| ||||||||||||||||||||||||||||||
|
|
|||||||||||||||||||||||||||||
| Copyright © 2009. National Academy of Sciences. All rights reserved. Terms of Use and Privacy Statement |
Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter.
Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.
Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.
OCR for page 125
Page 125
5
Evidence Concerning Pertussis Vaccines and Deaths Classified as
Sudden Infant Death Syndrome
CLINICAL DESCRIPTION, DIAGNOSIS, AND
PATHOLOGY
Prior to the 1960s, little was known about the epidemiology of
the sudden infant death syndrome (SIDS). Deaths that occurred
suddenly and unexpectedly were generally certified as being due to
another cause of death such as pneumonitis rather than an unknown
cause (Peterson, 1980). In an international conference in 1969,
SIDS became defined as "the sudden death of any infant or young
child, which is unexpected by history, and in which a thorough
postmortem examination fails to demonstrate an adequate cause of
death" (Bergman et al., 1970, p. 18). The postmortem examination to
be performed was specified to include gross examination of the
thorax, abdomen, brain, and larynx; histologic examination of the
brain, heart, lungs, liver, kidney, and any other organs suspected
to be involved by either history or macroscopic findings; and any
additional studies (e.g., cultures and toxicology) indicated by any
of those findings. In many children who die from SIDS, petechiae
are found on the surfaces of the lung, pericardium, and thymus and
have been ascribed to nonspecific agonal anoxia. However, there are
no pathognomonic findings; the diagnosis therefore is one of
exclusion, a process that depends on the training, experience, and
judgment of the examiner (Peterson, 1980).
It was not until 1975 that the coding of such deaths was
modified, so that these deaths could be classified specifically as
SIDS. The use of a standard
OCR for page 126
Page 126
definition and the specific classification of SIDS as a distinct
syndrome has facilitated identification of such cases, permitting
the emergence of the descriptive epidemiology of SIDS in the 1970s
and 1980s.
DESCRIPTIVE EPIDEMIOLOGY
SIDS occurs almost exclusively in infants between the ages of 2
weeks and 1 year. In industrialized countries, it is the most
common diagnosis in infants who die between the ages of 1 month and
1 year (Thach, 1986). The age distribution of cases peaks at age 2
to 3 months and then gradually subsides, with only a small
percentage of cases occurring after age 6 months. In the words of
Peterson (1980, p. 100), "This [age} pattern has been documented
time after time and constitutes the single most consistent,
provocative and unique characteristic of SIDS yet identified."
Crude mortality as a result of SIDS reported from throughout the
world has ranged from 0.3 to 5.2 per 1,000 live births (Golding et
al., 1985). Although these differences in reported rates may be
explained partly by differences in classification of deaths caused
by SIDS, most of the variation in rates is probably due to real
differences in the occurrence of SIDS in diverse populations. The
great majority of SIDS deaths occur at home or en route to a
hospital (Golding et al., 1985). A number of investigators have
reported seasonal variations in SIDS mortality rates, with a
relative increase in frequency in winter months (Golding et al.,
1985).
Predictors of SIDS include individual characteristics (male sex,
low birth weight, multiple births, and black race), maternal
characteristics (young age, low education, and cigarette smoking),
and low family income (Haglund and Cnattingius, 1990; Hoffman et
al., 1987; Kraus et al., 1989). Rates in blacks have consistently
been reported to be higher than those in whites; however, in one
analysis (Kraus et al., 1989), this difference disappeared after
controlling for maternal education and family income.
It has been postulated that apnea during sleep is a mechanism of
SIDS, and evidence concerning this hypothesis has recently been
reviewed (Sullivan, 1988). Ventilatory patterns during sleep have
been studied (Keens et al., 1985), and home apnea monitors have
been used for infants thought to be at risk for SIDS (Bryan, 1988).
However, it remains uncertain whether there is a relationship
between abnormal ventilatory patterns or recurrent apnea episodes
and SIDS. In the National Institute of Child Health and Human
Development (NICHD) SIDS Cooperative Epidemiologic Study (reviewed
below), only 6 of the first 400 SIDS cases (1.5 percent) studied
and 1 (0.3 percent) of the matched controls had medically
documented apnea (Damus et al., 1988).
