive) or controlled (ana- lytic). Among the various study designs, experimental studies generally have the advantage of random assignment to exposures and are therefore the most influen- tial in assessing causality. Uncontrolled observational studies are important but are generally considered less definitive than controlled studies. In uncontrolled observational studies, where observations are made over time, confounding fac- tors such as changing case definitions or improving case detection may affect the apparent incidence and prevalence of the adverse outcomes studied. Case reports and case series are generally inadequate by themselves to estab- lish causality. Despite the limitations of case reports, the causality argument for at least one vaccine-related adverse event (the relationship between vaccines containing tetanus toxoid and Guillain-Barre syndrome) was strengthened most by a single, well-documented case report on recurrence of the adverse event following re-administration of the vaccine, a situation referred to as a "rechallenge" (IOM, 1994a). Biological Mechanisms The committee's causality assessments must be guided by an understanding of relevant biological processes. Evidence considered in the scientific assessment

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VACCINATIONS AND SUDDEN UNEXPECTED DEATH IN INFANCY 23 of biological mechanisms] includes human, animal, and in vitro studies related to biological or pathophysiological processes by which immunizations could cause an adverse event. When convincing statistical or clinical evidence of causality is available, biological data add support. But this committee is often faced with circumstances in which the epidemiologic evidence is judged inadequate to accept or reject a causal association between a vaccine exposure and an adverse event of concern. It is then left with the task of examining proposed or conceivable biological mechanisms that might be operating if an epidemiologically sound association could be shown between a vaccine exposure and an adverse event. The biological data alone cannot be invoked as proof of causality, however. The committee has established three general categories of evidence on bio- ogical mechanisms: 1. Theoretical. A reasonable mechanism can be hypothesized that is com- mensurate with scientific knowledge and does not contradict known physical and biological principles, but has not been demonstrated in whole or in part in hu- mans or in animal models. Postulated mechanisms by which a vaccine might cause a specific adverse event but for which no coherent theory exists would not qualify for this category. Thus, "theoretical" is not a default category, but one that requires thoughtful and biologically meaningful suppositions. 2. Experimental. A mechanism can be shown to operate in in vitro systems, animals, or humans. But, experimental evidence often describes mechanisms that represent only a portion of the pathological process required for expression of disease. Showing that multiple portions of a process operate in reasonable experi- mental models strengthens the case that the mechanisms could possibly result in disease in humans. Some experimental evidence is derived under highly contrived conditions. For example, achieving the results of interest may require extensive manipulation of the genetics of an animal system, or in vivo or in vitro exposures to vaccine antigen that are extreme in terms of dose, route, or duration. Other experimental evidence is derived under less contrived conditions. For example, a compelling animal or in vitro model might demonstrate a pathologic process analogous to human disease when a vaccine antigen is administered under conditions similar to human use. Experimental evidence can also come from studies in humans. In any case, biological evidence is distinct from the epidemiologic evidence ob- tained from randomized controlled trials and other population-based studies that are the basis for the causality assessment. 3. Evidence that the mechanism results in known disease in humans. For example, the wild-type infection causes the adverse health outcome associated 1For a discussion of the evolution of the terminology concerning biological mechanisms, see the committee's earlier reports (TOM, 2001 a,b; 2002a,b,c).

