National Academies Press: OpenBook

Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy (2003)

Chapter: Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy

« Previous: Executive Summary
Suggested Citation:"Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy." Institute of Medicine. 2003. Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy. Washington, DC: The National Academies Press. doi: 10.17226/10649.
×
Page 17
Suggested Citation:"Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy." Institute of Medicine. 2003. Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy. Washington, DC: The National Academies Press. doi: 10.17226/10649.
×
Page 18
Suggested Citation:"Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy." Institute of Medicine. 2003. Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy. Washington, DC: The National Academies Press. doi: 10.17226/10649.
×
Page 19
Suggested Citation:"Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy." Institute of Medicine. 2003. Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy. Washington, DC: The National Academies Press. doi: 10.17226/10649.
×
Page 20
Suggested Citation:"Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy." Institute of Medicine. 2003. Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy. Washington, DC: The National Academies Press. doi: 10.17226/10649.
×
Page 21
Suggested Citation:"Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy." Institute of Medicine. 2003. Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy. Washington, DC: The National Academies Press. doi: 10.17226/10649.
×
Page 22
Suggested Citation:"Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy." Institute of Medicine. 2003. Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy. Washington, DC: The National Academies Press. doi: 10.17226/10649.
×
Page 23
Suggested Citation:"Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy." Institute of Medicine. 2003. Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy. Washington, DC: The National Academies Press. doi: 10.17226/10649.
×
Page 24
Suggested Citation:"Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy." Institute of Medicine. 2003. Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy. Washington, DC: The National Academies Press. doi: 10.17226/10649.
×
Page 25
Suggested Citation:"Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy." Institute of Medicine. 2003. Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy. Washington, DC: The National Academies Press. doi: 10.17226/10649.
×
Page 26
Suggested Citation:"Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy." Institute of Medicine. 2003. Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy. Washington, DC: The National Academies Press. doi: 10.17226/10649.
×
Page 27
Suggested Citation:"Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy." Institute of Medicine. 2003. Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy. Washington, DC: The National Academies Press. doi: 10.17226/10649.
×
Page 28
Suggested Citation:"Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy." Institute of Medicine. 2003. Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy. Washington, DC: The National Academies Press. doi: 10.17226/10649.
×
Page 29
Suggested Citation:"Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy." Institute of Medicine. 2003. Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy. Washington, DC: The National Academies Press. doi: 10.17226/10649.
×
Page 30
Suggested Citation:"Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy." Institute of Medicine. 2003. Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy. Washington, DC: The National Academies Press. doi: 10.17226/10649.
×
Page 31
Suggested Citation:"Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy." Institute of Medicine. 2003. Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy. Washington, DC: The National Academies Press. doi: 10.17226/10649.
×
Page 32
Suggested Citation:"Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy." Institute of Medicine. 2003. Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy. Washington, DC: The National Academies Press. doi: 10.17226/10649.
×
Page 33
Suggested Citation:"Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy." Institute of Medicine. 2003. Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy. Washington, DC: The National Academies Press. doi: 10.17226/10649.
×
Page 34
Suggested Citation:"Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy." Institute of Medicine. 2003. Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy. Washington, DC: The National Academies Press. doi: 10.17226/10649.
×
Page 35
Suggested Citation:"Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy." Institute of Medicine. 2003. Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy. Washington, DC: The National Academies Press. doi: 10.17226/10649.
×
Page 36
Suggested Citation:"Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy." Institute of Medicine. 2003. Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy. Washington, DC: The National Academies Press. doi: 10.17226/10649.
×
Page 37
Suggested Citation:"Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy." Institute of Medicine. 2003. Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy. Washington, DC: The National Academies Press. doi: 10.17226/10649.
×
Page 38
Suggested Citation:"Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy." Institute of Medicine. 2003. Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy. Washington, DC: The National Academies Press. doi: 10.17226/10649.
×
Page 39
Suggested Citation:"Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy." Institute of Medicine. 2003. Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy. Washington, DC: The National Academies Press. doi: 10.17226/10649.
×
Page 40
Suggested Citation:"Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy." Institute of Medicine. 2003. Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy. Washington, DC: The National Academies Press. doi: 10.17226/10649.
×
Page 41
Suggested Citation:"Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy." Institute of Medicine. 2003. Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy. Washington, DC: The National Academies Press. doi: 10.17226/10649.
×
Page 42
Suggested Citation:"Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy." Institute of Medicine. 2003. Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy. Washington, DC: The National Academies Press. doi: 10.17226/10649.
×
Page 43
Suggested Citation:"Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy." Institute of Medicine. 2003. Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy. Washington, DC: The National Academies Press. doi: 10.17226/10649.
×
Page 44
Suggested Citation:"Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy." Institute of Medicine. 2003. Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy. Washington, DC: The National Academies Press. doi: 10.17226/10649.
×
Page 45
Suggested Citation:"Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy." Institute of Medicine. 2003. Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy. Washington, DC: The National Academies Press. doi: 10.17226/10649.
×
Page 46
Suggested Citation:"Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy." Institute of Medicine. 2003. Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy. Washington, DC: The National Academies Press. doi: 10.17226/10649.
×
Page 47
Suggested Citation:"Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy." Institute of Medicine. 2003. Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy. Washington, DC: The National Academies Press. doi: 10.17226/10649.
×
Page 48
Suggested Citation:"Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy." Institute of Medicine. 2003. Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy. Washington, DC: The National Academies Press. doi: 10.17226/10649.
×
Page 49
Suggested Citation:"Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy." Institute of Medicine. 2003. Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy. Washington, DC: The National Academies Press. doi: 10.17226/10649.
×
Page 50
Suggested Citation:"Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy." Institute of Medicine. 2003. Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy. Washington, DC: The National Academies Press. doi: 10.17226/10649.
×
Page 51
Suggested Citation:"Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy." Institute of Medicine. 2003. Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy. Washington, DC: The National Academies Press. doi: 10.17226/10649.
×
Page 52
Suggested Citation:"Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy." Institute of Medicine. 2003. Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy. Washington, DC: The National Academies Press. doi: 10.17226/10649.
×
Page 53
Suggested Citation:"Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy." Institute of Medicine. 2003. Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy. Washington, DC: The National Academies Press. doi: 10.17226/10649.
×
Page 54
Suggested Citation:"Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy." Institute of Medicine. 2003. Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy. Washington, DC: The National Academies Press. doi: 10.17226/10649.
×
Page 55
Suggested Citation:"Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy." Institute of Medicine. 2003. Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy. Washington, DC: The National Academies Press. doi: 10.17226/10649.
×
Page 56
Suggested Citation:"Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy." Institute of Medicine. 2003. Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy. Washington, DC: The National Academies Press. doi: 10.17226/10649.
×
Page 57
Suggested Citation:"Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy." Institute of Medicine. 2003. Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy. Washington, DC: The National Academies Press. doi: 10.17226/10649.
×
Page 58
Suggested Citation:"Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy." Institute of Medicine. 2003. Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy. Washington, DC: The National Academies Press. doi: 10.17226/10649.
×
Page 59
Suggested Citation:"Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy." Institute of Medicine. 2003. Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy. Washington, DC: The National Academies Press. doi: 10.17226/10649.
×
Page 60
Suggested Citation:"Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy." Institute of Medicine. 2003. Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy. Washington, DC: The National Academies Press. doi: 10.17226/10649.
×
Page 61
Suggested Citation:"Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy." Institute of Medicine. 2003. Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy. Washington, DC: The National Academies Press. doi: 10.17226/10649.
×
Page 62
Suggested Citation:"Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy." Institute of Medicine. 2003. Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy. Washington, DC: The National Academies Press. doi: 10.17226/10649.
×
Page 63
Suggested Citation:"Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy." Institute of Medicine. 2003. Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy. Washington, DC: The National Academies Press. doi: 10.17226/10649.
×
Page 64
Suggested Citation:"Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy." Institute of Medicine. 2003. Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy. Washington, DC: The National Academies Press. doi: 10.17226/10649.
×
Page 65
Suggested Citation:"Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy." Institute of Medicine. 2003. Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy. Washington, DC: The National Academies Press. doi: 10.17226/10649.
×
Page 66
Suggested Citation:"Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy." Institute of Medicine. 2003. Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy. Washington, DC: The National Academies Press. doi: 10.17226/10649.
×
Page 67
Suggested Citation:"Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy." Institute of Medicine. 2003. Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy. Washington, DC: The National Academies Press. doi: 10.17226/10649.
×
Page 68
Suggested Citation:"Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy." Institute of Medicine. 2003. Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy. Washington, DC: The National Academies Press. doi: 10.17226/10649.
×
Page 69
Suggested Citation:"Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy." Institute of Medicine. 2003. Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy. Washington, DC: The National Academies Press. doi: 10.17226/10649.
×
Page 70
Suggested Citation:"Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy." Institute of Medicine. 2003. Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy. Washington, DC: The National Academies Press. doi: 10.17226/10649.
×
Page 71
Suggested Citation:"Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy." Institute of Medicine. 2003. Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy. Washington, DC: The National Academies Press. doi: 10.17226/10649.
×
Page 72
Suggested Citation:"Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy." Institute of Medicine. 2003. Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy. Washington, DC: The National Academies Press. doi: 10.17226/10649.
×
Page 73
Suggested Citation:"Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy." Institute of Medicine. 2003. Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy. Washington, DC: The National Academies Press. doi: 10.17226/10649.
×
Page 74
Suggested Citation:"Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy." Institute of Medicine. 2003. Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy. Washington, DC: The National Academies Press. doi: 10.17226/10649.
×
Page 75
Suggested Citation:"Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy." Institute of Medicine. 2003. Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy. Washington, DC: The National Academies Press. doi: 10.17226/10649.
×
Page 76
Suggested Citation:"Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy." Institute of Medicine. 2003. Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy. Washington, DC: The National Academies Press. doi: 10.17226/10649.
×
Page 77
Suggested Citation:"Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy." Institute of Medicine. 2003. Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy. Washington, DC: The National Academies Press. doi: 10.17226/10649.
×
Page 78
Suggested Citation:"Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy." Institute of Medicine. 2003. Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy. Washington, DC: The National Academies Press. doi: 10.17226/10649.
×
Page 79
Suggested Citation:"Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy." Institute of Medicine. 2003. Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy. Washington, DC: The National Academies Press. doi: 10.17226/10649.
×
Page 80
Suggested Citation:"Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy." Institute of Medicine. 2003. Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy. Washington, DC: The National Academies Press. doi: 10.17226/10649.
×
Page 81
Suggested Citation:"Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy." Institute of Medicine. 2003. Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy. Washington, DC: The National Academies Press. doi: 10.17226/10649.
×
Page 82
Suggested Citation:"Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy." Institute of Medicine. 2003. Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy. Washington, DC: The National Academies Press. doi: 10.17226/10649.
×
Page 83
Suggested Citation:"Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy." Institute of Medicine. 2003. Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy. Washington, DC: The National Academies Press. doi: 10.17226/10649.
×
Page 84

Below is the uncorrected machine-read text of this chapter, intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text of each book. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

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

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

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-

20 ....................... ~ ~3 fit . , En .......................... - , ~7 i= ~ 03 O U ~ ~ _s ._ X ~ . ~ ~ 1- 1.o ~ \ ._ E cat ,~ _ ~ - 1 i= ~ ,~Q ~ ,oo _r r a, ~ m ~ In ._ 3 a a, Do, _ _ 40 CO hi, .o _ 9 / f / f ~ ~ ,o o C:) o a.> /—\ a} JO o CO _ ~ C: C Q A_ ~ ~ .~ ~ Eo_ . . Co a, e _ ~ ~~ tip ~ 75 I_ tv c} ~ ~ -a='> ~ \ ~ _' In o to 5: ^1'm- ~ ~ C I_. o X

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.)

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

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).

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-

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-

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~.

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-

28 IMMUNIZATION SAFFI Y REVIEW pared with 51.4 for non-Hispanic white infants and 34.7 for Hispanic infants (Anderson, 2002~. Postneonatal mortality rates for SIDS were also high for American Indian/Alaskan Native infants (103.2~. The lowest rate was for infants who were classified as Asian or Pacific Islander (19.9~. By definition, the cause or causes of SIDS are unknown, but a variety of often interrelated risk factors have been identified. From their review of the research literature, Sullivan and Barlow (2001) point to maternal characteristics, prenatal factors, and postnatal conditions. Factors related to the mother that in- crease the risk of SIDS include lower socioeconomic status, less education, and a first pregnancy before age 20. Maternal smoking appears to be an important SIDS risk factor for infants. The risks associated with prenatal versus postnatal expo- sure (to smoking by the mother or others in the household) remain unclear (Sullivan and Barlow, 2001), however, a survey of the published data examining the risk of SIDS from paternal smoking, where the mother is a non-smoker, suggests that the increased SIDS risk may be predominately due to in utero exposure of the fetus rather than postnatal environmental smoke (Mitchell and Milerad, 1999~. Infants who are premature or have a low birth weight are also at increased risk for SIDS. Some researchers note that risk factors of SIDS are common to those of explained deaths (Leach et al., 1999~. Many postnatal risk factors for SIDS are linked to infant care practices (Sullivan and Barlow, 2001~. Most notably, babies who are put to sleep on their stomachs are at substantially increased risk. Sleeping on soft surfaces that may obstruct breathing such as cushions or foam pads, sheepskin rugs, waterbeds, and loose bedding also appear to increase the risk of SIDS (Gilbert-Barness et al., 1991~. Overwrapping an infant, which can possibly result in overheating, may also be a risk factor. Sullivan and Barlow (2001) note mixed findings regarding the risk to an infant who shares a bed with an adult, but they point to clearer indications that sharing a room with an adult has a beneficial effect. No agreement yet exists on the pathologies or mechanisms associated with the risk factors for SIDS. Some investigations suggest that abnormalities in the brainstem or other areas of the brain might impair ventilatory or circulatory responses during sleep or to conditions such as a lack of oxygen or an excess of carbon dioxide (e.g., Harper, 2001; Kinney et al., 2001~. Others report evidence of an abnormal inflammatory response in some SIDS deaths (e.g., Howat et al., 1994; Vege and Rognum, 1999~. Chronic hypoxemia has been suggested as a final common pathway to SIDS. Studies have demonstrated elevated levels of fetal hemoglobin in postmortem blood samples from SIDS infants compared to age-matched living and deceased control infants (Cochran-Black et al., 2001; Fagan and Walker, 1992; Gilbert-Barness et al., 1993; Perry et al., 1997~. It has also been suggested that cardiac arrhythmias and congenital long-QT syndrome may be responsible for some cases of SIDS (Schwartz et al., 1998; 2000~. One study demonstrated spontaneous mutations in cardiac ion channels in approxi-

VACCINATIONS AND SUDDEN UNEXPECTED DEATH IN INFANCY TABLE 1 Triple Risk Hypotheses in Sudden Infant Death Syndrome 29 Triple Risk Model Filiano and Kinney, 1994 Fatal Triangle Triple Risk Hypothesis Rognum and Saugstad, 1993 Wedgewood, 1972 A vulnerable infant (e.g., an underlying brain abnormality) A critical developmental period in homeostatic control (e.g., regulation of sleep and wake patterns, breathing, and temperature) Predisposing factors (e.g., astrogliosis, genetic make-up) General factors that increase the probability of death from any cause (e.g., poverty, prematurity, gender, and race) A vulnerable developmental Age-specific risks related to an stage of central nervous infant's developmental status system and mucosal immunity An exogenous stressor (e.g., A trigger event (e.g., Precipitating factors (e.g., infection, hyperthermia, infection) sleep state, position, and sleep position) infection) SOURCE: Guntheroth and Spiers, 2002; Filiano and Kinney, 1994. mately 2 percent of the SIDS cases in the cohort evaluated (Ackerman et al., 2001). Several researchers have proposed variations on a "triple-risk" hypothesis to try to account for the pathogenesis of at least a portion of SIDS deaths (Filiano and Kinney, 1994; Rognum and Saugstad, 1993; Wedgewood,1972~. According to these models, SIDS can occur through the interaction of three factors: (1) an infant with an underlying vulnerability, (2) a critical developmental period, and (3) exposure to an exogenous stressor (see Table 1~. The widely used Filiano and Kinney model is currently cited on the CDC website (www.cdc.gov/nip/vacsafe/concerns/sids/default.htm) and reflected in the strategic plan on SIDS from the National Institute of Child Health and Human Development at NIH (NICHD, 2001~. Guntheroth and Spiers (2002), however, question the contribution of these triple-risk models to the overall understanding of the pathogenesis of SIDS. In particular, they assert that abnormalities in neu- rotransmitter systems found in the brains of some infants who died of SIDS cannot be proven to have had a prenatal rather than a postnatal origin. Some deaths given a diagnosis of SIDS undoubtedly represent cases of mis- diagnosis. For example, investigators have found indications of underlying meta- bolic disorders in a small percentage of infant deaths diagnosed as SIDS (e.g., Bennett and Powell, 1994; Boles et al., 1998~. Also, the American Academy of Pediatrics (2001) cites reports that in the past up to 5 percent of SIDS deaths might have been the result of child abuse.