Although deaths from SIDS are, by definition, unexpected,
children who
OCR for page 127
Page 127
die of SIDS tend to be in poorer health than their peers in the
week or two prior to death. Stanton and colleagues (1978) found
that parents reported symptoms considered severe enough to warrant
medical attention or close supervision in the 48 hours before death
or interview for 69 of 145 (48 percent) children who died of SIDS
and only 19 of 154 (12 percent) control children. Gilbert and
colleagues (1990), in a similar study found that parents reported
major or minor signs of illness in the previous week in 66 of 95
(69 percent) SIDS victims and only 71 of 190 (41 percent) control
children matched with cases for age, area of residence, and time of
year. In addition, Gilbert and colleagues (1990) found that 17 (18
percent) SIDS victims had been seen by their general practitioner
during the week preceding death, whereas 11 (6 percent) control
children had been seen by their general practitioner in the
corresponding period. Less pronounced differences in the relative
frequencies of reported symptoms before death or interview were
found in the NICHD SIDS Cooperative Epidemiologic Study (Hoffman et
al., 1988). Although parents of children who died from SIDS may be
more likely to recall and thus report more symptoms in their
children, reporting of doctor's visits over a short time period is
likely to be complete for both cases and controls.
It is noteworthy that some of the factors associated with SIDS,
such as low birth weight, young maternal age, and black race, are
also associated with delaying early childhood immunization past the
recommended age (Hoffman et al., 1987; Walker et al., 1987). The
influence of such delays on the time of occurrence of SIDS in
relation to the time of DPT immunization would depend on the
specific ages over which such delays occurred. The effect could be
to cause children to be immunized at ages associated with either
higher or lower than expected rates of SIDS, and thus produce
spurious direct or inverse associations, respectively, between SIDS
and DPT immunization. Clearly, all factors associated with delaying
immunization should be measured and controlled for as far as
possible in studies of SIDS in relation to DPT vaccine
administration. The ages of study subjects should be considered as
precisely as possible as well. Although the Immunization Practices
Advisory Committee advises the deferral of routine DPT immunization
only for those with a febrile illness (Centers for Disease Control,
1985), in practice, some clinicians may postpone immunizations
because of other minor illnesses (American Academy of Pediatrics,
1986). Since minor illnesses often precede SIDS, the effect of
delaying immunization during such illnesses would be to produce a
spuriously low rate of SIDS in the immediate postimmunization
period. Thus, in addition to age and possible delaying factors, the
potential role of minor illnesses in the timing of immunization is
important to address in evaluating the studies of SIDS and DPT
vaccine administration.
OCR for page 128
Page 128
HISTORY OF SUSPECTED ASSOCIATION WITH
PERTUSSIS VACCINES
In 1933, Madsen reported on two infants who received
immunizations against pertussis shortly after birth and died within
2 hours of their second shot at ages 4 and 11 days, respectively.
Although there were other isolated case reports of death following
DPT immunization, current concern about pertussis and SIDS dates
from March 1979, when the Tennessee Department of Health
(Hutcheson, 1979a,b) reported that four sudden and unexplained
deaths had occurred since November 1978; these infants had all died
within 24 hours following their first DPT immunization. All four
children had received vaccine from the same lot (lot A), which was
the predominant lot in use in Tennessee at that time. A subsequent
investigation confirmed a greater than expected temporal relation
between lot A DPT vaccine and SIDS. However, the overall incidence
of SIDS in Tennessee did not increase during the time period when
lot A was in use, samples of lot A were found acceptable with
regard to potency and freedom from toxicity when tested, and no
other clusters of cases of SIDS associated with lot A (361,000
doses distributed) were reported (Bernier et al., 1982). Therefore,
no other evidence was found to support a causal relationship.
However, that report as well as other case reports prompted further
investigation of the possibility of a relationship between DPT
immunization and SIDS.
EVIDENCE FROM STUDIES IN HUMANS
Case Reports and Case Series
In addition to those just cited, case reports of SIDS include
the deaths of 5- and 10-month-old twins within 3 and 24 hours,
respectively, of DPT immunization (Roberts, 1987; Werne and Garrow,
1946). Episodes of death following administration of DPT vaccine
were reported for six additional children, five of whom died within
48 hours of immunization (Coulter and Fisher, 1985). Torch (1986)
summarized case reports of more than 150 deaths, post-DPT
immunization, which had been reported by 37 authors in 12
countries; approximately 50 percent of these deaths occurred within
24 hours, 75 percent within 72 hours, and 90 percent within 1 week
following DPT administration. For most of these events, no specific
cause of death could be found, and many of these cases were
designated as SIDS. (This summary of case reports was published in
abstract form only.)