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24 IMMUNIZATION SAFFI Y REVIEW with the vaccine, or another vaccine has been demonstrated to cause the same adverse outcome by the same or a similar mechanism. Data from population- based studies of the risk of adverse outcomes following vaccination constitute evidence regarding causality, not biological mechanisms. If the committee identifies evidence of biological mechanisms that could be operating, it will offer a summary judgment of that body of evidence as weak, moderate, or strong. Although the committee tends to judge biological evidence in humans as "stronger" than biological evidence from highly contrived animal models or in vitro systems, the summary judgment of the strength of the evidence also depends on the quantity (e.g., number of studies or number of subjects in a study) and quality (e.g., the nature of the experimental system or study design) of the evidence. Obviously, the conclusions drawn from this review depend both on the specific data and scientific judgment. To ensure that its own summary judg- ment is defensible, the committee intends to be as explicit as possible regarding the strengths and limitations of the biological data. The committee's examination of biological mechanisms reflects their opin- ion that available information on possible biological explanations for a relation- ship between immunization and an adverse event should influence the design of epidemiologic studies and analyses. Similarly, the essential consideration of con- founders and effect modifiers in epidemiologic studies depends on an under- standing of the biological phenomena that could underlie or explain the observed statistical relationship. The identification of sound biological mechanisms can also guide the development of an appropriate research agenda and aid policymakers, who frequently must make decisions without having definitive information regarding causality. In addition, investigating and understanding possible biological mechanisms is often of value even if the available epidemiologic evidence suggests the ab- sence of a causal association. A review of biological data could give support to the negative causality assessment, for example, or it could prompt a reconsidera- tion or further investigation of the epidemiologic findings. If new epidemiologic studies were to question the existing causality assessment, the biological data could gain prominence in the new assessments. Published and Unpublished Data Published reports carry the most weight in the committee's assessment be- cause their methods and findings are laid out in enough detail to be assessed. Furthermore, those published works that undergo a rigorous peer review are subject to comment and criticism by the entire scientific community. In general, the committee cannot rely heavily on unpublished data in making its scientific assessments (regarding either causality or biological mechanisms) because they usually lack the comment and criticism provided by peer review and must there-

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VACCINATIONS AND SUDDEN UNEXPECTED DEATH IN INFANCY 25 fore be interpreted with caution. The committee also relies on editorial and peer- review procedures to ensure the disclosure of potential conflicts of interest that might be related to the source of funding for the research study. The committee does not investigate the source of funding of the published research reports it reviews, nor does the funding source influence the committee's interpretation of the evidence. Unpublished data and other reports that have not undergone peer review do have value, however, and are often considered by the committee. They might be used, for example, in support of a body of published, peer-reviewed literature with similar findings. If the committee concluded that the unpublished data were well described, had been obtained using sound methodology, and presented very clear results, the committee could report, with sufficient caveats in the discus- sion, how the unpublished data fit with the entire body of published literature. Only in extraordinary circumstances, however, could an unpublished study refute a body of published literature. The Immunization Safety Review Committee's scope of work includes con- sideration of clinical topics for which high-quality experimental studies are rarely