30 Inborn Errors of Metabolism IMMUNIZATION SAFER EVIL Inborn errors of metabolism (IEM) include over 400 genetically transmitted conditions involving deficiencies of specific enzymes or transport proteins (McInnes and Clarke, 2002~. One set of these disorders is related to fatty acid oxidation (FAO). Oxidation of fatty acids in the mitochondria is a key source of energy for the heart and skeletal muscles, and it plays an essential role during periods of fasting or when illness or stress require higher energy consumption (McInnes and Clarke, 2002; Rinaldo et al., 1999; 2001~. FAO defects can result in cardiomyopathy, acute metabolic crisis (hepatic encephalopathy with hypoketotic hypoglycemia), or skeletal myopathy (Mathur et al., 1999), and they pose a particular risk of sudden unexpected death in infancy (Bennett and Powell, 1994; Mathuret al., 1999; McInnes and Clarke, 2002; Strauss et al., 1995~. Deaths from these metabolic disorders generally occur during periods of increased fat metabolism, including birth, illness, and fasting. It is estimated that approximately 1 to 5 percent of all cases of sudden unexpected death in infancy are the result of an FAO disorder (Boles et al., 1998; Rinaldo et al., 1999; Wilcox et al., 2002~. If correctly diagnosed, many patients can be successfully treated with simple and inexpensive therapeutic measures such as the avoidance of fasting, careful control of diet, and vigilance during illness. Some disorders can be detected through newborn screening programs; similar techniques are also being used to test postmortem samples for evidence of FAO and other IEM disorders. FAO disorders are probably the most common form of IEM, with at least 22 different FAO disorders characterized thus far (Rinaldo et al., 1999~. Among the more common deficiencies are medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency, long- chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency, carnitine uptake defect (primary carnitine deficiency), carnitine palmitoyltransferase (CPT) defi- ciencies I and II, carnitine-acylcarnitine translocase deficiency, and glutaric aci- demia type II (McInnes and Clarke, 2002~. Over 35 IEMs, including some FAO disorders, can now be identified through analysis of blood or bile specimens using a process of tandem mass spectrometry (Chace and Naylor, 2002~. In the United States, four laboratories are currently able to perform such analyses which are sometimes conducted as part of a "meta- bolic autopsy" in cases of sudden unexpected infant death (Wilcox et al., 2002~. Because early detection of IEM can improve the management of these disorders, there is also interest in including metabolic analyses as part of newborn screening programs. Analysis can also be done later, using the dried blood spot on the newborn screening card. Several states already include screening for certain IEMs as part of standard newborn testing, and studies and cost-benefit analyses of the use of tandem mass spectrometry for an expanded program of routine newborn

VACCINATIONS AND SUDDEN UNEXPECTED DEATH IN INFANCY 31 screening are in progress (Filiano et al., 2002; Naylor and Chace, 1999; Schoen et al., 2002). Anaphylaxis Anaphylaxis is a potentially life-threatening allergic response. It occurs when an allergen enters the blood stream, causing widespread activation of tissue mast cells associated with blood vessels. This disseminated mast cell activation causes increased vascular permeability and constriction of smooth muscle in the air- ways. There can be a loss of fluid from the blood, a drop in blood pressure, and swelling of connective tissue, leading to shock and organ damage (Parham,2000~. Anaphylaxis is a type I, immediate hypersensitivity immunologic reaction. Type I reactions can range from mild allergic rhinitis such as that triggered by pollens, to wheel and flare skin reactions following an insect bite, to severe and poten- tially fatal systemic anaphylaxis. An immediate reaction generally occurs within minutes of exposure to an antigen in a person who has been "sensitized" through a previous exposure to that antigen (Parham, 2000~. A second, much more slowly evolving "late phase" hypersensitivity reaction is also possible, 4 to 8 hours after the immediate reac- tion subsides. Whereas immediate reactions are the direct result of activation of mast cells, late phase reactions result from the effects of leukocytes (including eosinophils and type 2 helper T [Th21 cells) recruited to the site and the proinflammatory mediators and cytokines that they release there. (Busse and Lemanske, 2001; Parham, 2000~. Anaphylaxis is known to be a rare but causally related adverse event follow- ing the administration of some vaccines. Anaphylaxis related to vaccination has been discussed in detail in previous IOM reports (IOM, 1991; 1994a). Vaccines Routinely Administered During Infancy Current recommendations call for children to receive multiple doses of seven different vaccines over the course of their first year of life (see Figure 2~. These vaccines are the combination product diphtheria-tetanus-acellular pertussis vac- cine (DTaP) and individual vaccines against Haemophilus influenzas type b (Hib), hepatitis B (HepB), polio (IPV), and pneumococcus (PCV). Often, several vac- cines are administered at the same time. HepB is administered to many children within 24 hours after birth, making it the only vaccine routinely administered during the neonatal period. Children usually begin receiving the other recommended vaccines at about 2 months of age and receive additional doses of some of the vaccines at 4 and 6 months. The timing of these vaccine doses coincides with the period of peak incidence of SIDS. Most of the currently recommended vaccines have been added to the child-

32 of JO Up Ct I · - C) I I Ct ·~ 8 o == ~111NT: - v C) ·. 0 ~ N ~ " "o rip ~ 0o 0 E NE ~ mp ~ - r "E L ~ ~ 1::::::::::1 i::::::::::1 1::::::::::1 - , ~ ~ 2 C] I ~ _ ~ o o U] E _ ~1— m _ _ m .~ ._ Q T . _ .m s ~ .'. ~ ~ .0 ~ a i- ._ ~ A g c ~ E ~ _ ., E IO ~ , try A ._ > - o o 2 .~ ~ .~ 2 Q 2 I N - oo ~ ~ C s ~ s CL ~ O O CNt ~ O sm (~1 U~ C ~ - - ~ O E ~ <0 . 4~ ~ s~ ~ ~ ~ ., ~ ~ ~ ~ 8 o ~ ~ ~ s~ s ~ ° C ·o o ~ ~ ~ ·O o ~ (D, ., ., . ~ s .m O_ .> ,°. ·, o ~ ~ ,o U' o ~ ~ o 4~ ~ >, ,. ~ ~ U' == o E 8 2 ~ E O.C 12 s ~ ~ ° — ~ ~ E C, ~ o s ~d $ ~ ~ ~ ~ ~, CL

33 O ~ .= Q ~ ~ O ~a.~= ~~ '. f t-"~'$ Baa al O O 0 O _ ~ ~ O O o ~ ~ - ~ ~ ~ ~ ~ - o— ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ 3 ° ~ ~ S ~ O . ~ ~ ~ 9 a E ~ # a ° O # a 0 a 0 . e g ~ ~ a ~ # ~ # s ~ ~ ~ ! ~ s E ~ a a e ,~ a Q o E a, . A a o ~ ~ ° ~ C I ~ ~ ~ ~ ~ ~ e ~ E ~ ~ c in, .~ ~ A, so 3 '' ~ ~ s ~ ID ~ ~ us ~ ~ ° ~ s ~ ~ ~ ~ ~ ~ s ~ .= g ~ g O ~ ·m ~ ~ Q ~ ~ ~ o O ~ ~ X ~ ~ ~ ~ ~ s~ ~ ~ ~ ~ ~ ~ ~ m ~-~ o E 3 E 2 _ ~ ~ .> ·- ' ~ o s ~ ~o ~ .o F s ~ ~ ~ CD s 5 5 B o ~ 5 5 E a y E E . # ' # ' ~ ~, I # ~ a ~ y ~ (q,, 10 ~ O., c C ~ C ~ ' ~ o ° ~ ' ° ' 3 ° ~ .2 . s ~ C' s ~ CD ~ C Y s ~ ~ . , ~ ~o c' s ~ ~ m i: ~ 2 E · ' ~ ~ ~ io ~ ~ ar ~ ~ ~ ~ C I 8 ~ m 3 o ° ~ ~ C ~C E ° ~ ~ C I - , .c ~ ~u o ° ° ' ° E ~ ~ , ~ s ~ ~ o .~ ,_ ~ a, E ~ ~ E— E C E .Q.~ . , ~ · E r ~ I ]9 ~— ~~~ N g! ~~~ C O ~ ~ ~q i 0 E G _ ._ O Q · - C/' Z C~ m~ ~ O a) o E ~ C a) · Q U)- =0 ~ ., V, N S ~ N C ~ ,C ,C E ° E ~ ~,o _ .o ~ ~ ~n N O o E .~ ~ — .N ' {t tn .o E .o z E ~ a) 0 U j U o~ . .o~ ~ E ~ Q o ~o ·- ~ ~ N O ~ E _ ~ i C . - :O s ._ o E ~; ., s ~ i C . ~, ., i~ ._

34 IMMUNIZATION SAFFI Y REVIEW hood immunization schedule since 1990 (see Appendix C). Between 1963 and 1990, children in the United States generally received only the diphtheria-teta- nus-whole-cell pertussis vaccine (DTwP) and an oral polio vaccine (OPV) dur- ing their first year of life. Those vaccines were replaced by DTaP and IPV in the mid- 1990s. Hib and HepB were added to the childhood immunization schedule in 1991 and 1992, respectively. PCV was added in 2000. Two other recommended vaccines measles-mumps-rubella and varicella have not been considered by the committee for this report because they are usually administered for the first time after the first year of life at 12 to 15 months of age. SCIENTIFIC ASSESSMENT The committee's scientific assessment focuses on epidemiologic evidence regarding a possible association between vaccinations and sudden unexpected death in infancy, as well as on evidence concerning biological mechanisms through which vaccination might contribute to that outcome. One causal relationship established in reviews by previous IOM committees (IOM, 1991; 1994a) was not reexamined for the present report. This was the relationship for myocarditis as a consequence of infection with the vaccine-strain poliovirus used in OPV (IOM, 1994a). An infant died 4 days after receiving the second dose of OPV and DTP, and postmortem studies isolated vaccine-strain poliovirus from the infant's myocardium. The present committee concluded that further investigation of the role of vaccine-strain infections in infant deaths was not warranted however, because current U.S. immunization recommendations do not call for administration of any live-virus vaccines during the first year of life. Causality The committee's review of the epidemiologic evidence on the association between exposure to vaccines and sudden unexpected death in infancy focused on three outcomes: SIDS, SUDI, and neonatal death. Where available, evidence related to a single vaccine is reviewed first, followed by a discussion of evidence related to specific combinations of vaccines or to any combination of vaccines. The committee notes that individual vaccines are usually administered in combi- nation with other vaccines and are rarely, if ever, given individually. Passive surveillance data from the Vaccine Adverse Events Reporting Sys- tem (VAERS) on infant deaths following vaccination, including published re- ports, are briefly described when they are available for a given outcome and vaccine. As discussed in previous IOM reports (IOM, 1991; 1994a,b) and in other published articles (Chen, 2000; Ellenberg and Chen, 1997), such passive surveil- lance data are of limited value in assessing causality.

VACCINATIONS AND SUDDEN UNEXPECTED DEATH IN INFANCY 35 Included in the committee's review of the evidence on vaccines and sudden unexpected infant deaths is anaphylaxis (severe, immediate type I hypersensitiv- ity reaction), which on rare occasions can be fatal (CDC, 1996b). The biological mechanism underlying anaphylactic reactions to a foreign antigen (e.g., a food, drug, or environmental allergen) is well elucidated.2 When anaphylaxis occurs, it generally does so within a few hours of exposure to the antigen. The vast majority of these reactions can be readily resolved if medical treatment is received in a timely manner, but when treatment is not received, anaphylactic reactions can, although rarely, lead to death. To assure that the review of SUDI was comprehen- sive, the committee examined the evidence on infant death due to anaphylactic reactions. The committee also considered the possibility that SUDI could occur as the result of fatal late-phase anaphylactic reaction following a mild immediate- hypersensitivity reaction that was clinically missed. Such a delayed, unexpected reaction is discussed as a potential biological mechanism later in this report. The committee notes that for SIDS the focus was on reviewing epidemio- logic data that have become available since the completion of previous IOM reports on vaccine safety (1991; 1994a). The approach used in these reports for the review of the earlier epidemiologic evidence was judged comparable to the approach of the present committee. Allowing for a possible concern that SIDS deaths might be missed through misclassification, the committee took note of unpublished data that were presented at its scientific meeting in October 2002. These data, from a study conducted through the Vaccine Safety Datalink (VSD) project, showed no significant association between receipt of any specific vac- cines and deaths from all causes within 1 week or 1 month of vaccination for children between ages 1 month and 7 years (Ward, 2002~. A detailed review of the evidence concerning vaccination and infant deaths from all causes was judged as falling outside the committee's charge to focus on sudden unexpected infant death. Sudden Infant Death Syndrome The committee reviewed data on any relationship between SIDS and the individual DTwP, DTaP, HepB, Hib, and polio vaccines. The committee also reviewed data on any relationship between SIDS and specific combinations of vaccines or any combination of vaccines. The committee notes that individual vaccines are usually administered in combination with other vaccines and are rarely, if ever, given individually. 2For further discussion on anaphylaxis, see the biological mechanisms section of this report, as well as Busse and Lemanske (2001) and Parham (2000).

