Immunization Safety Review Vaccinations and Sudden Unexpected Death in Infancy (2003) / Chapter Skim
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Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy
Immunization Safety Review: Vaccinations and Sudden Unexpected Death in Infancy
Pages 17-84
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From page 17... ...
The committee's mandate also includes assessing 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.
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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.
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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.
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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")
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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.
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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.
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The committee's examination of biological mechanisms reflects their opinion that available information on possible biological explanations for a relationship between immunization and an adverse event should influence the design of epidemiologic studies and analyses. Similarly, the essential consideration of confounders and effect modifiers in epidemiologic studies depends on an understanding of the biological phenomena that could underlie or explain the observed statistical relationship.
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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.
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From page 26... ...
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~.
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From page 27... ...
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~.
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From page 28... ...
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~.
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From page 29... ...
For example, investigators have found indications of underlying metabolic 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)
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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 "metabolic autopsy" in cases of sudden unexpected infant death (Wilcox et al., 2002~.
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Anaphylaxis is known to be a rare but causally related adverse event following the administration of some vaccines. Anaphylaxis related to vaccination has been discussed in detail in previous IOM reports (IOM, 1991; 1994a)
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32 of JO Up Ct I · C)
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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)
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From page 35... ...
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.
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From page 36... ...
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.
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From page 37... ...
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)
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. 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)
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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.
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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 identified through a network of professionals and lay organizations (Leach et al., 1999)
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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%)
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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 medical status.
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of the SIDS deaths. A total of 1,800 controls was randomly selected from all births in the study regions (except home births)
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With the assumption that all cases with missing immunization records had been immunized (the assumption most likely to provide an indication of any increased risk associated with immunization) , no changes in significance were seen in the multivariate odds ratios for birth, 3 months, and 5 months.
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Nine cases of SIDS were identified: six deaths occurred among infants who received the combined vaccine, and three deaths occurred among those who received the vaccines separately. Autopsies were performed for all of the SIDS deaths.
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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%~.
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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 multiple vaccines and all sudden unexpected death in infants (SUDI)
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From page 48... ...
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)
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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)
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case-con~1 Cases: 118 SIDS deaths of haunts born between January 1983Dece~er 1987 Controls: 332 haunts matched Scoring ~ sex, bow dam, Ad Me ~ dead France At least 1 dose of te~av~ent dipbtber1~-tetanus-pertussispoHo vaccine or ~v~ent dipbtber1~-tetanus-pertussis .
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unavailable. weaknesses in the study limit its contribution to the causality argument.
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the study period New Zealand Cot Death Study SIDS
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causality argument.
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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~.
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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.
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From page 56... ...
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)
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Controls sudden unexpected deaths Univariate OR (explained deaths were (95% CI ) classified as SUDI)
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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~.
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From page 59... ...
provided sufficient evidence to indicate a link between vaccines, anaphylaxis, and infant death. Further support of causality is based on the wellestablished biologic mechanism that anaphylaxis can occur after exposure to a foreign antigen or drug and by the temporal sequence of observed events following vaccination.
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From page 60... ...
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 condition)
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From page 61... ...
Because of the nature of the available case reports and the limited, unpublished epidemiological data, the committee 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
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From page 62... ...
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.
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From page 63... ...
Other research suggests that a subset of SIDS deaths may result from a developmental abnormality in a medullary network of serotonergic neurons that leads to the failure of protective responses to stressors during sleep (e.g., asphyxia, hypoxia) (Kinney et al., 2001~.
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From page 64... ...
and receipt of whole-cell pertussis vaccines (DTwP, DTwP-HiB)
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From page 65... ...
, 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 disorders generally occur under circumstances, such as illness or fasting, that limit the supply of glucose and increase fat metabolism.
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From page 66... ...
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.
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From page 67... ...
In the absence of experimental or human evidence demonstrating the ability of vaccines to stimulate an abnormal inflammatory response in the lung leading to sudden unexpected infant death, the committee concludes that this mechanism is only theoretical. Anaphylaxis and related hypersensitivity reactions.
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From page 68... ...
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)
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From page 69... ...
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.
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From page 70... ...
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 vaccine 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.
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From page 71... ...
Except in the case of an immediate anaphylactic reaction resulting in death, the evidence regarding biological mechanisms was essentially theoretical, reflecting in large measure the lack of knowledge concerning the pathogenesis 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.
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From page 72... ...
The committee encourages greater emphasis on population-based surveillance of vaccine recipients as a basis for epidemiologic studies, together with continued basic and clinical research 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.
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From page 73... ...
The committee notes that in future studies of infant death it would be especially important to identify the timing of death in relation to vaccine administration. Clear distinctions should be made whenever possible between SIDS deaths and sudden unexpected infant deaths with an identifiable cause.
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From page 74... ...
Also available is an international standardized protocol for autopsies 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)
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From page 75... ...
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 unexpected infant deaths.
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From page 78... ...
.1996a. Guidelines for Death Scene Investigation of Sudden, Unexplained Infant Deaths: Recommendations of the Interagency Panel on Sudden Infant Death Syndrome.
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From page 79... ...
2001. The relation between newborn hemoglobin F fractions and risk factors for sudden infant death syndrome.
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2002. The triple risk hypotheses in sudden infant death syndrome.
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1995. Sudden infant death syndrome and diphtheria-tetanuspertussis-poliomyelitis vaccination status.
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1997. Fetal hemoglobin levels in sudden infant death syndrome.
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From page 83... ...
2001. Review of risk factors for sudden infant death syndrome.
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From page 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
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