available. Many other panels making clinical recommendations using evidence- based methods are able to require that randomized trials be available to reach strong conclusions, but, the IOM committee was convened specifically to assess topics that are of immediate concern yet for which data of any kind may just be emerging. Given the unique nature of this project, therefore, the committee deemed it important to review and consider as much information as possible, including unpublished reports. The committee does not perform primary or sec- ondary analyses of unpublished data, however. In reviewing unpublished mate- rial, the committee applies generally accepted standards for assessing the quality of scientific evidence, as described above. (All unpublished data reviewed by the committee and cited in this report are available in the form reviewed by the committee through the public access files of the National Academies. Informa- tion about the public access files is available at 202-334-3543 or www.national- academies . org/publicacces s . ~ UNDER REVIEW: VACCINATIONS AND SUDDEN UNEXPECTED DEATH IN INFANCY Infant Mortality: Rates and Causes of Death Infant mortality refers to deaths that occur between birth and 1 year of age. In 2000, there were approximately 28,000 infant deaths in the United States, and the infant mortality rate was 6.9 deaths per 1,000 live births (Mining et al., 2002~. This rate in 2000 is the lowest ever recorded in the United States and is 25 percent lower than the rate of 9.2 in 1990. The decline in the infant mortality rate during the 1990s is attributed in part to the use of surfactants and other medical interven-

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26 IMMUNIZATION SAFFI Y REVIEW lions that improved the survival of premature and low-birth-weight infants, and, in part to reductions in sudden infant death syndrome (SIDS) that resulted from the spreading adoption of recommendations that prone positions be avoided for infant sleep. Various characteristics of infants or their mothers are associated with differ- ences in the infant mortality rate (Mathews et al., 2002~. The rate is higher for male infants (7.2) than for female infants (6.0~. Low birth weight and premature birth are associated with especially high rates of infant mortality; in 2000, the mortality rate for infants born weighing less than 1,500 grams was 244.3 per 1,000 births, compared with 2.5 for infants who weighed 2,500 grams or more at birth. Low birth weight and prematurity contribute to an even higher mortality rate in multiple births (Branum, 2002~. Higher infant mortality rates are also associated with lack of prenatal care, births to teenage mothers, and maternal smoking during pregnancy. Among racial and ethnic groups in 2000, the lowest infant mortality rate was 3.5, seen for children born to mothers of Chinese origin. For children of non- Hispanic white mothers, the rate was 5.7. The overall rate for infants born to Hispanic mothers was 5.6, but within the Hispanic population it was highest for children of Puerto Rican mothers (8.2~. For children born to American Indian mothers, the rate was 8.3. Infant mortality was highest for the non-Hispanic black population, with 13.6 deaths per 1,000 live births (Branum, 2002; Mathews et al., 2002~. Some of the difference among racial and ethnic groups is accounted for by their differences in rates of low birth weight. About two-thirds of infant deaths occur within 27 days of birth, a period designated as neonatal. In 2000, approximately 80 percent of neonatal deaths occurred within the early part of the neonatal period the first 6 days of life and most early neonatal deaths occurred less than 24 hours after birth (Branum, 2002; Mathews et al., 2002~. For 2000, the neonatal mortality rate was 4.6 deaths per 1000 births (Mathews et al., 2002~. The postneonatal mortality rate deaths at ages 28 days to 1 year was 2.3. Most deaths occurring during the neonatal period are related to problems arising during gestation or delivery. The five leading causes of neonatal mortality in 2000 were (1) disorders related to short gestation and low birth weight, (2) congenital anomalies, (3) effects of maternal complications of pregnancy, (4) effects of pregnancy complications related to the cord or placenta, and (5) respi- ratory distress (Branum, 2002~. In contrast to the neonatal period, the leading causes of infant death during the postneonatal period reflect the impact of social and environmental factors, as well as biological ones. The five leading causes of postneonatal infant mortality in 2000 were (1) SIDS, (2) congenital anomalies, (3) unintentional injuries, (4) diseases of the circulatory system, and (5) assault (Branum, 2002~.