36 DTwP Vaccine IMMUNIZATION SAFER EVIL Both the 1991 and 1994 IOM vaccine safety committees concluded from their reviews that the evidence favored rejection of a causal relationship between DTwP vaccine and SIDS (IOM, 1991; 1994a). Detailed descriptions of the stud- ies reviewed can be found in the earlier IOM reports. Since the completion of those two reports, no additional epidemiologic studies examining the association between exposure to DTwP vaccine and SIDS have been published. In 1997 DTaP replaced DTwP as the recommended vaccine in the childhood immuniza- tion schedule in the United States. Given that no additional analytical studies are available, the committee found no reason to reconsider the conclusions of the previous committees. Thus, the committee finds no basis for a change in the prior conclusion that the evi- dence favors rejection of a causal relationship between DTwP vaccine and SIDS. DTaP Vaccine Germany. In a prospective multicenter trial in Germany, Schmitt and col- leagues (1996) examined data on 22,505 infants to assess the safety, reactivity, and immunogenicity of three doses of DTaP vaccine. Subjects were recruited from pediatric outpatient clinics and private practices in six areas of the former West Germany. Excluded from the study were infants with any signs of previous pertussis infection, any other acute or chronic illness, or any indication of a possible allergic reaction to one of the vaccine components. The infants received their first dose of DTaP at 8 to 24 weeks of age, and the second and third vaccine doses after 28- to 35-day intervals. In accordance with the German immunization schedule, infants may also have received Hib vaccine and/or OPV. Researchers reported 95 percent power to detect rare events with an incidence of 1 per 10,000. Parents were given diaries to record any serious adverse events occurring over the 28 to 35 days after each vaccination. This provided for an observation period of approximately 3 months following receipt of the first dose. Serious adverse events included hospitalizations; events that were fatal, life threatening, or disabling; congenital abnormalities; or the occurrence of malignancies. Also recorded were severe early onset reactions, such as anaphylaxis, and other symp- toms considered serious by investigators. Researchers focused their analysis on SIDS, necrologic events, and hypotonic-hyporesponsive episodes. A total of 153 (0.23%) serious adverse events were reported for the 67,000 vaccine doses administered during the study period. Of these, nine were fatalities of which none were related to exposure to DTaP vaccine, according to the au- thors. Seven of the deaths were attributed to SIDS: three occurred 8 to 14 days after vaccination, another three occurred 15 to 30 days after vaccination, and one occurred 2 months after vaccination. One sudden unexpected death was reported in a 14-month-old, 10 months after receipt of the third dose. The authors reported

VACCINATIONS AND SUDDEN UNEXPECTED DEATH IN INFANCY 37 that the observed incidence of SIDS (0.031%) in the study was below the ex- pected annual incidence in the general population (0.1-0.17%~. The study is limited by the lack of a control group. In addition, the basis for the authors' conclusion that the fatalities were not related to vaccination was not made clear in the paper. It was also unclear how the cause of death was assessed. These flaws limit the study' s contribution to the committee' s causality assessment. Causality Argument The epidemiologic evidence regarding the relationship between SIDS and receipt of DTaP vaccine consists of one uncontrolled observational study (see Table 2~. The authors of that study (Schmitt et al., 1996) found no indication of an elevated incidence of SIDS in vaccinated infants. The committee also examined a published report (Braun et al., 2000) on passive surveillance data from VAERS for infants who received a pertussis-containing vaccine (DTaP, DTwP, or DTwPH [diphtheria, tetanus, whole-cell pertussis, and Hib vaccine]) between January 1, 1995, and June 30, 1998. Information on SIDS deaths was not provided, but the data appeared to suggest that DTaP was associated with fewer reports of adverse events than was DTwP. The VAERS data appear consistent with clinical trial results where fewer reactions were reported after receipt of DTaP than after receipt of DTwP vaccine (Decker et al.,1995; Decker and Edwards, 1996; Greco et al., 1996). The committee concludes that the evidence is inadequate to accept or reject a causal relationship between DTaP vaccine and SIDS. However, given the indication that DTaP is associated with fewer adverse reactions than DTwP, the committee found no reason to suspect that a causal relationship might exist between DTaP and SIDS when the evidence indicates that none exists with DTwP. Other Vaccines Hepatitis B Vaccine. An earlier IOM committee found no published studies on the relationship between HepB vaccine and SIDS. Only VAERS reports of SIDS following immunization with HepB vaccine were available. Based on those data, the earlier committee concluded that the evidence was inadequate to accept or reject a causal relationship between HepB vaccine and SIDS (IOM, 1994a). The present committee found no epidemiologic studies that examine the associa- tion between HepB vaccine and SIDS that had been published since the previous IOM report. Niu and colleagues (1999) describe 18 reports to VAERS between 1991 and 1998 of neonatal deaths following HepB vaccination. Autopsy reports were available for 17 cases, of which 12 were diagnosed as SIDS.3 Three cases initially attributed to SIDS were assigned other diagnoses following autopsy. gation. 3Dea~hs during the neonatal period are usually not attributed to SUDS, despite a negative investi-

38 IMMUNIZATION SAFFI Y REVIEW TABLE 2 Evidence Table: Exposure to DTaP Vaccine and Sudden Infant Death Syndrome Citation Design Population Assessment of Vaccine Exposure Outcomes Schmitt et al. Cohort (1996) 22,505 infants, each receiving 3 doses of DTaP Germany First dose of DTaP at age 8 to 24 weeks; 2nd and 3rd doses after 28- to 35-day intervals. Infants may also have received Hib and/or OPV. DTaP doses recorded by investigators as doses were administered. Serious at recorded l over 28- t period aft vaccinatic identified investigate Researche SIDS, net events, an hyporespc Children events fol year or lo Hib Vaccine. An earlier IOM vaccine safety committee found no published studies on the relationship between Hib vaccine and SIDS. Only VAERS reports following immunization with Hib vaccine were available. Based on those data, the earlier committee concluded that the evidence was inadequate to accept or reject a causal relationship between Hib vaccine and SIDS (IOM, 1994a). The present committee identified no studies on the relation between Hib and SIDS that had been published since the previous IOM report. Polio Vaccines. An earlier IOM vaccine safety committee noted that the possible causal relation between polio vaccines and SIDS has rarely been studied. Most studies examined the risk of SIDS after exposure both to DTwP and polio vaccines, and only one study reported the risk estimate for SIDS after receipt of OPV. VAERS reports of SIDS following OPV immunization were also available. A detailed description of the few studies reviewed by that group concerning OPV can be found in its report (IOM, 1994a). Based on the available data, the earlier committee concluded that the evidence was inadequate to accept or reject a causal relationship between polio vaccines and SIDS (IOM, 1994a). In September 1996, a recommendation was made to use IPV in place of OPV for the first two doses of the childhood polio immunization schedule in the

VACCINATIONS AND SUDDEN UNEXPECTED DEATH IN INFANCY rant 39 Contribution to Outcomes Results Comment Causality Argument t age 8 to Serious adverse events, Serious Adverse Observed SIDS The study provides rd doses recorded by parents Events: 153 incidence (0.031%) weak evidence of no Intervals. over 28- to 35-day Fatalities = 9 was lower than association between period after each SIDS = 7 cases the annual SIDS DTaP and SIDS; e received vaccination or Incidence = 0.031 incidence in weaknesses in the identified by per 100 general population study limit its investigators. (0.1-0.17%). contribution to the . by Authors note that causality argument. s were Researchers focused on fatalities were not SIDS, necrologic related to vaccine, events, and hypotonic- but do not state hyporesponsive episodes. reasons for this conclusion. Also, Children with necrologic no SIDS case events followed for 1 definition provided, year or longer. which may lead to misclassification bias. There were no controls in this study. United States. These vaccine doses are usually given at ages 2 and 4 months of age. Since the 1994 report, the present committee found only one published pas- sive surveillance study concerning OPV or IPV and SIDS. Wattigney and col- leagues (2001) examined VAERS reports submitted between January 1,1991 and December 31, 1998 that mentioned receipt of either IPV or OPV. Both vaccines were usually co-administered with other vaccines, including DTaP, Hib, and HepB. The authors note no indication of a marked change in reported adverse events following the recommendation for use of IPV. There were 72 reports of death following receipt of OPV or IPV in 1997 and 70 reports in 1998. A majority of these deaths were attributed to SIDS (44 in 1997 and 45 in 1998~. From January 1991 to September 1996, SIDS was mentioned in 8.6 percent of the IPV- related reports and 20.3 percent of OPV-related reports, concerning infants age 1 to 6 months. From October 1996 to December 1998, SIDS was mentioned in 22.2 percent of the IPV-related reports and 22.1 percent of the OPV-related reports in the same age group. The passive surveillance data available from VAERS do not contribute to assessing causality. Since the 1994 report, the present committee found no addi-

40 IMMUNIZATION SAFFI Y REVIEW tional epidemiologic studies concerning OPV and SIDS. The committee also notes that as of 2000, OPV is no longer part of the recommended childhood schedule in the United States. Neither the present committee nor the earlier IOM committee found epidemiologic studies that have examined the relationship be- tween IPV and SIDS. Causality Conclusion The committee concludes the evidence is inadequate to accept or reject causal relationships between SIDS and the individual vaccines Hib, HepB, OPV, and IPV. Since the 1991 and 1994 IOM reports, no additional epidemio- logic studies have been published. The limited data available are drawn from VAERS case reports, which alone are insufficient to establish any causal link. Multiple Vaccines Controlled Observational Studies United Kingdom. Fleming and colleagues (2001) conducted a case-control study to examine the association between immunization status under an acceler- ated immunization program and SUDI, including SIDS. In 1990, the immuniza- tion schedule in the United Kingdom was changed to administer DTwP and OPV at 2,3, and 4 months, instead of at 3,5, and 9 months. In 1992, Hib was added to the schedule. The study of immunization status was part of a study of sudden unexpected death in infancy for the Confidential Enquiry into Stillbirths and Deaths in Infancy (the CESDI SUDI study)(CESDI SUDI, 2000). The cases were infants aged 1 week to 1 year who died suddenly and unex- pectedly in various parts of England between February 1993 and January 1995 or April 1995 and March 1996. The study included infants whose deaths were explained and infants whose deaths were unexplained and diagnosed as SIDS. As described in another report on the CESDI SUDI study, infant deaths were identi- fied through a network of professionals and lay organizations (Leach et al., 1999). This method was found to have identified 98.3 percent of SUDI that occurred in the study regions. Each case was matched with four controls on the basis of age, locality, and time of last sleep. The controls for each case were selected from the population served by the health visitor who had been assigned to the infant who died.4 Interviews were conducted with the families of case and control infants generally within a week of the index death. For each control, a "reference sleep" 4A health visitor is a nurse with special training in community-based child health surveillance (Leach et al., 1999).

VACCINATIONS AND SUDDEN UNEXPECTED DEATH IN INFANCY 41 was identified that corresponded to the time of death of the matching case. Immu- nization histories were obtained from parental records. Immunization exposure was based on receipt of any component of the immunization program before a case infant's last sleep or before a control infant's reference sleep. For the case infants, a multidisciplinary team established a cause of death after a full pediatric postmortem examination, conducted according to a standard protocol. A total of 456 sudden unexpected infant deaths were identified, of which 363 were classified as SIDS. Families of 325 of these infants were interviewed (90%), and immunization histories were available for 303 of the 325 infants (93%~. For the remaining 93 explained deaths, 72 families were interviewed (77%), and immunization histories were available for 65 of 72 infants (90%~. A total of 1,588 controls were selected; immunization histories were available for 1,515 of the controls (95%~. (Analysis of the explained deaths is discussed in the subsequent section on SUDI.) The infants who died of SIDS were less likely to have been immunized than their matched controls. A univariate analysis gave an odds ratio for SIDS of 0.48 (95% CI 0.36-0.63) for infants who began or completed the immunization pro- gram. After adjusting for matching, the odds ratio was 0.23 (95% CI 0.14-0.37~. The difference between SIDS infants and control infants was consistent across the different age groups. A multivariate analysis that controlled for possible confounders such as birth weight, infant age, and socioeconomic variables pro- duced an odds ratio of 0.45 (95% CI 0.24-0.85~. The protective effect of immuni- zation in relation to SIDS was no longer seen when the analysis controlled for highly significant risk factors in an infant's sleeping environment (OR=0.67, 95% CI 0.31-1.43), but none of the analyses showed an elevated risk for SIDS. The authors concluded that immunization did not lead to SIDS, and that the results were consistent with a possible protective effect from immunization. France. Jonville-Bera and colleagues (2001) conducted a case-control study to examine the association between SIDS in infants between the ages of 30 and 90 days and exposure to diphtheria-tetanus vaccine, with or without exposure to whole-cell pertussis, polio, or Hib vaccines. Between February 1995 and March 1997, 28 SIDS Centres in France identified 114 cases of SIDS or sudden unex- pected death (SUDI) at ages 30 to 90 days for infants with a gestational age of more than 34 weeks. SIDS was defined as the sudden death of any infant or young child that is unexpected by medical history and for which an autopsy fails to demonstrate an adequate cause of death. SUDI was defined as the sudden death of any infant in good health until death for whom investigations failed to show an adequate explanation of death but without an autopsy. Of the 114 deaths, there were 90 SIDS cases (79%~; the other 24 cases were categorized as SUDI, but were included in the analysis. (A separate analysis of the SUDI cases is described below.) Additional information on each infant was obtained from an interview with the parents within 3 months of the infant's death.

42 IMMUNIZATION SAFFI Y REVIEW Three controls were selected for 113 of the cases; one case had only two controls. The controls were matched to cases according to age, sex, and maternity unit of birth. They were recruited by identifying the first 10 infants born after the index case in the same maternity unit; the first three infants whose parents gave consent served as the controls for that case. The consenting parents provided information through a telephone interview. Immunization histories were obtained from the health and development record. Vaccine exposure consisted of at least one dose of vaccines for diphthe- ria-tetanus and pertussis, polio, and/or Hib before death for cases and before a comparable age for controls. Other vaccine exposures for some infants included BCG and HepB. The unadjusted odds ratio for SIDS with exposure to vaccines for diphtheria, tetanus, pertussis, and polio, with or without Hib (DTPP _ Hib), was 0.87 (95% CI 0.43-1.68~. For infants who also received BCG vaccine, the odds ratio was 1.85 (95% CI 0.21-42.76~; for those who also received HepB, the odds ratio was 0.89 (95% CI 0.19-3.64~. Multivariate analysis, using a conditional logistic re- gression model, controlled for possible confounders, such as illness in the week before death, maternal smoking, birth weight, sleeping position, use of a firm mattress, breastfeeding, and sex. The multivariate odds ratio was 1.08 (95% CI 0.49-2.36~. The study had 74 percent power at a 5 percent level of significance to detect a twofold increase in the risk of SIDS. The authors conclude that receipt of DTPP +/-Hib was not a risk factor for SIDS for infants at ages 30 to 90 days. The authors note possible biases in the study, however. Selection bias in identification of cases was considered minimal because the study included most of the SIDS cases reported on death certificates. Determination of SIDS as a cause of death was considered more accurate for study cases than for death certificates, but misclassification bias could have existed because of the inclusion of the SUDI cases in the analysis. Selection bias could also arise from the exclu- sion of case or control infants whose parents could not be contacted or who did not agree to participate in the study. Recall bias may have affected cases and controls differently (median time from death to interview was 8.5 days for cases and 110 days for controls), but all immunization data were obtained separately from official records. Jonville-Bera and colleagues (1995) also conducted an earlier retrospective case-control study to assess the risk for SIDS in infants following exposure to tetravalent diphtheria-tetanus-pertussis (whole-cell)-polio vaccine (Tetracoq or DTCP) or to trivalent diphtheria-tetanus-pertussis (whole-cell) vaccine (DTC) plus polio vaccine. The cases consisted of 118 SIDS deaths of infants born between January 1, 1983 and December 31, 1987, who were identified through referrals to one of the authors. SIDS was defined as a sudden death not explained by the infant's medi- cal status. The diagnosis was based on a clinical examination, history of death, and an autopsy, when performed. Fourteen additional SIDS cases were excluded

VACCINATIONS AND SUDDEN UNEXPECTED DEATH IN INFANCY 43 because of lack of data. Two or three controls were selected for each case. The 332 controls in the study were matched to cases by sex, month, and year of birth, and they were seen by a medical practitioner within 2 weeks before or after the death of the matching case. To prevent misclassification bias, any child who died within one month after vaccination was excluded from the control group. The controls were selected from three sources: urban and rural clinics and private pediatric practices. Cases were considered vaccinated if they had received at least one vaccine dose. Controls were considered vaccinated if they had received at least one vac- cine dose by the age at which the matching case died. The article does not indicate whether information on immunizations was obtained from reports by parents or from medical records. Using a Miettinen X test (a test of independence for a retrospective case- control study) and an estimate of relative risk, the odds ratio for SIDS in vacci- nated children was 1.9 (95% CI 0.9-3.9~. The authors also commented on an analysis of the SIDS deaths that occurred at less than 3 months of age (68 cases and 191 controls). Six of the SIDS cases had been vaccinated, but none of the controls had. The difference was statistically significant (% = 3.97, p < 0.0001~. The authors cite several possible biases in this study. First, controls who were seen by private pediatricians were significantly more likely to be vaccinated than the controls from the urban or rural clinics. In addition, this group was vaccinated at a younger age than the other control groups. Thus, the usual source of care for the SIDS cases could have influenced their vaccination status, but it was not possible to match cases and controls in terms of source of care. Second, selection bias may also have occurred because cases and controls were not drawn from the same source. Differences between the two groups in terms of socioeco- nomic status or other factors related to the risk for SIDS could not be assessed. In addition, misclassification bias was possible because autopsies were performed for only 33 of the SIDS cases (28%~. New Zealand. Mitchell and colleagues (1995) conducted a case-control study to examine the association between immunization and SIDS in New Zealand. Data were obtained from the New Zealand Cot Death Study, which included 78 percent of all live births in New Zealand between November 1,1987 and October 31, 1990. A total of 716 postneonatal deaths were identified, of which 485 were classified as SIDS. Autopsies were performed for 474 (97%) of the SIDS deaths. A total of 1,800 controls was randomly selected from all births in the study regions (except home births). The controls were matched by age and randomly assigned to a time of day to generate a distribution corresponding to the distribu- tion of times of death of the cases. Parents of the SIDS cases were interviewed within one month of the death, and parents of control infants were interviewed within one week of a reference date and time.