Since SIDS occurs primarily in the first year of life, and since
in the United States most children receive three DPT immunizations
during this first year, some cases of SIDS are to be expected in
the early postimmunization period. Accordingly, in the United
States, approximately 55 cases of SIDS
OCR for page 129
Page 129
per year would be expected to occur within 24 hours of receipt
of DPT vaccine (Stetler et al., 1985). If one member of a twin pair
dies of SIDS, the other twin, who is also at higher risk of dying
of SIDS, could, by coincidence, die on the same day (Roberts,
1987). Thus, the deaths in twins cited above could be
coincidental.
Torch (1982) reported, though only in abstract form, preliminary
data on 70 of 200 (35 percent) "randomly reported" cases of SIDS.
He reported clustering of cases within the first 2 to 3 weeks
following DPT immunization. Autopsy findings in children who died
in this early postimmunization interval were no different from
those in other children who died from SIDS. Baraff and colleagues
(1983) were able to interview parents of 145 of 382 (38 percent)
identified cases of SIDS that occurred in Los Angeles County during
a 20-month period. Fifty-three cases had received DPT vaccine prior
to death, 11 percent within 1 day of death, 32 percent within 1
week of death, and 51 percent within 4 weeks of death. The authors
assumed that cases should have occurred with uniform frequency
throughout the 28 days following immunization, but noted instead a
significant increase in the frequencies of reported cases in both
the first day and the first week following DPT vaccination. These
investigators also noted a similar clustering of cases of SIDS
following physician visits that did not include DPT immunization, a
finding that suggests that the prior assumption of uniform
frequency was incorrect.
As pointed out by Mortimer and colleagues (1983), such analyses
are flawed because they do not take into account the age
distribution of cases of SIDS as noted above. Approximately 14
percent of cases of SIDS are age 2 months, 7 percent are age 3
months, and 3 percent are age 6 months at the time of death
(Hoffman et al., 1987). After about age 10 weeks, a day-by-day
decrease in the risk of SIDS has been observed in diverse
populations (Solberg, 1985). If DPT immunization is initiated at
about this age, more SIDS cases would be expected to occur in the
early postimmunization period than later, contrary to the
assumption made by Torch (1982) and Baraff and colleagues (1983).
In addition, both of these case series (Baraff et al., 1983; Torch,
1982) were limited by their failure to include all eligible cases;
only 35 and 38 percent of SIDS cases, respectively, were included
in these analyses, raising the question of whether those cases who
had been recently immunized were selectively included in these
studies.
Three hundred fifty cases of SIDS (ICD 9 code 798.0) occurring
within 28 days of DPT immunization were reported through the
Centers for Disease Control's Monitoring System for Adverse Events
Following Immunization system for 1978 to 1990, a period in which
approximately 80.1 million doses of DPT vaccine were administered
through public mechanisms in the United States (J. Mullen, Centers
for Disease Control, personal communication, 1990). Of these 350
cases, 332 (94.9 percent) occurred in infants
OCR for page 130
Page 130
who had received at least one other vaccine at the time when DPT
was administered. No follow-ups of the cases were conducted, and a
physician's diagnosis was not required.
For the reasons discussed above, reports of single or multiple
cases of death within hours, days, or weeks of DPT administration
offer limited insight into the possibility of a causal connection
between this immunization and the occurrence of SIDS. Therefore, it
is important to consider the reports of controlled studies of SIDS,
in which the questions of an increased risk in the early
postimmunization period can be addressed more adequately.
Controlled Epidemiologic Studies
Seven studies of DPT immunization and SIDS that include
age-matched controls have been published (Bouvier-Colle et al.,
1989; Griffin et al., 1988; Hoffman et al., 1987; Pollock et al.,
1984; Solberg, 1985; Taylor and Emery, 1982; Walker et al., 1987).
In general, these studies take one or both of the following two
approaches. Some investigators look for an association
between DPT immunization status and SIDS in children. This can be
done either through cohort studies of children vaccinated and not
vaccinated or through case-control studies comparing children who
died of SIDS with other children to see whether the SIDS cases were
more likely to have received DPT in an interval before the death.
These studies are summarized in Table 5-1. The second approach
involves comparison of the timing of SIDS deaths relative to DPT
vaccination, to see whether SIDS deaths are clustered in the few
days following vaccination. Because this approach is limited to
exposed cases only, that is, those children who receive DPT
vaccination and die of SIDS, the power to detect an elevated risk
is lower than in the first approach. On the other hand, potential
biases arising from inclusion of unvaccinated children are
avoided. The studies of the timing of SIDS cases relative to
DPT administration are summarized in Table 5-2.