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VACCINATIONS AND SUDDEN UNEXPECTED DEATH IN INFANCY Sudden Unexpected Death in Infancy 27 A death that occurs suddenly and unexpectedly in the first year of life, whether or not there is an underlying disorder that predisposes the infant to death, has been referred to collectively by the term "sudden unexpected death in in- fancy" (SUDI). It includes deaths that can be attributed to an identifiable cause as well as deaths for which the cause remains uncertain. SIDS is the diagnosis most commonly given to the deaths of uncertain cause. No generally accepted list of causes of death has been established to define SUDI. As a result, it is difficult to assess the national rate of SUDI in the popula- tion from vital statistics data. However, special investigations examining deaths in infants less than a year old in Quebec (Cote et al., 1999) and in several regions in the United Kingdom (Leach et al., 1999) found that about 80% of the SUDI cases in the study sample could be attributed to SIDS. The committee acknowledges that vaccines protect against diseases that con- tribute to infant mortality. The committee's charge, however, was to examine sudden unexpected infant death, not all-causes of death. For purposes of this report, the committee looked widely for all possible associations with SUDI but focused particularly on three distinct contributors to sudden unexpected death in infants SIDS, inborn errors of metabolism, and anaphylaxis in considering possible links to immunization. Sudden Infant Death Syndrome SIDS is defined as "the sudden death of an infant under 1 year of age, which remains unexplained after a thorough case investigation, including performance of a complete autopsy, examination of the death scene, and review of the clinical history" (Willinger et al., l991~. Although this definition calls for an autopsy and other investigation of the death before a diagnosis of SIDS is made, Sullivan and Barlow (2001) note that autopsy rates and protocols for investigation of infant deaths vary among countries and among regions within countries. In the United States in 2000, the 2,523 deaths from SIDS accounted for 9 percent of all infant deaths (Anderson, 2002~. Of those deaths, 2,319 occurred in the postneonatal period, representing 25 percent of all postneonatal deaths. SIDS deaths have been observed to peak at 2 to 4 months of age and to be somewhat higher in the colder fall and winter months than in spring and summer (Adams et al., 1998; Sullivan and Barlow, 2001~. Also characteristic of SIDS is higher mortality rates for male infants than for female infants. In 2000, the postneonatal SIDS mortality rate in the United States was 67.6 per 100,000 live births for males and 46.2 for females. SIDS deaths occur among all socioeconomic and racial and ethnic groups, but the rates vary widely. For non-Hispanic African-American infants in 2000, the postneonatal mortality rate from SIDS was 122.9 per 100,000 births, com-

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74 IMMUNIZATION SAFFI Y REVIEW The committee makes its recommendation for further research recognizing that it has no basis for judging whether the results of such research will alter the balance of evidence that led to the committee's conclusions in this report. Never- theless, any research that helps to elucidate the mechanisms underlying SIDS would inform future investigations of the potential association between sudden unexpected infant death and vaccines, or any other hypothesized trigger. Postmortem evaluation of infants varies widely across the country and the depth of the investigation is often related to the evaluation site, the diagnostic resources available, and the availability of specialists such as pediatric or neona- tal pathologists (AAP, 1999~. The committee recommends that a comprehen- sive postmortem workup, including a metabolic analysis, be done on all infants who die suddenly and unexpectedly. In SIDS cases for which metabolic analyses (such as those done using the