44 IMMUNIZATION SAFFI Y REVIEW Immunization histories were determined on the basis of the health and devel- opment record, which is kept by the parents and completed by the general practi- tioner during check-ups. Infants were considered immunized if they had received any of the vaccines that were appropriate for their age at death (cases) or at the reference date (controls). The New Zealand immunization program includes the following required vaccinations: BCG (at birth for infants at risk), DTwP at 6 weeks, DTwP and polio at 3 and 5 months. Requirements for HepB vaccination changed over the course of the study. Before March 1987, plasma-derived vac- cine was given at birth, 6 weeks, and 3 and 15 months to infants born to mothers who were HBeAg and HBsAg positive. From March 1987 through February 29, 1988, HepB was given to infants born to HBsAg-positive mothers and to all infants in selected high-risk regions. After February 29,1988, all infants received the vaccine. Beginning December 1, 1989, exclusive use of the recombinant vaccine began, with doses given at 6 weeks and at 3 and 15 months. Data from obstetric records, parental interviews, and immunization records were available for 317 cases and 1,524 controls. Those who were not interviewed were more likely to be Maori5 and to have smoked during pregnancy. Cases with missing immunization records were more likely to be children of a single Maori parent, who lived in the North Island. The analysis tested for an association between SIDS and, unlike other studies that examine exposure to immunizations, lack of age-appropriate immunizations. The univariate odds ratio was 0.9 (95% CI 0.7-1.1) at birth, 2.1 (95% CI 1.4-3.1) for immunization status at 6 weeks, 2.5 (95% CI 1.6-4.0) at 3 months, and 2.0 (95% CI 1.1-3.9) at 5 months. A multivariate analysis controlled for potential confounding from sociodemographic characteristics of the family and factors related to the pregnancy, the infant, and the postnatal environment. The adjusted odds ratios for the risk of SIDS were 1.1 (95% CI 0.8-1.6) at birth, 2.1 (95% CI 1.2-3.5) at 6 weeks, 1.3 (95% CI 0.7-2.5) at 3 months, and 2.6 (95% CI 0.9-7.5) at 5 months. Recognizing the potential for bias because immunization status was un- known for a greater proportion of cases than controls, the researchers further analyzed the data to include cases without an immunization record. With the assumption that all cases with missing immunization records had been immu- nized (the assumption most likely to provide an indication of any increased risk associated with immunization), no changes in significance were seen in the multi- variate odds ratios for birth, 3 months, and 5 months. The odds ratio for not being immunized at 6 weeks was no longer significant (OR = 1.6, 95% CI 1.0-2.7~. A larger proportion of controls than cases were found to have been immu- nized within 4 days of their reference date or date of death. An analysis of the risk for SIDS within 0 to 9 days of immunization showed no increase in risk for any Indigenous people of New Zealand.

VACCINATIONS AND SUDDEN UNEXPECTED DEATH IN INFANCY 45 interval and a significant reduction in risk at 4 days after immunization (OR = 0.5,95% CI 0.2-0.9~. Controlling for confounding factors did not alter the results. The authors noted some possible limitations of their study. Controls were more likely to have immunization records, possibly contributing to a selection bias. As noted, a sensitivity analysis was performed to test the effect of either full immunization or no immunization among those without records. The assumption of full immunization failed to show a significant risk for SIDS. The authors also acknowledge the possibility of unrecognized confounding from factors related to the risk for SIDS or for immunization. Efforts were made, however, to control for possible confounding from sociodemographic factors, differences in use of health care services, and prior illness. The authors concluded that the findings suggest there is no increased risk of SIDS with hepatitis B immunization or DTwP immu- nization at 6 weeks of age. Uncontrolled Observational Study California. Black and others (1993) examined the safety of the combination vaccine product containing the oligosaccharide conjugate Hib vaccine, diphtheria and tetanus toxoids, and whole cell pertussis vaccine (HbOC-DTwP) compared with HbOC and DTwP given separately. Between November 1,1990 and July 26, 1991, 2-month-old infants were enrolled in the study from the 13 largest centers of the Kaiser Permanente Medical Care Program (KPMCP), a prepaid health plan with an ethnically and socioeconomically diverse membership of 2.4 million people in Northern California. A total of 6,644 infants received 18,359 doses of the combined DTwP and Hib vaccine, and 3,913 infants received 10,196 doses of each of the two vaccines in separate injections. The vaccines were given at 2, 4, and 6 months of age. The outcomes studied included SIDS, local and systemic reactions, hospitalizations, and emergency room visits. Nine cases of SIDS were identified: six deaths oc- curred among infants who received the combined vaccine, and three deaths oc- curred among those who received the vaccines separately. Autopsies were per- formed for all of the SIDS deaths. No temporal clustering of SIDS cases was observed. The deaths occurred from 1 to 67 days following receipt of the com- bined vaccine and from 1 to 51 days after receipt of the two separate vaccines. The authors state that rate of SIDS deaths in the study was compared with rates in the five counties served by KPMCP and among infants enrolled in KCMCP who did not participate in the study. The SIDS rates in those comparison populations were not reported in the article. Ecologic Study Scotland. Essery and colleagues (1999) conducted an ecological analysis that compared SIDS rates in Scotland before and after an October 1990 change in

46 IMMUNIZATION SAFFI Y REVIEW the immunization schedule that called for immunization to begin at 2 months rather than at 3 months. The incidence of SIDS in Scotland for the years 1986- 1990 was compared with the rates for 1991-1996, by age at death in months. Rates were lower in the 1991-1996 period for ages 2 to 12 months. The largest differences were seen at ages 2 to 6 months, and the maximum difference was at 4 months (the ratio of 1991-1996 rates to 1986-1990 rates was 0.31~. The com- mittee judged that this study contributed little to the causality argument because of its ecological nature and because of the confounding effect on changes in SIDS rates of a "back to sleep" campaign that began in October 1991. Passive Surveillance Data VAERS. Silvers and colleagues (2001) reviewed all deaths reported to VAERS from July 1990 through June 1997. FDA physicians reviewed autopsy reports, death certificates, and case histories included in the reports, and they classified the causes of deaths according to the following categories: congenital, infectious, neoplastic, SIDS, other, or unknown. A total of 1,266 fatalities were reported, of which 531 were SIDS. SIDS accounted for 47.6 percent of all deaths reported to VAERS, and 69.5 percent of all reported infant deaths. The majority of SIDS deaths occurred at 2 to 4 months of age (70%~. The median interval between immunization and SIDS deaths was 3 days, with 25 percent occurring within 24 hours of vaccination and another 25 percent occurring 1 week or more after vaccination. The five most common vaccine combinations in the pediatric cases were the following: DTP, Hib, and OPV; DTP, Hib, OPV, and Hib; DTP, OPV, and DTPH; Hib and OPV; and DTPH and OPV. The number of SIDS deaths peaked at 100 cases during the 1992-1993 study year and steadily declined in subsequent years. In 1996-1997, there were 49 reports of SIDS deaths. These changes in the numbers of VAERS reports reflect a broader change in the epidemiology of SIDS as a result of the "Back to Sleep" campaign; moreover, the consistency of these trends would be expected if a substantial proportion of SIDS deaths reported to VAERS were coincidental. Because the data from VAERS are produced by passive surveillance, this study contributes little to the committee' s causality argument. The committee also received summary data from CDC on reports of SIDS received by VAERS from January 1991 through November 2002. A total of 763 unique reports (excluding foreign reports) concerning infants less than 12 months of age mentioned SIDS in conjunction with receipt of multiple vaccines. Ap- proximately 51 percent of the reported deaths occurred within 3 days after vacci- nation. Cases were identified on the basis of terms (e.g., SIDS) used in the VAERS report, not on a formal medical diagnosis.

VACCINATIONS AND SUDDEN UNEXPECTED DEATH IN INFANCY Causality Argument 47 In the four controlled observational studies reviewed by the committee, ex- posure to multiple vaccines was not associated with an elevated risk of SIDS deaths (see Table 31. The committee notes that most of the studies reviewed were on multiple vaccines since most vaccines are usually administered in combina- tion with other vaccines. These studies are subject to limitations, often related to a possible selection bias because of inclusion of SUDI cases in some of the analyses, controls whose immunization records could not be located, or parents who could not be interviewed or did not agree to participate in the study. Never- theless, findings from studies in three different countries produced consistent results. One study (Fleming et al., 2001) suggested a protective effect, but not significant, of vaccines against SIDS. The committee also reviewed an uncon- trolled cohort study, an ecologic study, and a report on VAERS data. The find- ings in these latter studies contribute little to the assessment of causality, but provide no signals of risks. The committee concludes that the evidence favors rejection of a causal relationship between exposure to multiple vaccines and SIDS. Sudden Unexpected Death The committee reviewed data on the association between exposure to mul- tiple vaccines and all sudden unexpected death in infants (SUDI). The section on multiple vaccines and all sudden unexpected death in infants is followed by the section on anaphylaxis. As anaphylaxis is known to be a rare but causally related adverse event following the administration of some vaccines, the committee reviewed evidence regarding anaphylaxis following vaccination in infants. Multiple Vaccines Controlled Observational Studies United Kingdom. Fleming and colleagues (2001) in the case-control study described above examined the association between immunization status under an accelerated immunization program and SUDI. The cases were infants aged 1 week to 1 year who died suddenly and unexpectedly in various parts of England between February 1993 and January 1995 or April 1995 and March 1996. The study included infants whose deaths were explained and infants whose deaths were unexplained and diagnosed as SIDS. The findings on SIDS were discussed in the previous section. A total of 456 sudden unexpected infant deaths were identified, of which 93 were explained. Interviews were conducted with parents of 72 of the 93 infants (77%), and immunization histories were available for 65 of those 72 infants

48 IMMUNIZATION SAFFI Y REVIEW TABLE 3 Evidence Table: Exposure to Multiple Vaccines and Sudden Infant Death Syndrome Citation Design Assessment of Population Vaccine Exposure Outcomes Fleming et al. Case-control (2001) Jonville-Bera et al. Case-control (2001) Cases: sudden At least one dose of DTP, unexpected deaths, OPV, and/or Hib. age 1 week to <1 year, from Feb 1993-March 1996. Immunization information from parent-held records. 303 SIDS Infant considered immunized if 65 explained deaths received any component of the Controls: 1,515 infants, matched according to age, locality, and time of reference sleep England . . . . ~mmun~zahon program prior to last or reference sleep. Cases: 114 sudden At least one dose of diphtheria, unexpected deaths tetanus _ pertussis, (90 SIDS, 24 SUD) poliomyelitis, or Haemophilus of infants between vaccine (DTPP +/-Hib). ages 30 and 90 days, Feb 1995- Other vaccines received: March 1997. BCG, HepB. Controls: 341 Vaccine exposure determined infants, matched from Health and Development for sex, gestational Record. age, and born immediately after the case in the same maternity unit France Multi-centre Explained sudden un (unexplai~ SIDS) Multidisci committee cause of c pediatric ] examinati protocol. Explained unrecogni accidental congenital non-accid metabolic bowel ohs bronchop~ dysplasia, cardiomy~ SIDS = so unexpecte for which mortem en to demon adequate SUDI = so infant in death for investigat show adept explanatic mortem e

VACCINATIONS AND SUDDEN UNEXPECTED DEATH IN INFANCY n Infant 49 Outcomes Results Comment Contribution to Causality Argument DTP, Cation from munized if ent of the m prior Leep. diphtheria, mophilus b). ted: termined elopment Explained or unexplained SIDS vs. Controls Authors noted that The study provides sudden unexpected deaths OR (95% CI ) results were strong evidence of no (unexplained deaths = consistent with a association between SIDS) Univariate possible protective exposure to multiple 0.48 (0.37-0.63) effect from vaccines and SIDS. Multidisciplinary committee established Mulitvariate cause of death after full 0.45 (0.24-0.85) pediatric postmortem examination to a standard Adjusted for protocol. sleeping environment Explained deaths: 0.67 (0.31-1.43) unrecognized infection, accidental injury, congenital anomalies, non-accidental injury, metabolic disorders, bowel obstruction, bronchopulmonary dysplasia, and cardiomyopathy. Explained deaths vs. controls Univariate OR (95% CI) 0.51 (0.21-1.26) SIDS = sudden death, SIDS unexpected by history and Univariate OR for which thorough post (95% CI) mortem examination fails DTPP + Hib: to demonstrate an 0.87 (0.43-1.68) adequate cause of death. Plus: SUDI = sudden death of BCG: 1.85 infant in good health until (0.21-42.76) death for whom HepB: 0.89 investigations failed to (0.19-3.64) show adequate explanation; no post mortem examination. Multivariate OR (95% CI) 1.08 (0.49-2.36) . . . mmumzahon. Possible The study provides misclassification weak evidence of no bias from inclusion association between of SUDI cases. exposure to multiple Possible selection vaccines and SIDS in bias from missed cases or from exclusion of cases or controls who could not be located or did not agree to participate. Possible differential recall bias between cases and controls because length of time between death (or reference date) and interview differed by almost 100 days. early infancy; weaknesses in the study limit its contribution to the causality argument. continued on next page

TABLE 3 Coated Citation Design Population Assessment of Vaccine Exposure Outcomes JonvUle-Bera et at. Specie ( 1993) case-con~1 Cases: 118 SIDS deaths of haunts born between January 1983- Dece~er 1987 Controls: 332 haunts matched Scoring ~ sex, bow dam, Ad Me ~ dead France At least 1 dose of te~av~ent dipbtber1~-tetanus-pertussis- poHo vaccine or ~v~ent dipbtber1~-tetanus-pertussis . . .. . vaccine plus polio vaccine. Source of 1n~rm~1on on 1m~n~on emus not repoded. SIDS = s- expl~ned status; do on clinica. used of autopsy rc perform

VACCINATIONS AND SUDDEN UNEXPECTED DEATH IN INFANCY 5 Outcomes Results Comment Contribution to Causality Argument ravalent rtussis- ~Llent rtussis Lccine. n on not SIDS = sudden death not OR (95% CI) Possible The study provides explained by medical for SIDS misclassification weak evidence of no status; diagnosis based bias because association between on clinical examination, All Children autopsy performed exposure to multiple history of death and 1.9 (0.9-3~9) for only 28% of vaccines and SIDS; autopsy report, when performed Age < 3 months No OR reported (Miettinen x test: 3.97, p = 0.0001) SIDS cases. Possible health- care-seeking bias because controls from private pediatricians more often vaccinated infants at a younger age. Possible selection bias because cases and controls selected from different populations. Cases were identified from referrals by general practitioners; controls were selected from urban and rural clinics and private practices. Information on possible confounders , . . E.g., socioeconomic status) unavailable. weaknesses in the study limit its contribution to the causality argument. continued on next page

52 TABLE 3 Continued IMMUNIZATION SAFFI Y REVIEW Citation Design Assessment of Population Vaccine Exposure Outcomes Mitchell et al. Case-control (1995) Cases: 317 SIDS At least one dose of BCG, deaths, infants aged DTP, polio, or HepB at 28 days to 1 year specified ages (birth, 6 weeks, (postneonatal), 3 months, 5 months). from Nov 1987 Immunization status determined through Oct 1990. from health and development record (HDR), which is kept Controls: 1,524 by parents and completed by infants born during the general practitioner. the study period New Zealand Cot Death Study SIDS

VACCINATIONS AND SUDDEN UNEXPECTED DEATH IN INFANCY 53 Outcomes Results Comment Contribution to Causality Argument BCG, at 6 weeks, determined lopment is kept feted by her. SIDS OR for SIDS if not immunized (95% CI) The study provides weak evidence of no association between exposure to multiple Univariate records more likely vaccines and SIDS; Birth 0.9 (0.7-1.1) to be missing for weaknesses in the 6 weeks 2.1 cases than controls. study limit its (1.4-3.1) Parents of excluded contribution to the 3 months 2.5 (1.6-4.0) 5 months 2.0 (1 ~ 1-3.9) Authors note possible selection bias, with . . . 1mmunlzahon Multi v ari ate Birth 1.1 (0.8-1.6) 6 weeks 2.1 (1.2-3.5) 3 months 1.3 (0.7-2.5) 5 months 2.6 (0.9-7.5) Sensitivity analysis Assumed excluded cases with incomplete . . . 1mmunlzahon records were fully . · . mmunlzea: 6 weeks 1.6 (1.0-2.7) for other time periods, OR changed slightly OR for SIDS based on time since . . . mmunlzahon (0 to 9 days! 4 days: 0.5 (0.2-0.9) other intervals not significant cases tended to be single and Maori. Cases and controls excluded for lack of parent interview were more likely to have been Maori and have a mother who smoked during pregnancy. More cases (35%) than controls (15%) were excluded from the analysis. causality argument.