In a study reported as a letter to the editor (Taylor and Emery,
1982), 26 children who died from SIDS were identified over a 3-year
period in Sheffield, England, and 2 age-matched controls were
selected for each child who died from SIDS. Five of 26 (19 percent)
cases and 19 of 52 (37 percent) controls had had a previous DPT
immunization. No significant association of SIDS with DPT
immunization was demonstrated, but the study had a small sample.
The committee's power calculations suggest, for example, that with
a study of this size, a fivefold increase in the risk of SIDS would
have less than an 80 percent chance of being detected, and a
tripling of the risk would have only slightly more than an even
chance of being detected.
Pollock and colleagues (1984) studied a cohort of children
attending regional immunization clinics in Hertfordshire, England,
of whom 6,004
OCR for page 131
OCR for page 132
OCR for page 133
OCR for page 134
OCR for page 135
OCR for page 136
OCR for page 137
OCR for page 138
OCR for page 139
OCR for page 140
OCR for page 141
OCR for page 142
OCR for page 143
Representative terms from entire chapter:
sudden infant
Page 131
were immunized with DPT vaccine and 4,024 were immunized with DT
vaccine. All children were scheduled to receive the primary series
of three immunizations starting at age 3 months. Follow-up was
conducted by a study nurse within 2 days following each
immunization and again 6 to 8 weeks afterward. Combining all doses,
13,917 DPT and 10,601 DT immunizations were administered. Although
the ages at the time of immunization were reportedly similar among
those receiving DPT and DT vaccines, age was not formally
controlled for in the analysis. In addition, other factors that, if
distributed differently between the two groups of children, could
have influenced the relative risk of SIDS were not addressed in
that report.
There were seven cases of SIDS within 6 weeks of immunization,
three (2.2 per 10,000 doses) in the DPT group, at 4, 20, and 37
days, and four (3.8 per 10,000 doses) in the DT group, at 2, 5, 37,
and 40 days. Treating the children who received DT as a control
group, the relative risk of SIDS is 0.6, with a 95 percent
confidence interval of 0.1 to 2.3.1 Although this finding indicates an
inverse association between DPT vaccine and SIDS, the relative risk
is not significantly below 1.0. Because the sample size was very
small, however, the study had low power to detect direct (or
inverse) associations. For example, the relative risk would have
had to be 4.0 to achieve 50 percent power and 7.4 to achieve 80
percent power.
In an investigation of 24 postneonatal deaths in Oslo, Norway,
occurring from 1979 through 1982, it was noted that among 12
children who died within 4 weeks of DPT immunization, there was an
apparent excess of deaths in the first week. Therefore, a larger
study was conducted of 222 deaths from SIDS in five parishes in
Norway (including Oslo and the original 12 cases) from 1975 through
1982 (Solberg, 1985). Within 4 weeks of DPT administration, 53
deaths from SIDS occurred. They were distributed as expected on the
basis of the age distribution of the occurrence of SIDS in three
U.S. populations. Fifteen cases occurred in the first 7 days
following DPT vaccination, and 15.2 cases were expected. Thus, no
relation was found between DPT vaccine and SIDS. The power of this
study was relatively high. A relative risk of 2.0 had an 80 percent
chance of being detected, and the study had 50 percent power
against a relative risk of 1.6. When the original cluster of cases
was examined by this same methodology, an increased rate of SIDS in
the first week post-DPT immunization relative to that observed in
the later period was evident, a result that tends to validate the
author's methods of investigation. Solberg also noted that other
areas of Norway in which the same lot of vaccine was used as was
used in
1 The relative
risk and confidence interval were calculated by the committee from
data provided by Pollock et al. (1984).