tandem mass spectrometry method dis- cussed above) were not done at birth, it may useful to conduct such analyses using samples obtained at autopsy or, if available, stored blood samples (bloodspots) originally obtained for newborn screening tests. Basic and clinical research, surveillance and epidemiologic studies, and post- mortem investigations would all be strengthened by use of standard definitions of SIDS and SUDI. The committee's efforts to reach conclusions regarding causal- ity were hampered by inconsistencies in the epidemiologic reports in the use of these terms. The committee notes the development of various resources in the United States and internationally to aid in standardizing approaches to the diagnosis of SIDS. In the United States, the accepted definition of SIDS specifies "the sudden death of an infant under 1 year of age which remains unexplained after a thorough case investigation, including performance of a complete autopsy, examination of the death scene, and review of the clinical history" (Willinger et al., 1991~. The definition agreed to at more recent international consensus conferences does not restrict SIDS to infants under 1 year of age (Byard et al., 1996; Sullivan and Barlow, 2001~. Guidance from CDC (1996a) and the AAP (1999; 2001) emphasizes the importance of postmortem examinations and thorough investigation of death scenes to rule out other causes, especially child abuse, before deaths are attrib- uted to SIDS. Also available is an international standardized protocol for autop- sies in cases of sudden unexpected infant death (Krous, 1996~. In the United States, however, requirements for investigation of unexpected infant deaths are officially established by state and local statutes (CDC, 1996a). The committee encourages efforts by CDC, AAP, and others to promote the development and consistent use throughout the United States of national guidelines for investigation, diagnosis, and reporting of SIDS cases. SUDI, unlike SIDS, is not a single, officially recognized cause of death. It can include deaths that are attributed to many different causes but that are linked

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VACCINATIONS AND SUDDEN UNEXPECTED DEATH IN INFANCY 75 by being sudden and unexpected. Despite the heterogeneity of SUDI, it is a useful concept for research on infant deaths following vaccination. The committee recommends the development of standard definitions and guidance for diag- nosis and reporting of SUDI for research purposes. Consistent application of the criteria related to SIDS and SUDI will aid interpretation of reports of vaccine-related deaths and enhance the comparability of results from surveillance, epidemiologic, and biological investigations. SUMMARY With current recommendations calling for infants to receive multiple doses of vaccines during their first year of life and with suddent infant death syndrom (SIDS) the most frequent cause of death during the postneonatal period, it is important to respond to concerns that vaccination might play a role in sudden unexpected infant death. A death that occurs suddenly and unexpectedly in the first year of life, whether or not there is an underlying disorder that predisposes to death, has been referred to by the term "sudden unexpected death in infancy" (SUDI). SUDI includes deaths that can be attributed to identifiable causes and deaths for which the causes remain uncertain. SIDS is the diagnosis most com- monly given to the deaths of uncertain cause. The committee reviewed epidemio- logic evidence focusing on three outcomes: SIDS, all SUDI, and neonatal death (infant death, whether sudden or not, during the first 4 weeks of life). Based on this review, the committee concluded that the evidence favors rejection of a causal relationship between some vaccines and SIDS; and that the evidence is inadequate to accept or reject a causal relationship between other vaccines and SIDS, SUDI, or neonatal death. The evidence regarding biological mechanisms is essentially theoretical, reflecting in large measure the lack of knowledge con- cerning the pathogenesis of SIDS. Anaphylaxis related to vaccination has been discussed in detail in previous IOM reports and is reexamined in the report; the committee observed that anaphylaxis is known to be a rare but causally related adverse event following the administration of some vaccines. Fatal anaphylaxis in infants is extraordinarily rare. The committee found no basis for a review of current immunization policies, but saw a clear need for continued research on adverse event following vaccination and on the biological basis for sudden unex- pected infant deaths. See Box 2 for a summary of all conclusions and recommen- dations.