54 IMMUNIZATION SAFFI Y REVIEW (90%~. Each case was matched with four controls on the basis of age, locality, and time of last sleep. A total of 1,588 controls were selected for the entire study; immunization histories were available for 1,515 of the controls (95%~. Infant deaths were identified through a network of professionals and lay organizations (Leach et al., 1999~. This method was found to have identified 98.3 percent of SUDI in the study regions. Cause of death was established by a multidisciplinary team after a full pediatric postmortem examination, conducted according to a standard protocol. Immunization histories were obtained from health records held by parents. Immunization exposure was based on receipt of any component of the immunization program before a case infant's last sleep or before a control infant's reference sleep. Of the infants who died of explained causes, 54 percent received some im- munization compared with 61 percent of the control infants, a difference that was not statistically significant (univariate odds ratio was 0.51 [95% CI 0.21-1.261~. For those who died of infection, the univariate odds ratio (OR) was 0.44 (95% CI 0.11-1.65~. The authors concluded that immunization was not associated with sudden unexpected death in infancy. France. The risk for sudden unexpected death in immunized infants between the ages of 30 and 90 days was examined by Jonville-Bera and her colleagues (2001) in a case-control study described above in the review of studies on SIDS. Immunized infants were exposed to diphtheria-tetanus vaccine, with or without exposure to whole-cell pertussis, polio, or Hib vaccines. The study identified 114 sudden deaths of 30- to 90-day-old infants who had a gestational age of more than 34 weeks. These deaths occurred between February 1995 and March 1997. Of the 114 deaths, 24 cases were categorized as SUDI defined as the sud- den death of any infant in good health for whom investigations failed to show an adequate explanation of death but without an autopsy. Controls were matched to cases according to age, sex, and maternity unit of birth. The analysis showed that immunization was not associated with SUDI (OR = 0.42, 95% CI 0.06-1.8~. Causality Argument The committee reviewed two published studies (see Table 4) that examined the association between exposure to multiple vaccines and sudden unexpected death in infants.6 The committee relied on the fairly rigorous study by Fleming and colleagues (2001) since the cause of death was determined by a standard examination protocol. In contrast, the Jonville-Bera and colleagues study (2001) 6Anaphylaxis was not listed among the outcomes discussed in either study.

VACCINATIONS AND SUDDEN UNEXPECTED DEATH IN INFANCY 55 was subject to misclassification bias since autopsies were not performed on any of the SUDI cases. Thus, based on only one methodologically strong study, the committee concludes that the evidence is inadequate to accept or reject a causal relationship between exposure to multiple vaccines and sudden unex- pected death in infancy, other than SIDS. An aphyl axis The present committee examined deaths due to anaphylaxis (severe, imme- diate type I hypersensitivity reaction) after receipt of a vaccine, and it reexamined the conclusions from previous IOM committees that reviewed this relationship.7 In summary, a 1994 IOM committee reviewed fatal anaphylaxis cases in which symptoms began within 4 hours of vaccine administration. Based on two case reports in adults in which death was associated with the administration of tetanus toxoid given as a single antigen (Regamey, 1965; Staak and Wirth, 1973), the committee found a causal relationship between tetanus toxoid containing vaccines and death from anaphylaxis. No epidemiologic studies were available, nor were definitive reports in infants available. The same committee found a causal relationship between HepB vaccine and fatal anaphylaxis. (The 1994 com- mittee noted there was no direct evidence for this, but based its conclusion on the evidence establishing a causal relationship between HepB vaccine and anaphy- laxis and on the fact that, in general, anaphylaxis is very rarely fatal.) Based on case reports, a 1991 IOM committee concluded that the evidence established a causal relation between DTwP vaccine and anaphylaxis. In a re- view of the literature published since the completion of the 1991 report, the current committee found no additional epidemiologic studies examining the asso- ciation between exposure to DTwP vaccine and anaphylaxis. It is important to note that the previous committee (1991) did not come to a conclusion on DTwP vaccine and deaths from anaphylaxis, nor did it form a conclusion specific to infants. In 1997, DTaP replaced DTwP as the recommended vaccine in the child- hood immunization schedule in the United States. Given that no additional ana- lytic studies are available, the present committee finds no basis for a change in 7Adverse events of Pertussis and Rubella Vaccines (IOM, 1991) provides an in-depth review of the literature concerning the adverse events associated with whole-cell pertussis containing vaccine (DTwP), as well as rubella vaccine. The charge to the Vaccine Safety Committee (IOM, 1994) was to examine adverse events associated with tetanus toxoid as well as with tetanus and diphtheria toxoid combination preparations and other childhood vaccines. It was beyond the 1994(a) committee's charge to form conclusions about pertussis vaccine or DTP. Note that in contrast to the scope of the present study, the charges to the 1991 and 1994 committees were not limited to infants. 8The 1991 conclusion is reworded here for consistency with the causality categories established by the 1994 committee.

56 IMMUNIZATION SAFFI Y REVIEW TABLE 4 Evidence Table: Exposure to Multiple Vaccines and Sudden Unexpected Death in Infancy Citation Design Assessment of Population Vaccine Exposure Outcomes Fleming et al. Case-control (2001) Jonville-Bera et al. Case-control (2001) Cases: sudden At least one dose DTP, OPV, unexpected deaths, and/or Hib. age 1 week to <1 year, from Feb 1993-March 1996. 303 SIDS 65 explained deaths Controls 1,515 infants, matched according to age, locality, and time of reference sleep England Immunization information from parent-held records. Infant considered immunized if received any component of the immunization program prior to last or reference sleep. Cases: 114 sudden At least one dose of diphtheria, unexpected deaths tetanus + pertussis, (90 SIDS, 24 poliomyelitis, or Haemophilus SUDI) of infants vaccine (DTPP + Hib). between ages 30 and 90 days, Other vaccines received: Feb 1995- BCG, HepB. March 1997. Controls: 341 infants, matched for sex, gestational age, and born immediately after the victim in the same maternity unit France Multi-centre Vaccine exposure determined from Health and Development Record. Outcomes explained sudden un (explainer classified Multidisci committee cause of c pediatric ] examinati standard ~ Explained unrecogni accidental congenita: non-acc~d metabolic bowel ohs bronchop~ dysplasia, cardiomy~ SUDI = so infant in ~ until deaf] investigat show adept explanatic mortem e

VACCINATIONS AND SUDDEN UNEXPECTED DEATH IN INFANCY 57 Outcomes Results Comment Contribution to Causality Argument 'P. OPV, Cation Cards. munized onent of Gram nce sleep. diphtheria, mophilus )). ted: termined elopment Outcomes included both SUDL Explained explained or unexplained vs. Controls sudden unexpected deaths Univariate OR (explained deaths were (95% CI ) classified as SUDI). 0.51 (0.21-1.26) Multidisciplinary committee established cause of death after full pediatric postmortem examination to a standard protocol. Explained deaths: unrecognized infection, accidental injury, congenital anomalies, non-accidental injury, metabolic disorders, bowel obstruction, bronchopulmonary dysplasia, and cardiomyopathy. SUDI = sudden death of infant in good health until death for whom investigations failed to show adequate explanation; no post mortem examination. Death due to infection Univariate OR (95% CI ) 0.44 (0. 1 1- 1.65) SUDI (OR 95% CI) DTPP + Hib: 0.42 (0.06-1.8) results were consistent with a possible protective effect from . . . 1mmunlzahon. Authors noted that The study provides strong evidence of no association between exposure to multiple vaccines and SUDI; weaknesses in the study limit its contribution to the causality argument. Possible selection bias from missed cases, exclusion of cases, or controls who could not be located or did not The study provides weak evidence of no association between exposure to multiple vaccines and SUDI in early infancy; agree to participate. weaknesses in the Possible differential study limit its recall bias between contribution to the cases and controls causality argument. because length of time between death (or reference date) and interview differed by almost 100 days.

58 IMMUNIZATION SAFFI Y REVIEW the prior conclusion that the evidence establishes a causal relation between DTwP and anaphylaxis. One case report (Werne and Garrow, 1946), discussed in both the 1991 and 1994 reports, described identical twins who died 16 and 20 hours after receipt of the second diphtheria toxoid and pertussis antigen (DwP) vaccine given at 10 months. Autopsies showed evidence of the vascular smooth muscle contraction and increased capillary permeability expected with anaphylaxis. (Adverse reac- tions were not reported in other infants who received the same batch of the vaccine, and the injected material was shown to be sterile.) The delayed response was noted by the authors of the study to be atypical of the anaphylactic reactions reported at that time.9 In an effort to identify any subsequent cases, the present committee reviewed VAERS data provided by CDC on reports of anaphylaxis between January 1991 and November 2002. Of the 36 reports of anaphylaxis in infants less than 1 year of age, one report was for an infant who died. This death occurred outside the United States, following administration of vaccines not previously associated with anaphylaxis. Moreover, CDC notes that these 36 cases were identified on the basis of terms (e.g., anaphylaxis, anaphylactic shock) used in the reports, not as formal medical diagnoses. Thus the cause of death due to anaphylaxis was not verified. As with other passive surveillance data discussed in this report, this individual case is of limited value in assessing causality. Causality Argument A causal relationship has been established by previous IOM committees between DTwPl° vaccine and anaphylaxis (IOM, 1991~. They also established causal relationships between tetanus toxoid-containing vaccinesll l2 as well as between hepatitis B vaccines,l3 l4 and death from anaphylaxis (IOM, 1994a). 9This case is discussed further in the section on fatal late-phase anaphylactic reactions as a theoretical biological mechanism for SUDI. In infants and children. In children and adults. No data were available for infants. 12The 1994 IOM committee based its conclusion on two case reports in adults in which death was associated with the administration of tetanus toxoid given as single antigen. One case (Regamey, 1965) was immunized in 1933, and his reaction may have been related to the use of blood compo- nents from horses during toxoid production at that time (Ehrengut and Staak, 1973). In the second case (Steak and Wirth, 1973), Spiess and Staak (1973) raised the possibility of inadvertent intravas- cular injection and Ehrengut and Staak (1973) noted that the vaccine was given "in both arms," suggesting that equine antiserum might have been given in addition to the vaccine. In children and adults. No data were available for infants. 14The 1994 IOM committee noted that there was no direct evidence for a causal relationship between hepatitis B vaccine and fatal anaphylaxis, but based its conclusion on the evidence estab- lishing a causal relationship between hepatitis B vaccine and anaphylaxis and on the fact that in general anaphylaxis is very rarely fatal.

VACCINATIONS AND SUDDEN UNEXPECTED DEATH IN INFANCY 59 Although very rare, anaphylaxis from any cause (e.g., food, drug, or environmen- tal allergen) can lead to sudden unexpected death. However, death of infants from anaphylaxis following vaccination has been reported in only one well-documented case report from 1946 (of identical twin infants following administration of the second dose of a DwP vaccine, described above. See also Table 5~. The present committee concludes that the evidence favors acceptance of a causal rela- tionship between diphtheria toxoid and whole cell pertussis vaccine and death due to anaphylaxis in infants. It should be noted however, that despite the more than 50 years subsequent to the publication of the 1946 case report and despite the widespread use of vaccines in infants, the committee could not iden- tify in the medical literature any additional reports of death in infants due to anaphylaxis. This lack of data probably reflects two things: the relatively rare occurrence of anaphylaxis in response to vaccines, and the availability of an effective treatment that resolves the condition for anaphylaxis. The committee notes that causality is usually addressed by epidemiologic studies, but in their absence, individual case reports and case series are relied upon (provided that the nature and timing of the adverse event following vaccine administration and the absence of likely alternative etiologic candidates gave reasonable certainty that causality could be inferred from one or more case re- ports) (IOM, 1994a). When such information (particularly concerning timing) is unavailable, it is difficult or impossible to infer causality for that case. For the present review, the committee felt that the Werne and Garrow case report (1946) provided sufficient evidence to indicate a link between vaccines, anaphylaxis, and infant death. Further support of causality is based on the well- established biologic mechanism that anaphylaxis can occur after exposure to a foreign antigen or drug and by the temporal sequence of observed events follow- ing vaccination. On the basis of the case reports, evidence indicates that anaphy- laxis can occur after vaccination. However, the very limited number of case reports of fatal vaccine-induced anaphylaxis (one published report involving two deaths, and one case in VAERS) underscores that such an occurrence is an exceedingly rare event. Nonetheless, the timing and the unmistakable classic presentation of anaphylaxis in the Werne and Garrow case report indicate that vaccines can cause anaphylaxis and fatal anaphylaxis in infants. Neonatal Death Only HepB vaccine is administered during the neonatal period (the first 27 days of life).

60 IMMUNIZATION SAFFI Y REVIEW TABLE 5 Evidence Table: Exposure to DwP Vaccine and Fatal Anaphylaxis Citation Design Population Assessment of Vaccine Exposure Outcomes Werne and Garrow (1946) Case-report of Identical twins two twins aged 10 months Second injection of diphtheria toxoid and whole-cell pertussis antigen given at 10 months. Fatal anal Hepatitis B Vaccine Controlled Observational Study, Unpublished Report Vaccine Safety Datalink. At the committee's October 2002 meeting, Ward (2002) presented unpublished data on an analysis of neonatal mortality following hepatitis B vaccination. A total of 1,124 infants who had been enrolled in the Northern and Southern California Kaiser Permanente health plans from 1993 to 1998 and who died of any cause before 29 days of age were included in the study. Exposure to the hepatitis B vaccine was determined by review of computerized files created for the Vaccine Safety Datalink (VSD) project and by medical chart review. Fifty-nine infants received the hepatitis B vaccine, and a total of 159 matched controls who had not received the Hep B vaccine were selected from the cohort of neonatal deaths to serve as controls. The proportion of "unexpected deaths" (the presence or absence of a potentially fatal neonatal or perinatal condi- tion) in the unvaccinated and vaccinated groups was compared. The rate of unex- pected mortality was equivalent in the vaccinated and unvaccinated groups, sug- gesting a lack of association between vaccine and subsequent death. The difference in the distributions was not significant (p = 0.9~. Because the study is unpublished, the committee did not find that the study contributed to its assess- ment of causality.