Page 132
Page 133
TABLE 5-1 Summary of Controlled Studies Evaluating Estimated
Relative Risk (RR) of SIDS Associated with DPT
Immunization
Population,
Percent Immunized with DPT
Powerb
Reference
Design
Years
No. Births
Description
No. SIDS
No. Controls
SIDS
Controls
RR (95% CI)a
50%
80%
Taylor and Emery, 1982
Matched case-control
1979-1982
~30,000
Sheffield, England
26
52 age-matched
19
37
0.4 (0.1-1.3)
3.2
5.4
Pollock et al., 1984
Cohort
1978-1980
10,028
6,004 and 4,024 children who received 13,917 DPT
and 10,601 DT immunizations, respectively, in Hertfordshire,
England
7 within 6 weeks of DPT or DT immunization
Compare number of SIDS per number of DPT (3)
versus DT (4) immunizations
0.6 (0.1-2.3)
4.0
7.4
Hoffman et al., 1987
Matched case-control
1978-1979
347,800
Six sites that included ~10% of U.S. births
1. 716 autopsy confirmed
1. 757 age-matched
40
55
0.5 (0.4-0.7)
1.4
1.6
2. Same
2. 757 age-, race-, low-birth-weight matched
40
53
0.6 (0.5-0.7)
1.2
1.2
Walker et al., 1987
Matched case-cohort
1972-1983
26,500
Members of Group Health Cooperative, Puget
Sound
29 healthy at birth with birth weight g
262 healthy at birth with birth weight of 2,500 g,
random sample age and period-matched (to generate expected number
of cases)
79
95
0.2 (0.05-0.4)
2.9
4.7
Bouvier-Colle et al., 1989
Matched case-control
1986
Unknown
322 of 522 (62%) registered deaths in France over
3 months in children ages 85 to 365 days in which physician
responded to a questionnaire
1. 152 of 230 (66%) registered SIDS cases
1. 173 of 292 (59%) registered other deaths
40
29
1.6 (1.0-2.5)
1.6
1.9
2. 135 of 152 item 1 above
2. 401 living age-and sex-matched
40
47
0.7 (0.5-1.1)
1.6
1.9
aRR (95% CI), Estimated relative
risk (95 percent confidence interval). RRs and CIs for Pollock et
al. (1984), Walker et al. (1987), and Bouvier-Colle et al. (1989)
were calculated by the committee using data from these reports (see
Appendix D).
b"Power" denotes the probability that a statistical test based on a
sample of the same size as the one in the study cited would find a
statistically significant increased risk (with alpha = 0.05), given
that the true RR in the population being studied is the number
stated in the table. The numbers tabulated are the RRs such that
the powers are 50 and 80 percent, respectively.
Page 134
Page 135
TABLE 5-2 Summary of Controlled Studies Among Immunized Children
Only, Evaluating Estimated Relative Risk (RR) of SIDS in the Time
Interval Immediately Following DPT Immunization
Population,
No. Immunized in Interval
Powerb
Reference
Design
Years
No. Births
Description
No. SIDS
No. Controls
Interval
Observed
Expected
RR (95% CI)a
50%
80%
Solberg, 1985
Ecologic
1975-1982
161,379
Five parishes that included ~40% of Norway's
births
53 within 28 days of immunization
Age distribution of observed SIDS cases compared
with expected distribution based on three U.S. populations
days
15
15.2
1.0 (0.6-1.6)
1.6
2.0
Hoffman et al., 1987
Matched case-control
1978-1979
347,800
Six sites that included ~10% of U.S. births
1. 285 autopsy-confirmed
1. 416 age-matched
<24 hours
5
13.2
0.3 (0.1-0.9)
3.0
4.8
2. Same
2. 403 age-, race-, low-birth-weight matched
5
8.0
0.8 (0.3-2.4)
3.0
4.8
Walker et al., 1987
Matched case-cohort
1972-1983
26,500
Members of Group Health Cooperative, Puget
Sound
23 healthy at birth with birth weight g
262 healthy at birth with birth weight of g,
random sample age and period-matched (to generate expected number
of cases)
=3 days
4
1.4
7.3 (1.7-31.0)
4.2
7.9
Griffin et al., 1988
Cohort
1974-1984
129,834
Children born in Tennessee and immunized at four
county public health clinics
109
Rates of SIDS 0-3 days compared with those days
post-DPT, controlling for age
days
2
7
0.2 (0.04-0.8)
4.4
8.4
aRR (95% CI), Estimated relative
risk (95 percent confidence interval).
b
"Power" denotes the probability that a statistical test based on a
sample of the same size as the one in the study cited would find a
statistically significant increased risk (with alpha = 0.05), given
that the true RR in the population being studied is the number
stated in the table. The numbers tabulated are the RRs such that
the powers are 50 and 80 percent, respectively.
Page 136
Oslo did not have such a clustering of cases of SIDS following
vaccination. He concluded that the original cluster was a chance
occurrence unrelated to the lot of vaccine used.