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76 IMMUNIZATION SAFFI Y REVIEW

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VACCINATIONS AND SUDDEN UNEXPECTED DEATH IN INFANCY 77

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78 IMMUNIZATION SAFETY REVIEW REFERENCES AAP (American Academy of Pediatrics). 1999. Committee on Child Abuse and Neglect and Com- mittee on Community Health Services. Investigation and Review of Unexpected Infant and Child Deaths (RE9921) Policy Review. Pediatrics. 104(5):1158-60. AAP. 2000. Changing concepts of sudden infant death syndrome: implications for infant sleeping environment and sleep position. American Academy of Pediatrics. Task Force on Infant Sleep Position and Sudden Infant Death Syndrome. Pediatrics 105(3 Pt 1):650-6. AAP. 2001. Committee on Child Abuse and Neglect. Distinguishing Sudden Infant Death Syndrome from Child Abuse Fatalities (RE0036) Policy Statement. Pediatrics 107(2):437-441. Ackerman MJ, Siu BL, Sturner WQ, Tester DJ, Valdivia CR, Makielski JC, Towbin JA. 2001. Postmortem molecular analysis of SCN5A defects in sudden infant death syndrome. JAMA 286(18):2264-9. Adams EJ, Chavez OF, Steen D, Shah R. Iyasu S. Krous HF. 1998. Changes in the epidemiologic profile of sudden infant death syndrome as rates decline among California infants: 1990-1995. Pediatrics 102(6):1445-51. Anderson R. 2002. Deaths: Leading Causes for 2000. National Vital Statistics Report 50(No. 16). Bennett MJ, Powell S. 1994. Metabolic disease and sudden, unexpected death in infancy. Hum Pathol 25(8):742-6. Black SB, Shinefield HR, Ray P. Lewis EM, Fireman B. Hiatt R. Madore DV, Johnson CL, Hackell JO. 1993. Safety of combined oligosaccharide conjugate Haemophilus influence type b (HbOC) and whole cell diphtheria-tetanus toxoids-pertussis vaccine in infancy. The Kaiser Permanente Pediatric Vaccine Study Group. Pediatr Infect Dis J 12(12):981-5. Blood-Siegfried J. Nyska A, Lieder H. Joe M, Vega L, Patterson R. Germolec D. 2002. Synergistic effect of influenza A virus on endotoxin-induced mortality in rat pups: A potential model for sudden infant death syndrome. Pediatr Res 52(4):481-90. Boles RG, Buck EA, Blitzer MG, Platt MS, Cowan TM, Martin SK, Yoon H. Madsen JA, Reyes- Mugica M, Rinaldo P. 1998. Retrospective biochemical screening of fatty acid oxidation disor- ders in postmortem livers of 418 cases of sudden death in the first year of life. J Pediatr 132(6):924-33. Branum A. 2002. Infant Mortality in the US: An Introductory Exploration. Presentation to Immun zation Safety Review Committee: Irvine, CA. Braun MM, Terracciano G. Salive ME, Blumberg DA, Vermeer-de Bondt PE, Heijbel H. Evans G. Patriarca PA, Ellenberg SS. 1998. Report of a US public health service workshop on hypo- tonic-hyporesponsive episode (HHE) after pertussis immunization. Pediatrics 102(5):E52. Braun MM, Mootrey GT, Salive ME, Chen RT, Ellenberg SS. 2000. Infant immunization with acellular pertussis vaccines in the United States: Assessment of the first two years' data from the Vaccine Adverse Event Reporting System (VAERS). Pediatrics 106(4):E51. Buckley MG, Variend S. Walls AF. 2001. Elevated serum concentrations of beta-tryptase, but not alpha-tryptase, in sudden infant death syndrome (SIDS). An investigation of anaphylactic mechanisms. Clin Exp Allergy 31 (11): 1696-704. Busse WW, Lemanske RF Jr. 2001. Asthma. N Engl J Med 344(5):350-62. Byard RW, Becker LE, Berry PJ, Campbell PE, Fitzgerald K, Hilton JM, Krous HF, Rognum TO. 1996. The pathological approach to sudden infant death-consensus or confusion? Recommen- dations from the Second SIDS Global Strategy Meeting, Stavangar, Norway, August 1994, and the Third Australasian SIDS Global Strategy Meeting, Gold Coast, Australia, May 1995. Am J Forensic Med Pathol 17(2): 103-5. CDC (Centers for Disease Control and Prevention).1996a. Guidelines for Death Scene Investigation of Sudden, Unexplained Infant Deaths: Recommendations of the Interagency Panel on Sudden Infant Death Syndrome. MMWR 45(RR-10):1-6.