VACCINATIONS AND SUDDEN UNEXPECTED DEATH IN INFANCY hylaxis 61 Outcomes Results Comment Contribution to Causality Argument liphtheria 1 pertussis months. Fatal anaphylaxis Infants died 16 and Autopsy showed 20 hours after evidence of the receipt of the vascular smooth second injection of muscle contraction diphtheria toxoid and increased and pertussis capillary antigen. permeability expected with anaphylaxis. Adverse reactions were not reported in other infants who received the same batch of the vaccine. Injected material was shown to be sterile. The well-documented case report provides evidence of a causal relationship between exposure to DwP vaccine and death due to anaphylaxis in infants. Passive Surveillance Data VAERS. As previously described, Niu and colleagues (1999) reviewed re- ports to VAERS of neonatal deaths following receipt of HepB vaccine. The reports were received between January 1, 1991 and October 5, 1998. There were a total of 18 reports of death, of which 17 had autopsy results. Of those 17 deaths, 12 deaths were attributed to SIDS. Other causes of death included infections, intracerebral hemorrhage, accidental suffocation, and congenital heart disease. Causality Argument The committee reviewed data on neonatal death following receipt of HepB vaccine from one unpublished controlled observational study and from one pub- lished report describing VAERS data. Because of the nature of the available case reports and the limited, unpublished epidemiological data, the commit- tee concludes that the evidence is inadequate to accept or reject a causal relationship between hepatitis B vaccine and neonatal death. Biological Mechanisms Although biological data do not provide an independent basis for evaluating causality, they can help validate epidemiologically based conclusions that are for

62 IMMUNIZATION SAFFI Y REVIEW or against causal associations. Such data can also guide further investigation when epidemiological evidence is inconclusive. For this report, the committee's task was to consider the evidence regarding biological mechanisms that might link vaccination during the first year of life with sudden unexpected death in infancy. Some of these deaths can be attributed to various identifiable causes, which provide a basis for identifying and evaluat- ing potential mechanisms that might be related to vaccination. Most sudden unexpected deaths in infancy, however, are diagnosed as SIDS, specifically because all other known causes have been eliminated, and the lack of a clear understanding of the causal pathways in SIDS complicates the task of identifying any mechanisms by which vaccination might be thought to contrib- ute. For guidance, the committee looked to the various lines of research on SIDS, as reflected in the triple-risk models and focused on vaccination as a potential source of stressors. Considering both explained and unexplained infant deaths, the committee reviewed the evidence regarding biological mechanisms that might be related to vaccination in terms of three possible pathways: neuroregulatory abnormalities (including homeostatic and autonomic functions), inborn errors of metabolism, and adverse immune responses. The committee's assessment included consider- ation of certain widely recognized reactions to vaccination, particularly fever and decreased appetite, that are relevant to those pathways. The committee empha- sizes that these and several other reactions commonly observed in infants follow- ing vaccination (e.g., pain at the injection site, irritability, drowsiness, or sleep- lessness) are generally self-limited and not considered a cause for concern by themselves. Neuroregulatory Abnormalities Epidemiologic studies have shown that risk factors for SIDS include the prone sleeping position, exposure to pro- and postnatal maternal smoking, and elevated body temperature (Sullivan and Barlow, 2001~. The mechanisms through which these risks operate are unknown, but possibilities include rebreathing car- bon dioxide entrapped near the face when an infant is prone, upper airway ob- struction and compromised airway reflexes, impaired arousal thresholds in the prone position, altered vestibular influences on blood pressure recovery systems, and hyperthermia due to overwrapping or failure of facial heat dissipation while prone. Some hypotheses regarding SIDS posit an interaction between exogenous stimuli (e.g., prone positioning or tobacco smoke) and neuroregulatory abnor- malities. Such a process might involve the respiratory or cardiovascular systems, or both, and a failure of compensatory mechanisms. The abnormalities may in- volve alteration in neurotransmitter receptors in regions of the brain that are involved in chemoreception and cardiovascular control (Harper, 2000~. Vaccina-

VACCINATIONS AND SUDDEN UNEXPECTED DEATH IN INFANCY 63 tion might be thought to pose the risk of producing reactions for example, fever, listlessness, or altered sleep patterns that could serve as exogenous stimuli for abnormal neuroregulatory responses in vulnerable infants. Research on brains from SIDS cases has shown abnormalities within and above the brainstem. Cerebellar areas appear to play a role in correcting abnormal breathing rates and blood pressure. In particular, some SIDS cases show brady- cardia prior to cessation of breathing, which suggest that death might result from an uncompensated blood pressure drop as a consequence of cerebellar or cerebel- lar-related structural damage and failure of that system to restore perfusion and maintain autonomic control (Harper, 2000, 2002~. Other research suggests that a subset of SIDS deaths may result from a developmental abnormality in a medul- lary network of serotonergic neurons that leads to the failure of protective re- sponses to stressors during sleep (e.g., asphyxia, hypoxia) (Kinney et al., 2001~. The committee considered evidence for the following two biologic mecha- nisms that might link vaccination and neuroregulatory abnormalities: impaired respiratory responses and impaired arousal. Impaired respiratory responses. At one time, clinical impressions had sug- gested that DTP immunization was associated with an increased frequency of prolonged apnea, which was thought to potentially increase the risk for SIDS (Steinschneider et al., 1991~. But, two studies failed to demonstrate an associa- tion between DTP immunization and increased respiratory abnormality during sleep in children considered at risk for SIDS. One study compared breathing patterns during sleep on the nights before and after DTP immunization for subse- quent siblings of SIDS victims, infants with unexplained apnea, and infants in a control group (Keens et al., 1985~. None of the groups showed an increase in respiratory abnormalities following vaccination. The second study monitored the occurrence of prolonged apnea or bradycardia following DTP vaccination in a series of 100 subsequent siblings of SIDS cases. No episodes of prolonged apnea or bradycardia occurred during the 10 days before and after vaccination; one episode occurred in the 10- to 20-day period after vaccination (Steinschneider et al., 1991~. However, the possible relationship between apnea and SIDS appears com- plex. Findings reviewed by Harper and colleagues (2000) show that infants who later succumbed to SIDS had fewer breathing pauses than other infants and that some apnea appears to occur normally in other infants (where it is associated with movement and brief increases in blood pressure and may be a compensatory mechanism to maintain homeostatic control). Thus, the pattern in the infants who later died might suggest underlying abnormalities, possibly neurological in ori- gin, in interactions between respiration and regulation of blood pressure. Viewed in this context, the study by Keens and colleagues (1985) also shows that the total amount of apnea or periods of briefly interrupted ("peri- odic") breathing as a percentage of total sleep time before DTP immunization

64 IMMUNIZATION SAFFI Y REVIEW TABLE 6 Duration of Apnea and Periodic Breathing as Percentages of Total Sleep Time, Before and After DTP Immunization Control group (N = 30) Pre-DTP Subsequent siblings of SIDS Cases (N = 33) Post-DTP Pre-DTP Post-DTP Total sleep time, min 549+14 528+16 549+15 539+15 Apnea (%) 0.31+0.06 0.18+0.04 0.24+0.05 0.20+0.04 Periodic breathing (%) 1.09+0.59 0.71+0.32 0.41+0.16 0.36+0.12 NOTE: Values are mean + standard error of measurement. SOURCE: adapted from Keens et al., 1985. tended to be lower, though not significantly so, for the subsequent siblings of SIDS cases (apnea: 0.24%+0.05; periodic breathing: 0.41%+0.16) compared with the controls (0.31+0.06; 1.09+0.59~. In both groups, the percentages of sleep time with apnea or periodic breathing were lower after immunization but not significantly different from the preimmunization levels or between the two groups (SIDS siblings: apnea: 0.20%+0.04; periodic breathing: 0.36%+0.12~; (controls: apnea: 0.18%+0.04; periodic breathing: 0.71%+0.32~. The results do not suggest that immunization has an adverse effect on breathing patterns during sleep (see Table 6~. It should be noted that the studies by Keens and colleagues (1985) and by Steinschneider and colleagues (1991) included infants "considered at risk" for SIDS and SIDS siblings and that none of these infants died of SIDS during the course of the study. Caution should be used in interpreting the results of these studies as there is currently no proof that SIDS is familial or has a genetic cause. Impaired arousal. Concerns about impaired arousal might arise because of an established link between hypotonic-hyporesponsive episodes (HHE) and re- ceipt of whole-cell pertussis vaccines (DTwP, DTwP-HiB) (IOM, 1991~. HHE refers to the sudden onset of limpness, decreased responsiveness, and pallor or cyanosis in a child under the age of 10 years, within 48 hours after an immuniza- tion. The episode can last from 1 minute to 48 hours. All three symptoms must be present for a diagnosis of HHE to be confirmed; it is not considered to have occurred if there is urticaria or anaphylaxis during the episode, if normal skin color is maintained during the episode, if the cause of the signs can be identified, or if the child is sleeping (Braun et al., 1998~. HHE has also been observed, less frequently, following immunization with DTaP, and some cases have been re- ported following DT, HiB, and HepB vaccinations (DuVernoy and Braun, 2000; Heijbel et al., 1997~.

VACCINATIONS AND SUDDEN UNEXPECTED DEATH IN INFANCY 65 Studies have not associated HHE with mortality or with any long-term mor- bidity (Gold, 2002), despite assertions in successful claims under the National Vaccine Injury Compensation Program that HHE led to death (Ridgway, 1998~. The evidence points to HHE being a generally benign, self-limited syndrome, with children returning to their prevaccination state within 6 to 24 hours (DuVernoy and Braun, 2000~. Although some providers regard HHE as a con- traindication to revaccination with pertussis vaccine, the data suggest that the rate of recurrence is low (DuVernoy and Braun, 2000~. The current CDC Advisory Committee on Immunization Practices guidelines (ACIP) list HHE as a precau- tion, but not a contraindication to subsequent vaccinations (CDC, 1997~. Vaccination might also be thought to affect arousal mechanisms in two other ways: through increases in body temperature as a result of fever, or through disruptions in sleeping patterns because of irritability or increased sleepiness. Evidence indicates that the increased sleepiness of ill or feverish patients may be related to changes in the activity of interleukin 1 (IL-1) and tumor necrosis factor (TNF), which appear to be important mediators of sleep regulation (Krueger and Majde, 1995; Krueger et al., 2001~. However, evidence from a study of 14 healthy human infants who received DTwP, Hib, and OPV offers no support for an effect of this sort related to immunization. Although the infants' mean core temperature during sleep was significantly higher after immunization, arousal thresholds and sleep patterns were not significantly altered (toy et al., 1998~. In the absence of experimental or human evidence regarding the ability of common side effects of immunization, including fever and anorexia, to trigger sudden unexpected death in infants with underlying neuroregulatory abnormalities, the committee concludes that this mechanism is only theoreti- cal. Inborn Errors of Metabolism As discussed above, IEM involves deficiencies of specific enzymes or trans- port proteins (McInnes and Clarke, 2002), and those disorders related to defects in FAO have been linked to sudden unexpected infant deaths (e.g., Bennett and Powell, 1994; Mathur et al., 1999; Strauss et al., 1995~. Deaths from FAO disor- ders generally occur under circumstances, such as illness or fasting, that limit the supply of glucose and increase fat metabolism. Fever or anorexia following vac- cination might be thought to induce metabolic responses similar to illness or fasting in infants with undiagnosed FAO disorders, thus posing a risk of sudden unexpected death. The committee found no published reports of studies in humans or animals with known FAO disorders that have examined metabolic responses following vaccination. The committee also found that reports discussing the detection of IEM among deaths initially attributed to SIDS provided no information on the vaccination status of infants found to have IEM or on the timing of those deaths

66 IMMUNIZATION SAFFI Y REVIEW following vaccination. It is possible that the processes that produce fever follow- ing vaccination are not related to those aspects of illness that can induce a meta- bolic crisis in a susceptible infant. To learn more about exposure to vaccines among children with metabolic disorders, committee members informally queried clinicians at seven medical centers specializing in the care of such children (Goodman, 2002; Kaback, 2002~. At one center, children are generally not vaccinated. However, physicians from the six other centers reported that immunizations are regularly given according to the recommended schedule, with careful observation of the infants but no special precautions to prevent fever (e.g., administration of aspirin or acetaminophen). At one center, infants receive less protein on the day before and the day after immunization. No problems related to vaccination were reported. In the absence of experimental or human evidence regarding the ability of common side effects of immunization, including fever and anorexia, to trigger an acute metabolic crisis in patients with IEM, the committee con- cludes that this mechanism for vaccine-related sudden unexpected infant death is only theoretical. Adverse Immune Responses Signs in some SIDS cases of recent immunological or inflammatory activity, such as higher levels of immunoglobulins, inflammatory cells, and inflammatory cytokines, provide a basis for a hypothesis that in vulnerable infants SIDS might result from an exaggerated immune response to common respiratory pathogens (Vege and Rognum, 1999~. Some also propose that SIDS might be linked to an extreme immune response in the form of anaphylaxis (Buckley et al., 2001~. Vaccines might be suspected of contributing to sudden unexpected infant death by provoking exaggerated immune responses like those thought to be related to infection or by provoking allergic responses like anaphylaxis. The committee examined biological mechanisms related to two types of immune response: inflammatory reactions related to respiratory infections, and anaphylaxis and related hypersensitivity reactions. Inflammatory reactions related to respiratory infections. In some stud- ies, more than half the infants who died of SIDS have had signs of a minor infection, particularly from respiratory viruses, prior to death (Forsyth, 1999; Vege and Rognum, 1999~. However, it is not yet known if such infections are causally related to SIDS, contributory in conjunction with other risk factors, or only coincidental; it is particularly difficult to distinguish between these possi- bilities because of the high frequency of respiratory tract infections in infancy. Studies have found various markers of inflammatory activity in SIDS cases. Howat and colleagues (1994) found greater numbers of inflammatory cells, in- cluding T lymphocytes, B lymphocytes, and eosinophils, in the lungs of SIDS

VACCINATIONS AND SUDDEN UNEXPECTED DEATH IN INFANCY 67 cases compared with the lungs of infants in a control group who died without pulmonary inflammation. The researchers suggested that products of eosinophil degranulation could cause epithelial damage and pulmonary edema, which could be associated with the respiratory obstruction and hypoxia observed with SIDS. Other studies have demonstrated elevated levels of the cytokine interleukin-6 (IL-6) in the cerebrospinal fluid of SIDS victims (Vege et al., 1995~. IL-6 can induce fever, anorexia, and the acute phase response, and in the context of central nervous system (CNS) inflammatory conditions such as meningitis, IL-6 may contribute to respiratory depression. Although the concentrations of IL-6 in the cerebrospinal fluid of infants with SIDS are in some cases greater than those in controls, they are lower than those found in infants with CNS inflammatory conditions (Vege et al., 1995; Vege and Rognum, 1999~. Some have speculated that IL-6 may contribute to respiratory depression in a subset of children who are vulnerable, but there is no direct evidence to support this conjecture. It has been known for some time that infection can prime the immune system to hyper-respond in such a way that challenge with a normally sublethal dose of endotoxin (a component of gram-negative bacteria) or with another infectious agent can lead to sudden unexpected death from systemic shock (Freudenberg et al., 1998; Galanos and Freudenberg, 1993; Gumenscheimer et al., 2002~. A re- cent study in rats suggests that there may be a period during which the infant's developing immune system may be particularly vulnerable to such priming. In- fecting the rats with a nonlethal strain of influenza A virus, followed 1 to 5 days later by a sublethal dose of endotoxin, resulted in unexplained deaths in infant rats that were similar in pathology, organ damage, and vascular collapse (Blood- Siegfried et al., 2002~. Although the authors of this report suggest that the pathol- ogy is consistent with that seen in SIDS, these findings are not specific. Further, under other conditions this mechanism is operative in adult as well as infant animals. For these reasons and because the amounts of endotoxin needed to induce death were still quite large, the relevance of this model to SIDS is only speculative. Although some studies suggest that SIDS may result from an inappropriate immune response to common respiratory pathogens, data are not available to show that vaccination triggers the production of inflammatory cells or cytokines like those found in SIDS cases or that those cells and cytokines are causally related to SIDS. In the absence of experimental or human evidence demon- strating the ability of vaccines to stimulate an abnormal inflammatory re- sponse in the lung leading to sudden unexpected infant death, the committee concludes that this mechanism is only theoretical. Anaphylaxis and related hypersensitivity reactions. Anaphylaxis and other type I hypersensitivity reactions occur when soluble antigens bind to anti- gen-specific immunoglobulin E (IgE) on mast cells. This binding triggers the release of preformed inflammatory mediators, such as histamine and TNFoc, that