The largest study to date is the NICHD SIDS Cooperative
Epidemiologic Study (Hoffman et al., 1987). All cases of SIDS were
identified in six geographically distinct areas of the United
States in which there were altogether nearly 350,000 live births
during a 15-month period in 1978 and 1979. Using strict pathologic
criteria and including as cases only singleton births with known
immunization status, the investigators identified 716 cases of
SIDS, of whom 40 percent had received at least one DPT
immunization. In two sets of control children, the first set
matched only for age and the second for age, race, and birth
weight, 55 percent (416 of 757) and 53 percent (403 of 757),
respectively, had been immunized. The odds ratio for the risk of
SIDS is 0.5 with a 95 percent confidence interval from 0.4 to 0.7
with the first control group and 0.6 with a confidence interval
from 0.5 to 0.7 with the second control group. This study also has
high power; an increased odds ratio of only 1.6 with the first
control group and 1.25 with the second control group would have an
80 percent chance of being detected with a sample of this size; the
comparable figures for 50 percent power are 1.4 and 1.2.2 After adjustment for 11 other
potential risk factors for SIDS, including maternal age, education,
cigarette smoking, and infant low birth weight, the odds ratios
were 0.7 for vaccinees versus each of the control groups. This
slight decrease in magnitude of the inverse association indicates
that some of these factors are also associated with a failure to
have children immunized at an appropriate age.
A further analysis of the timing of SIDS relative to DPT
vaccination in the Hoffman data was confined to children who had
received at least one DPT immunization and their matched controls:
5 of 277 (1.8 percent) cases of SIDS had been immunized within 24
hours of death compared with 21 of 416 (5 percent) age-matched
controls (odds ratio, 0.3) and 9 of 403 (2.2 percent) controls
matched for age, race, and birth weight (odds ratio, 0.8).
Therefore, there was no evidence for an increased risk of SIDS in
the early postimmunization period. The power of this analysis,
however, is considerably weaker than the one described above
because fewer cases are involved. With either control group, the
analysis had only 50 percent power against an odds ratio of 3.0 and
80 percent power against an odds ratio of 4.8.
A group of 43 infants identified as possible cases of SIDS but
excluded
2 The stated
confidence intervals were calculated by the committee, ignoring the
matching between cases and controls, because the requisite data
were not available to make the proper matched calculation. Assuming
a positive correlation between cases and controls, these intervals
thus overstate the degree of uncertainty in the estimates by an
unknown degree and understate the power to detect an elevated odds
ratio.
Page 137
from the previous analyses because they did not meet the strict
case definition had a history of immunization indistinguishable
from that of the definite cases (37 versus 40 percent,
respectively). Thus, no SIDS-like group of deaths was found to be
associated with DPT immunization.
Walker and colleagues (1987) linked vital records and the
membership files of the Group Health Cooperative of Puget Sound
from 1972 to 1983 to identify all deaths at ages from 30 to 365
days among children who had been born at Group Health Cooperative
hospitals. Twenty-nine deaths from SIDS occurred among
approximately 26,500 children with normal birth weights and no
serious medical conditions at birth. Immunization records of cases
were compared with those of a sample of 262 other children in the
total birth cohort. Cases of SIDS were less likely to have been
immunized with DPT (the estimated relative risk in the matched
analysis was 0.2 with a 95 percent confidence interval of 0.05 to
0.4) than were controls. Despite this finding of a statistically
significant inverse association, the study had relatively low power
to detect direct (or inverse) associations. A study of this size
has 50 percent power against a relative risk of 2.9 and 80 percent
power against a relative risk of 4.7.
Among those who received at least one immunization in this
study, the rate of SIDS in the 0 to 3 days following immunization
was 7.3 times higher than that in the period beginning 30 days
after immunization. Although this ratio is based on only four cases
of SIDS in the 0 to 3 days following immunization, the relative
risk is significantly increased (the 95 percent confidence interval
runs from 1.7 to 31.0). No non-SIDS death occurred in close
temporal proximity to an immunization (Walker, 1990).