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VACCINATIONS AND SUDDEN UNEXPECTED DEATH IN INFANCY 81 IOM. 2002a. Immunization Safety Review: Hepatitis B Vaccine and Demyelinating Neurological Disorders. Washington, DC: National Academy Press. IOM. 2002b. Immunization Safety Review: Multiple Immunizations and Immune Dysfunction. Wash- ington, DC: National Academy Press. IOM. 2002c. Immunization Safety Review: SV40 Contamination of Polio Vaccine and Cancer. Wash- ington, DC: National Academy Press. Jonville-Bera AP, Autret E, Laugier J. 1995. Sudden infant death syndrome and diphtheria-tetanus- pertussis-poliomyelitis vaccination status. Fundam Clin Pharmacol 9(3):263-70. Jonville-Bera AP, Autret-Leca E, Barbeillon F. Paris-Llado J. 2001. Sudden unexpected death in infants under 3 months of age and vaccination status a case-control study. Br J Clin Pharmacol 51(3):271-6. Kaback M. 2002. Personal communication with representatives from Toronto, NYC/Sinai, Boston Children's Hospital, UCLA, UCSF, and UCSD. Keens TO, Ward SL, Gates EP, Andree DI, Hart LD. 1985. Ventilatory pattern following diphtheria- tetanus-pertussis immunization in infants at risk for sudden infant death syndrome. Am J Dis Child 139(10):991-4. Kemp SF, Lockey RF. 2002. Anaphylaxis: A review of causes and mechanisms. J Allergy Clin Immunol 110(3):341-8. Kinney HC, Filiano JJ, White WF. 2001. Medullary serotonergic network deficiency in the sudden infant death syndrome: Review of a 15-year study of a single dataset. J Neuropathol Exp Neurol 60(3):228-47. Krous H. 1996. Instruction and reference manual for the international standardized autopsy protocol for sudden unexpected infant death. J Sudden Infant Death Syndrome Infant Mortal 1 :203-46. Krueger JM, Majde JA. 1995. Cytokines and sleep. Int Arch Allergy Immunol 106(2):97-100. Krueger JM, Obal FJ, Fang J. Kubota T. Taishi P. 2001. The role of cytokines in physiological sleep regulation. Ann NYAcad Sci 933:211-21. Leach CE, Blair PS, Fleming PJ, Smith IJ, Platt MW, Berry PJ, Golding J. 1999. Epidemiology of SIDS and explained sudden infant deaths. CESDI SUDI Research Group. Pediatrics 104(4):e43. Loy CS, Horne RS, Read PA, Cranage SM, Chau B. Adamson TM. 1998. Immunization has no effect on arousal from sleep in the newborn infant. J Paediatr Child Health 34(4):349-54. Mathews TJ, Menacker F. MacDorman MF. 2002. Infant Mortality Statistics from the 2000 Period Linked Birth/Infant Death Data Set. CDC: National Vital Statistics Report 50(12). Mathur A, Sims HF, Gopalakrishnan D, Gibson B. Rinaldo P. Vockley J. Hug G. Strauss AW. 1999. Molecular heterogeneity in very-long-chain acyl-CoA dehydrogenase deficiency causing pedi- atric cardiomyopathy and sudden death. Circulation 99(10):1337-43. McInnes RR, Clarke JTR. 2002. Chapter 9: Metabolic Disorders. Rudolph CD, Lister G. Hostetter MK, ed. Rudolph's Pediatrics 21st Edition. Appleton and Lange. Minino AM, Arias E, Kochanek KD, Murphy SL, Smith BL. 2002. Deaths: Final data for 2000. National Vital Statistics Report 50(15). Mitchell EA, Milerad J. 1999. Smoking and sudden infant death syndrome. International Consulta- tion on Environmental Tobacco Smoke (ETS) and Child Health. Geneva: World Health Organi- zation: 105-129. Mitchell EA, Stewart AW, Clements M. 1995. Immunisation and the sudden infant death syndrome. New Zealand Cot Death Study Group. Arch Dis Child 73(6):498-501. Naylor EW, Chace DH. 1999. Automated tandem mass spectrometry for mass newborn screening for disorders in fatty acid, organic acid, and amino acid metabolism. J Child Neurol 14 (Suppl 1):S4-8. NICHD (National Institute of Child Health and Human Development). 2001. Targeting Sudden Infant Death Syndrome (SIDS): A Strategic Plan. Washington, DC. Niu MT, Salive ME, Ellenberg SS. 1999. Neonatal deaths after hepatitis B vaccine: The Vaccine Adverse Event Reporting System, 1991-1998. Arch PediatrAdolesc Med 153(12):1279-82.

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84 NIH- National Institutes of Health NIP - National Immunization Program NVPO - National Vaccine Program Office OPV - oral polio vaccine OR- Odds Ratio PCV - pneumococcus vaccine SIDS - Sudden Infant Death Syndrome SUDI - Sudden Unexpected Death in Infancy TNF - Tumor Necrosis Factor VAERS - Vaccine Adverse Events Reporting System VLCAD- Very Long Chain acyl-CoA dehydrogenase VSD - Vaccine Safety Datalink ., IMMUNIZE TION SAFETYREVIEW UNEDITED, UNCORRECTED PROOFS