68 IMMUNIZATION SAFFI Y REVIEW are stored in granules in the mast cell. As described above, a type I reaction is immediate, occurring within seconds to minutes. It may also be followed by a late-phase reaction that is triggered by cytokines and other inflammatory media- tors some 4 to 8 hours after the immediate reaction subsides. Whereas immediate reactions are the direct result of activation of mast cells, late-phase reactions result from the synthesis and secretion from activated mast cells of inflammatory mediators (including leukotrienes, chemokines, cytokines, and prostaglandins) and subsequent infiltration of the site by inflammatory cells (including eosino- phils and type 2 cytokine producing Th2 T cells) (Busse and Lemanske, 2001; Parham, 2000). A link between SIDS and anaphylaxis has been proposed. An elevated level of the mast cell enzyme p-tryptase in post-mortem serum samples is thought to be a marker for anaphylaxis (Kemp and Lockey, 2002), and the enzyme has been detected in the blood of SIDS victims (Buckley et al., 2001~. An alternative hypothesis, however, is that the increased tryptase levels observed in SIDS cases could be a result of non-IgE-related mast-cell degranulation, possibly due to hypoxia from prone sleeping, rather than an allergic response (Edston et al., 1999; Holgate et al., 1994~. Anaphylaxis and other allergic reactions are known to occur in response to vaccine antigens or to other vaccine components. Previous IOM committees (IOM, 1991, 1994a) have established causal relationships between DTwP,l5 teta- nus-toxoid-containing vaccines,l6 and hepatitis B vaccinel7 and anaphylaxis. A1- though very rare, anaphylaxis from any cause (e.g., food, drug, or environmental allergen) can lead to sudden unexpected death. The previous IOM reports considered cases of anaphylaxis occurring within 4 hours after immunization (IOM, 1994a). The present committee identified one report of a pair of identical twins following the second administration of diphthe- ria toxoid and whole-cell pertussis antigen (Werne and Garrow, 1946), described above, in which symptoms began before 4 hours and progressed to death at 16 and 20 hours. Post-mortem analysis revealed edema, vasoconstriction, and in some tissues perivascular mononuclear and eosinophilic infiltrates, which are consistent with an immediate-phase accompanied by a late-phase type I hyper- sensitivity reaction. In the case presented by Werne and Garrow (1946), the initial, nonspecific signs of an immediate-hypersensitivity (i.e., anaphylactic) reaction appear to have been initially unrecognized, and it eventually progressed to death. The suggestion has also been made that a small subset of sudden, unexpected deaths in adults is due to clinically unrecognized anaphylaxis (e.g., following a bee sting) (Schwartz et al., 1995~. In infants and children In children and adults. No data were available for infants. In children and adults. No data were available for infants.

VACCINATIONS AND SUDDEN UNEXPECTED DEATH IN INFANCY 69 The inflammatory infiltrates found in SIDS cases by standard autopsy tech- niques most likely result from infection, but it is not possible to exclude a contri- bution of late-phase allergic responses to these infiltrates in some cases. How- ever, if properly performed, standard autopsy techniques are sufficient to exclude the vascular changes characteristic of anaphylaxis, including those found in the delayed anaphylactic deaths in the twin study by Werne and Garrow (1946~. Although a type I hypersensitivity reaction leading to death could possibly be missed both clinically and at post-mortem examination, and therefore misdiagnosed as SIDS, the committee concludes that this possibility is only theoretical. Conclusions Regarding Biological Mechanisms The biological evidence concerning mechanisms that might link vaccination and sudden unexpected infant deaths is limited. The situations and mechanisms discussed above neuroregulatory abnormalities, inborn metabolic errors, and adverse immune responses are the circumstances under which the committee considers it theoretically possible that responses to vaccination might contribute to sudden unexpected infant death from SIDS or other causes. In the case of anaphylaxis a serious, systemic allergic response of the immune system the biological mechanisms linking foreign antigens (including vaccines) and death are well established. However, the possibility of vaccination leading to a fatal, late-phase anaphylactic reaction (following a clinically missed mild immediate reaction) is only theoretical. Furthermore, without a clear understanding of the biological mechanisms underlying SIDS, it is difficult to make a meaningful assessment of the role that vaccination might play in those deaths. Thus, aside from a type I hypersensitivity or anaphylactic reaction to a vac- cine antigen or to vaccine components administered within 24 hours prior to death, the proposed mechanisms for vaccines to have a causal role in sudden unexpected death in infancy are only theoretical. SIGNIFICANCE ASSESSMENT The charge to the Immunization Safety Review Committee includes consid- eration of the public health response to the immunization safety concerns it examines. Most previous IOM studies on immunization safety, by contrast, were limited to conclusions from causality assessments and to recommendations for future research. The public health response to an immunization safety concern potentially encompasses a broad range of activities, including policy reviews, new research directions, and changes in communication to the public and health care providers about issues of immunization safety. In formulating the breadth and direction of the recommended public health response, the committee consid- ers not only its conclusions regarding causality and biological mechanisms, but

70 IMMUNIZATION SAFFI Y REVIEW also the significance of the immunization safety issues for society the context in which policy decisions must be made. In the present case, the committee considered the concern that vaccinations given during the first year of life might increase the risk of SIDS or other types of sudden unexpected death among infants. Vaccines have made a substantial and an undeniable contribution to reductions in the toll of illness and death from several major infectious diseases (CDC, 1999~. Nevertheless, vaccines are not completely free of risks, including a risk of fatal adverse events. For example, the scientific evidence reviewed by the committee supports the possibility that vacci- nation can occasionally cause anaphylaxis. To ensure that vaccines are as safe as possible and the value of vaccines is not undermined by fears about their use, it is essential to understand and minimize such risks. In the United States, current immunization recommendations call for vacci- nation of infants to begin at birth, with additional vaccines and vaccine doses given at 2, 4, and 6 months of age. These recommendations reflect the judgment of public health officials and health professionals that the health of infants and others will benefit. Infants are among the most vulnerable members of society after all, and protecting them from avoidable health risks is a responsibility that parents share with physicians, nurses, others who provide health care, and vac- cine manufacturers, as well as officials who shape and implement health policies. But, although the death of an infant from any cause is a grave loss to a family, infant deaths that might result from efforts to protect health must be a source of special concern. Fears related to vaccination and SIDS must, in the committee' s judgment, be considered a significant concern that deserves further attention. SIDS is the most common cause of death in the postneonatal period, with the highest incidence seen between the ages of 2 and 4 months (AAP, 2001; Adams et al., 1998), a time when most infants are also receiving many vaccines. But investigating the possible relationship between vaccination and SIDS is complicated by at least three factors. First, research has yet to determine the cause or causes of SIDS, making it difficult to know what biological mechanisms are relevant, with or without regard to vaccination. If certain environmental risk factors can trigger SIDS only in a subsets of the individuals with specific predisposing genetic factors, then theoretically, epi- demiological studies in which all SIDS cases are lumped together might fail to detect causal associations that actually exist. Vaccines could be associated. It is possible that only one subset of SIDS complicates a particular vaccine adminis- tration. However, this is simply speculation. To the extent that SIDS encompasses heterogeneous but still unknown causes of death, isolating any specific component that might be related to vaccination becomes more difficult. Careful postmortem examination is also essential to distinguish SIDS from other known causes of death. Data from the early l990s indicate that autopsies were performed in more than 90 percent of SIDS deaths

VACCINATIONS AND SUDDEN UNEXPECTED DEATH IN INFANCY 71 (CDC, 1996a; Overpeck et al., 2002), but national data on autopsy rates have not been available since 1994 (Overpeck et al., 2002~. Use of new screening tech- nologies will help in attributing some sudden unexpected infant deaths to causes such as metabolic disorders. Second, epidemiologic investigations covering the past 10 to 15 years must take into account several changes in SIDS-prevention efforts. Between 1983 and 2000 the SIDS mortality rate fell by almost 60 percent, from 146 deaths per 100,000 births (Overpeck et al., 2002) to 62 deaths per 100,000 births (Anderson, 2002~. The AAP recommended in 1992 to avoid infant prone sleeping, and in 1994, a Back to Sleep campaign was initiated as a joint effort of the U.S. Public Health Service, the AAP, the SIDS Alliance, and the Association of SIDS and Infant Mortality Programs (AAP, 2000~. Between 1992 and 1998, the proportion of U.S. infants sleeping prone decreased from more than 70 percent to about 20 percent. The committee acknowledges the possibility that SIDS risks associated with the vaccination schedule during this period might be masked by the large reductions in risk associated with changes in infant sleep position. If vaccine- related risks exist, all indications are that they are small. Third, controlled prospective cohort studies to assess possible vaccine-re- lated risks are difficult to conduct because SIDS deaths are increasingly rare and because most children in the United States are vaccinated. This along with effec- tive SIDS-prevention efforts further complicate the ability to assess the link between vaccines and SIDS. The VSD project, with its access to a large popula- tion of HMO members, offers one prospect of assembling a study population of sufficient size to produce statistically meaningful results. At its October 2002 meeting, the committee heard reports on studies of infant death that had been conducted through the VSD (Ward, 2002~. RECOMMENDATIONS FOR PUBLIC HEALTH RESPONSE With current public health recommendations calling for infants to receive multiple doses of vaccines during the first year of life and with 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. The committee's review supported conclusions that the evidence favors rejection of a causal relationship between some vaccines and SIDS and is inadequate to accept or reject a causal relationship between other vaccines and SIDS, SUDI, or neonatal death. Except in the case of an immediate anaphylactic reaction result- ing in death, the evidence regarding biological mechanisms was essentially theo- retical, reflecting in large measure the lack of knowledge concerning the patho- genesis of SIDS. The committee found no basis for a review of current immunization policies, but it did see a clear need for continued research on adverse events following vaccination and on the biological basis for sudden unexpected infant deaths.

72 IMMUNIZATION SAFFI Y REVIEW Policy Review The committee does not recommend a policy review of the recommended childhood vaccination schedule by any of the national or federal vaccine advisory bodies on the basis of concerns about sudden unexpected death in · ~ mlancy. Research Although SIDS is the leading cause of death during the postneonatal period, it is a rare event in epidemiologic terms and its biological basis is not yet fully understood. The biology of other causes of sudden unexpected infant death is better understood than that of SIDS, but such deaths are rarer than SIDS deaths. Because of these factors, research concerning any possible role for vaccination in sudden unexpected infant death faces serious challenges. The committee encour- ages greater emphasis on population-based surveillance of vaccine recipients as a basis for epidemiologic studies, together with continued basic and clinical re- search to elucidate the causes of sudden unexpected infant death, including SIDS. Surveillance and Epidemiologic Studies The committee emphasizes the need for continuing surveillance for adverse events following vaccination. Careful prospective monitoring of any vaccines added to the recommended infant immunization schedule is particularly impor- tant. The relatively small numbers of participants in clinical trials of new vac- cines and the limited period of follow-up in those studies mean that the full heterogeneity of the population ultimately receiving the vaccine may not be represented and that rare adverse events may not be detected. The Vaccine Ad- verse Events Reporting System (VAERS), the national post-marketing surveil- lance system administered by the FDA and CDC, is one tool for monitoring adverse events. However, reports to VAERS indicate a temporal, but not neces- sarily causal, relationship between an adverse event and a vaccine. Furthermore, coming as they do from a passive system, VAERS data are subject to a variety of limitations, including underreporting of adverse events and multiple reports of a single event. Although reports to VAERS have limitations, the committee encourages the continued systematic investigation by FDA of each report of an infant death. The new network of Clinical Immunization Safety Assessment (CISA) centers may also be helpful in this regard. These centers are a collaboration between CDC and clinical academic centers across the United States (Press et al., 2002~. They are specifically intended to serve as a source of clinical expertise for the evaluation of adverse events. The first five centers were funded in October 2001. The Vaccine Safety Satelink (VSD) is another important resource for sur-

VACCINATIONS AND SUDDEN UNEXPECTED DEATH IN INFANCY 73 veillance and investigation of adverse events. Because it is a population-based system, the VSD can also support the epidemiologic studies necessary to deter- mine whether a causal relationship exists between an adverse event and a vac- cine, even though such studies can be difficult to conduct when that adverse event such as sudden unexpected infant death is rare and the published re- ports are scarce and often based on individual case studies or small groups. The VSD is a collaborative effort between the CDC and seven large HMOs with more than six million members. The project captures information on the vaccines administered to the HMO members and monitors their medical records for ad- verse events. The results of several VSD-based epidemiologic studies have been published and additional studies are currently under way. (For an overview and bibliography of published studies see Chen et al., 2000; see also www.cdc.gov/ nip/vacsafe/vsd/research.htm.) At the committee's meeting in October 2002, two recent VSD-based studies on infant deaths were presented, one of which examined the association between hepatitis B vaccine and neonatal death. Because of the attention to the VSD datasets paid by vaccine safety advocates and the potential contributions of the studies to the vaccine safety literature, the committee urges prompt publica- tion of these and all other VSD results. The committee notes that in future studies of infant death it would be espe- cially important to identify the timing of death in relation to vaccine administra- tion. Clear distinctions should be made whenever possible between SIDS deaths and sudden unexpected infant deaths with an identifiable cause. In addition, studies should report as much demographic information, including race and ethnicity, as possible; studies of vaccine-related risks for SIDS could be con- founded by the risks associated with the sociodemographic characteristics of the infants or their families. Basic and Clinical Science Aside from fatal anaphylactic reactions, the biological mechanisms by which vaccines could cause sudden unexpected death in certain susceptible infants are only theoretical. Cases of SUDI, particularly SIDS, make a substantial contribu- tion to infant mortality. Although efforts such as the Back to Sleep campaign, which target recognized risk factors, are credited with substantial reductions in SIDS mortality during the 1990s, the biology of SIDS remains poorly under- stood. The committee recommends continued research on the etiology and pathology of SIDS. It notes that the National Institute of Child Health and Human Development (NICHD, 2001) is targeting five areas of research for this purpose: (1) the brain and homeostatic control, (2) autonomic development and function, (3) infant care and the sleep environment, (4) infection and immunity, and (5) genetics.

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

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.

76 IMMUNIZATION SAFFI Y REVIEW

VACCINATIONS AND SUDDEN UNEXPECTED DEATH IN INFANCY 77

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.