Griffin and colleagues (1988) linked computerized immunization
files from four Tennessee counties with vital records and
identified a cohort of 129,834 children born from 1974 through 1984
who received at least one DPT immunization in their first year of
life. In this cohort, 204 deaths were identified between the first
DPT immunization and 365 days of life; 109 of these were classified
as SIDS. The analysis was based on comparing the incidence of SIDS
per person-year of exposure by time postimmunization, and the
calculations were carried out within six age groups within which
the risk of SIDS was relatively homogeneous. Controlling for age,
the rates of SIDS in the 0- to 3- and 4- to 7-day intervals
postimmunization were about 80 percent lower than those in the
reference period more than 30 days postimmunization (odds ratio,
0.2). Similar results were found after controlling for sex, race,
year, birth weight, and enrollment in Medicaid (as an indicator of
socioeconomic status). Since vital records were used to identify
all deaths in the study cohort, it is unlikely that deaths that
occurred in the early postimmunization period were missed
selectively. The observed decreased risk is unexplained, although
the authors speculated that children may be immunized selectively
at times when they appear healthier, and may
Page 138
therefore be at decreased risk for SIDS. The authors also
examined the 95 deaths from causes other than SIDS. No increase in
these deaths in the early postimmunization period was observed.
A study of all deaths from SIDS in France from January through
March 1986 (Bouvier-Colle et al., 1989) followed the report of five
deaths from SIDS within 1 week of DPT immunization over a 2-week
period in March 1986. The investigators compared immunization
histories in 152 of 230 (66 percent) children who died of SIDS both
to 173 of 292 (59 percent) children who died of other causes and to
3 age- and sex-matched living controls per case. The estimated
relative risks (and 95 percent confidence intervals) for these
comparisons were 1.6 (1.0 to 2.5) for decedent controls and 0.7
(0.5 to 1.1) for living controls. As reported, these studies had
reasonable power for detecting positive (or inverse) associations
(approximately 80 percent for an estimated relative risk of 1.9 and
50 percent for an estimated relative risk of 1.6 for the decedent
control group and 1.8 and 1.5, respectively, for the living
controls), so the absence of a statistically significant increased
risk is important. These results are of limited value, however, in
view of the loss of large proportions of two study groups because
of missing information and the consequent potential for bias in
comparing the remaining subjects.
Because of the relatively small size of the samples used in the
studies of the timing of SIDS relative to DPT immunization, the
committee carried out a meta-analysis of these data, using the
methods described in Chapter 3 and Appendix D. Data on the
association between SIDS and vaccination status were not combined
because of the bias in these studies owing to confounding between
vaccination and SIDS because of the socioeconomic and medical
factors discussed by Fine and Chen (1991).
Data from three case series studies (Baraff et al., 1983;
Bernier et al., 1982; Torch, 1982) were also included in this
analysis, once a correction was made for the age pattern of SIDS
(see Appendix D). Estimates of the odds ratio of SIDS cases in
approximately the first 3 days postvaccination relative to
approximately days 8 to 30 postvaccination were estimated from all
studies and combined in a meta-analysis by using the model
developed by DerSimonian and Laird (1986).
The results depend on a number of statistical assumptions, but
the qualitative results are similar regardless of which assumptions
are made. The results of this analysis, shown in Figure 5-1,
reflect whether (1) data from all seven eligible studies with
information on the timing of SIDS relative to DPT vaccination or
only data from the four studies with appropriate controls are used;
(2) the studies were considered a random sample from all possible
studies of the same risk (in statistical terms, a random-effects
model) or a closed set of homogeneous estimates of the same
relative risk (a fixed-effects model); or (3) two, one, or neither
of the results for the two control groups from the study of Hoffman
et al. (1987) are included in the meta-
Page 139
analysis. Alternative assumptions were also made about including
cases occurring more than 30 days postvaccination and to test the
sensitivity of the results to the adjustment for the age pattern of
SIDS, but these had negligible effects on the results.
As Figure 5-1 shows, the pooled relative risk estimate is higher
if the poorly controlled studies are included and varies somewhat
with the treatment of the two control groups from the study of
Hoffman et al. (1987). As expected, the confidence intervals are
wider under the random-effects model, which seems more reasonable
on statistical grounds. None of the calculations, however, leads to
a significantly increased risk of SIDS in the early
postimmunization period. Indeed, if only the well-controlled
studies are
FIGURE 5-1 Meta-analysis results comparing
the estimated risk of SIDS in the
early period postvaccination with that in the late part of the
first month, under
various assumptions: (1) whether all studies or only
well-controlled studies are
included in the meta-analysis, (2) whether a fixed- or a
random-effects model is
assumed, and (3) whether the meta-analysis includes results from
the study of
Hoffman et al. (1987) based on age-matched controls (A) and age-,
race-, and
birth-weight-matched controls (B), on B alone, or on neither (0).
For each set of
assumptions, the mean and 95 percent confidence interval from the
meta-analysis
are shown on a logarithmic scale.