VACCINATIONS AND SUDDEN UNEXPECTED DEATH IN INFANCY 79 CDC. 1996b. Update: Vaccine Side Effects, Adverse Reactions, Contraindications, and Precautions: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 45(RR-12):8, 25. CDC. 1997. Pertussis Vaccination: Use of Acellular Pertussis Vaccines Among Infants and Young Children: Recommendations of the Advisory Committee on Immunization Practices (ACIP).MMWR 46(RR-7):1-25. C:DC:. 1999. Achievements in Public Health, 1900-1999 Impact of Vaccines Universally Recom- mended for Children-United States, 1900-1998. MMWR 48(12):243-48. CESDI SUDI (Confidential Enquiry into Stillbirths and Sudden Unexpected Deaths in Infancy). 2000. The CESDI SUDI Studies 1993-1996. Fleming P. Blair P. Bacon L, Berry J. Eds. Lon- don: The Stationery Office. Chace D, Naylor E. 2002. Screening for Inborn Errors of Metabolism. Presentation made to Immun zation Safety Review Committee: Irvine, CA. Chen RT. 2000. Special methodological issues in pharmacoepidemiology studies of vaccine safety. Strom B. Ed. Pharmacoepidemiology. Third ed. West Susses, England: John Wiley & Sons, Ltd. Pp. 707-732. Chen RT, DeStefano F. Davis RL, Jackson LA, Thompson RS, Mullooly JP, Black SB, Shinefield HR, Va&eim CM, Ward JI, Marcy SM. 2000. The Vaccine Safety Datalink: Immunization research in health maintenance organizations in the USA. Bull World Health Organ 78(2): 186- 94. Cochran-Black DL, Cowan LD, Neas BR. 2001. The relation between newborn hemoglobin F frac- tions and risk factors for sudden infant death syndrome. Arch Pathol Lab Med 125(2):211-17. Cote A, Russo P. Michaud J. 1999. Sudden unexpected deaths in infancy: What are the causes? J Pediatr 135(4):437-43. Decker MD, Edwards KM. 1996. The multicenter acellular pertussis trial: An overview. J Infect Dis 174 (Suppl 3):S270-5. Decker MD, Edwards KM, Steinhoff MC, Rennels MB, Pichichero ME, Englund JA, Anderson EL, Deloria MA, Reed GF. 1995. Comparison of 13 acellular pertussis vaccines: Adverse reactions. Pediatrics 96(3 Pt 2):557-66. DuVernoy TS, Braun MM. 2000. Hypotonic-hyporesponsive episodes reported to the Vaccine Ad- verse Event Reporting System (VAERS), 1996-1998. Pediatrics 106(4):E52. Edston E, Gidlund E, Wickman M, Ribbing H. Van Hage-Hamsten M. 1999. Increased mast cell tryptase in sudden infant death anaphylaxis, hypoxia, or artifact? Clin Exp Allergy 29(12): 1648-54. Ehrengut W. Staak M. 1973. [Anaphlylactic reaction following injection of tetanus immunization] Anaphylaktische reaktionen nach Tetanustoxoid-Injektion. Deutsche Medizinische Wochenschrift 98:517. Ellenberg S. Chen R. 1997. The complicated task of monitoring vaccine safety. Publ Health Re 112:10-20. Essery SD, Raza MW, Zorgani A, MacKenzie DA, James VS, Weir DM, Busuttil A, Hallam N. Blackwell C. 1999. The protective effect of immunisation against diphtheria, pertussis and tetanus (DPT) in relation to sudden infant death syndrome. FEMS Immunol Med Microbiol 25(1-2): 183-92. Fagan DG, Walker A. 1992. Haemoglobin F levels in sudden infant deaths. Br J. Haematol 82(2):422- 30. Filiano JJ, Kinney HC. 1994. A perspective on neuropathologic findings in victims of the sudden infant death syndrome: The triple-risk model. Biol Neonate 65(3-4):194-7. Filiano JJ, Bellimer SG, Kunz PL. 2002. Tandem mass spectrometry and newborn screening: Pilot data and review. Pediatr Neurol 26(3):201-4. Fleming PJ, Blair PS, Platt MW, Tripp J. Smith IJ, Golding J. 2001. The UK accelerated immunisation programme and sudden unexpected death in infancy: Case-control study. BMJ 322(7290):822.

80 IMMUNIZATION SAFETY REVIEW Forsyth KD. 1999. Immune and inflammatory responses in sudden infant death syndrome. FEMS Immunol Med. Microbiol 25(1-2):79-83. Freudenberg MA, Salomao R. Sing A, Mitov I, Galanos C. 1998. Reconciling the concepts of endotoxin sensitization and tolerance. Prog Clin Biol Res 397:261-8. Galanos C, Freudenberg MA. 1993. Mechanisms of endotoxin shock and endotoxin hypersensitivity. Immunobiology 187(3-5):346-56. Gilbert-Barness E, Hegstrand L, Chandra S. Emery JL, Barness LA, Franciosi R. Huntington R. 1991. Hazards of mattresses, beds and bedding in deaths of infants. Am J. Forensic Med. Pathol 12(1):27-32. Gilbert-Barness E, Kenison K, Carver J. 1993. Fetal hemoglobin and sudden infant death syndrome. Arch Pathol Lab Med 117(2): 177-9. Gold MS. 2002. Hypotonic-hyporesponsive episodes following pertussis vaccination: A cause for concern? Drug Saf 25(2):85-90. Goodman, S. 2002. Research Strategies for Investigating Inborn Errors of Metabolism. Presentation to Immunization Safety Review Committee: Irvine, CA Greco D, Salmaso S. Mastrantonio P. Giuliano M, Tozzi AK, Anemona A, Ciofi degli Atti ML, Giammanco A, Panei P. Blackwelder WC, Klein DL, Wassilak SG. 1996. A controlled trial of two acellular vaccines and one whole-cell vaccine against pertussis. Progetto Pertosse Working Group. N Engl J. Med 334(6):341-8. Gumenscheimer M, Mitov I, Galanos C, Freudenberg MA. 2002. Beneficial or deleterious effects of a preexisting hypersensitivity to bacterial components on the course and outcome of infection. Infect Immun 70(10):5596-603. Guntheroth WG, Spiers PS. 2002. The triple risk hypotheses in sudden infant death syndrome. Pediatrics 110(5):e64. Harper R. 2002. Neuroregulation and Sudden Infant Death. Presentation to Immunization Safety Review Committee: Irvine, CA. Harper RM. 2000. Sudden infant death syndrome: A failure of compensatory cerebellar mecha- nisms? Pediatr Res 48(2): 140-2. Harper RM. 2001. Autonomic control during sleep and risk for sudden death in infancy. Arch Ital Biol 139(3):185-94. Harper RM, Kinney HC, Fleming PJ, Thach BT. 2000. Sleep influences on homeostatic functions: Implications for sudden infant death syndrome. RespirPhysiol 119(2-3):123-32. Heijbel H. Ciofi degli Atti MC, Harzer E, Liese J. Preziosi MP, Rasmussen F. Schmitt HJ, Storsaeter J. Taranger J. Uberall M, Tozzi AK. 1997. Hypotonic hyporesponsive episodes in eight pertus- sis vaccine studies. Dev Biol Stand 89:101-3. Holgate ST, Walters C, Walls AF, Lawrence S. Shell DJ, Variend S. Fleming PJ, Berry PJ, Gilbert RE, Robinson C. 1994. The anaphylaxis hypothesis of sudden infant death syndrome (SIDS): Mast cell degranulation in cot death revealed by elevated concentrations of tryptase in serum. Clin Exp Allergy 24(12): 1115-22. Howat WJ, Moore IE, Judd M, Roche WR. 1994. Pulmonary immunopathology of sudden infant death syndrome. Lancet 343(8910):1390-2. IOM (Institute of Medicine). 1991. Adverse Events Following Pertussis and Rubella Vaccines. Wash- ington, DC: National Academy Press. IOM 1994a. Adverse Events Associated With Childhood Vaccines: Evidence Bearing on Causality. Washington, DC: National Academy Press. IOM. 1994b. DPT Vaccine and Chronic Nervous System Dysfunction: A New Analysis. Washington, DC: National Academy Press. IOM. 2001a. Immunization Safety Review: Measles-Mumps-Rubella Vaccine and Autism. Washing- ton, DC: National Academy Press. IOM. 2001b. Immunization Safety Review: Thimerosal-Containing Vaccines and Neurodevelopmental Disorders. Washington, DC: National Academy Press.

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.

82 IMMUNIZATION SAFETY REVIEW Overpeck MD, Brenner RA, Cosgrove C, Trumble AC, Kochanek K, MacDorman M. 2002. National underascertainment of sudden unexpected infant deaths associated with deaths of unknown cause. Pediatrics 109(2):274-83. Parham P. 2000. Elements of the immune system and their roles in defense. The Immune System. First ed. New York: Garland Publishing. Pp. 1-30. Perry GW, Vargas-Cuba R. Vertes RP. 1997. Fetal hemoglobin levels in sudden infant death syn- drome. Arch Pathol Lab Med 121(10):1048-54. Pless R. Casey C, Chen R. 2002. Clinical immunization safety assessment centers: Improving the evaluation, management and understanding of adverse events possibly related to immuniza- tion. [Online] Available: http://www.partnersforimmunization.org/cisa.pdf [accessed Decem- ber 9, 2002]. Regamey RH. 1965. Die Tetanus-Schutzimpfung. Herrlick A, Ed. Handbuch Der Schutzimpfungen. Berlin-Heidelberg-New York: Springer. Ridgway D. 1998. Disputed claims for pertussis vaccine injuries under the National Vaccine Injury Compensation Program. J Investig Med 46(4): 168-74. Rinaldo P. Yoon HR, Yu C, Raymond K, Tiozzo C, Giordano G. 1999. Sudden and unexpected neonatal death: A protocol for the postmortem diagnosis of fatty acid oxidation disorders. Semin Perinatol 23(2):204-10. Rinaldo P. Studinski AL, Matern D. 2001. Prenatal diagnosis of disorders of fatty acid transport and mitochondrial oxidation. Prenat Diagn 21(1):52-4. Rognum TO, Saugstad OD. 1993. Biochemical and immunological studies in SIDS victims. Clues to understanding the death mechanism. Acta Paediatr Suppl 82 Suppl 389:82-5. Schmitt HJ, Schuind A, Knuf M, Beutel K, Schulte-Wissermann H. Gahr M, Schult R. Folkens J. Rauh W. Bogaerts H. Bork HL, Clemens R. 1996. Clinical experience of a tricomponent acel- lular pertussis vaccine combined with diphtheria and tetanus toxoids for primary vaccination in 22,505 infants. JPediatr 129(5):695-701. Schoen EJ, Baker JC, Colby CJ, To TT. 2002. Cost-benefit analysis of universal tandem mass spectrometry for newborn screening. Pediatrics 110(4):781-6. Schwartz HJ, Yunginger JW, Schwartz LB. 1995. Is unrecognized anaphylaxis a cause of sudden unexpected death? Clin Exp Allergy 25(9):866-70. Schwartz PJ, Stramba-Badiale M, Segantini A, Austoni P. Bosi G. Giorgetti R. Grancini F. Marni ED, Perticone F. Rosti D, Salice P. 1998. Prolongation of the QT interval and the sudden infant death syndrome. NEngl JMed 338(24):1709-14. Schwartz PJ, Priori SG, Dumaine R. Napolitano C, Antzelevitch C, Stramba-Badiale M, Richard TA, Berti MR, Bloise R. 2000. A molecular link between the sudden infant death syndrome and the long-QT syndrome. N Engl J Med 343(4):262-7. Silvers LE, Ellenberg SS, Wise RP, Varricchio FE, Mootrey GT, Salive ME. 2001. The epidemiol- ogy of fatalities reported to the Vaccine Adverse Event Reporting System 1990-1997. Pharmacoepidemiol Drug Saf 10(4):279-85. Spiess H. Staak E. 1973. [Anaphlylactic reaction following active tetanus immunization] Anaphylaktische reaktionen nach aktiver Tetanus-Immunisierung. Deutsche Medizinische Wochenschrift 98:682. Staak M, Wirth E. 1973. [Anaphylactic reactions following active tetanus immunization] Zur problematik anaphylaktischer reaktionen nach aktiver Tetanus-Immunisierung. Deutsche Medizinische Wochenschrift 98:110-111. Steinschneider A, Freed G. Rhetta-Smith A, Santos VR. 1991. Effect of diphtheria-tetanus-pertussis immunization on prolonged apnea or bradycardia in siblings of sudden infant death syndrome victims. J Pediatr 119(3):411-4. Strauss AW, Powell CK, Hale DE, Anderson MM, Ahuja A, Brackett JC, Sims HF. 1995. Molecular basis of human mitochondrial very-long-chain acyl-CoA dehydrogenase deficiency causing cardiomyopathy and sudden death in chil&ood. Proc Natl Acad Sci USA 92(23): 10496-500.

VACCINATIONS AND SUDDEN UNEXPECTED DEATH IN INFANCY 83 Sullivan FM, Barlow SM. 2001. Review of risk factors for sudden infant death syndrome. Paediatr PerinatEpidemiol 15(2):144-200. Vege A, Rognum TO. 1999. Inflammatory responses in sudden infant death syndrome past and present views. FEMS Immunol Med. Microbiol 25(1-2):67-78. Vege A, Rognum TO, Scott H. Aasen AO, Saugstad OD. 1995. SIDS cases have increased levels of interleukin-6 in cerebrospinal fluid. Acta Paediatr 84(2):193-6. Ward J. 2002. Analysis of Mortality Risk Following Vaccination. Presentation to Immunization Safety Review Committee: Irvine, CA. Wattigney WA, Mootrey GT, Braun MM, Chen RT. 2001. Surveillance for poliovirus vaccine ad- verse events, 1991 to 1998: Impact of a sequential vaccination schedule of inactivated poliovi- rus vaccine followed by oral poliovirus vaccine. Pediatrics 107(5):E83. Wedgewood RJ. 1972. Review of USA Experience. Camps FE, Carpente RG, Eds. Sudden and Unexpected Death in Infancy (Cot Deaths). Bristol, England: Wright. P. 28. Werne J. Garrow I. 1946. Fatal Anaphylactic Shock: Occurrence in identical twins following second injection of diphtheria toxoid and pertussis antigen. JAMA 730-35. Wilcox RL, Nelson CC, Stenzel P. Steiner RD. 2002. Postmortem screening for fatty acid oxidation disorders by analysis of Guthrie cards with tandem mass spectrometry in sudden unexpected death in infancy. J Ped iatr 141 (6): 833-6. Willinger M, James LS, Catz C. 1991. Defining the sudden infant death syndrome (SIDS): Delibera- tions of an expert panel convened by the National Institute of Child Health and Human Devel- opment. Pediatr Pathol 11(5):677-84.

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

Next: Appendix A: Committee Recommendations and Conclusions from Previous Reports »
Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy Get This Book
×
Buy Paperback | $39.00 Buy Ebook | $31.99
MyNAP members save 10% online.
Login or Register to save!
Download Free PDF

With current recommendations calling for infants to receive multiple doses of vaccines during their first year of life and with sudden infant death syndrome (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.

The committee reviewed epidemiologic evidence focusing on three outcomes: SIDS, all SUDI (sudden unexpected death in infancy), 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 concerning the pathogenesis of SIDS.

  1. ×

    Welcome to OpenBook!

    You're looking at OpenBook, NAP.edu's online reading room since 1999. Based on feedback from you, our users, we've made some improvements that make it easier than ever to read thousands of publications on our website.

    Do you want to take a quick tour of the OpenBook's features?

    No Thanks Take a Tour »
  2. ×

    Show this book's table of contents, where you can jump to any chapter by name.

    « Back Next »
  3. ×

    ...or use these buttons to go back to the previous chapter or skip to the next one.

    « Back Next »
  4. ×

    Jump up to the previous page or down to the next one. Also, you can type in a page number and press Enter to go directly to that page in the book.

    « Back Next »
  5. ×

    To search the entire text of this book, type in your search term here and press Enter.

    « Back Next »
  6. ×

    Share a link to this book page on your preferred social network or via email.

    « Back Next »
  7. ×

    View our suggested citation for this chapter.

    « Back Next »
  8. ×

    Ready to take your reading offline? Click here to buy this book in print or download it as a free PDF, if available.

    « Back Next »
Stay Connected!