Page 140
included, the protective effect seen in some
of the individual studies begins to emerge as significant. Because
of questions surrounding the use of meta-analysis in epidemiologic
research (Fleiss and Gross, 1991; Spitzer, 1991), these results
cannot be viewed as definitive. They do indicate, however, that
combining the information from the existing studies of the timing
of SIDS and DPT vaccination is not likely to lead to a
statistically significant finding of an increased risk.
The meta-analysis results give a rough sense
of the power of the pooled data to detect elevated relative risk
estimates. The ratio of the upper confidence interval to the
average estimated relative risk in the meta-analysis results
(Figure 5-1) is about 2. This suggests that a doubling of the risk
of SIDS in the period immediately following DPT vaccination would
have only about a 50 percent chance of being detected, even with
the pooled data. On the basis of the studies at hand, about 10
percent of SIDS deaths that occur within 1 month after DPT
vaccination occur within 3 days of vaccination. If half of these, 5
percent, were caused by DPT, there would be only an even chance of
detecting it in the pooled analysis. In his paper prepared for the
committee, Walker (1990) estimated that about 20 percent of the
5,000 annual U.S. SIDS deaths occur within 2 weeks of immunization,
so perhaps 40 percent, or 2,000, occur within 1 month. A 5 percent
increase in this number, 100 cases per year, could go undetected in
the data available.
SUMMARY
All controlled studies that have compared
immunized versus nonimmunized children (Table 5-1) have found
either no association (Bouvier-Colle et al., 1989; Pollock et al.,
1984; Taylor and Emery, 1982) or a decreased risk (Hoffman et al.,
1987; Walker et al., 1987) of SIDS among immunized children. As a
group, these studies have good power, most having more than an 80
percent chance of being able to detect a doubling of the risk.
Although a protective effect of vaccine cannot be ruled out, it is
more plausible that children who are not immunized by the
recommended age are at an increased risk for SIDS because of other
factors, such as socioeconomic status, that are associated both
with delaying immunization and with SIDS (Fine and Chen, 1991). One
small controlled study of infants with unexplained apnea, who may
be at increased risk for SIDS, demonstrated improvement in
ventilatory patterns following DPT immunization (Keens et al.,
1985). There are no data that bear on a possible biologic basis for
a relation between DPT immunization and SIDS, but neither is there
biologic evidence to support a protective effect.
A number of studies offer some information on the timing of SIDS
relative to immunization. The controlled studies shown in Table 5-2
(Griffin et
Page 141
al., 1988; Hoffman et al., 1987; Solberg,
1985; Walker et al., 1987) differ substantially in their estimates
of the increased risk in the early postimmunization period. These
differences may arise because children who are at risk for SIDS
because of factors not included in the analyses are immunized on a
different schedule than their peers, thus, depending on the
comparison population, placing them either farther or closer to an
immunization at the time of death. However, the results of three of
these four studies indicate either an inverse association or no
association between SIDS and DPT immunization. The exception is the
study of Walker and colleagues (1987), which showed a significantly
elevated risk of SIDS in the 0 to 3 days following immunization. It
is possible that adverse events following administration of DPT
vaccine are lot-specific. However, the two studies that examined
vaccine lot as an etiologic factor in deaths from SIDS (Bernier et
al., 1982; Solberg, 1985) found no relation between vaccine lot and
deaths from SIDS.
Also worth considering is whether some deaths
following immunization are not classified as SIDS and therefore
would be missed in studies examining only deaths from SIDS.
In three of the studies, deaths from causes other than SIDS
were examined (Griffin et al., 1988; Hoffman et al., 1987; Walker,
1990). None of these showed an increased rate of deaths from
other causes in the early post-DPT immunization time period.
A meta-analysis of the data on timing of SIDS
deaths relative to DPT immunization shows that, although the
specific numerical estimates of the relative risk of SIDS depend to
some extent on the analytic assumptions that were made (see
preceding section and Appendix D), there is no indication of a
statistically significant increased risk of SIDS in the early
postimmunization period. Even with the pooled data, however, a
doubling of the risk of SIDS in the period immediately following
vaccination would have only about a 50 percent chance of being
found to be statistically significant.
CONCLUSION
The evidence does not indicate a causal
relation between DPT vaccine and SIDS. Studies showing a temporal
relation between these events are consistent with the expected
occurrence of SIDS over the age range in which DPT immunization
typically occurs.
REFERENCES
American Academy of
Pediatrics. 1986. The Red Book. Report of the Committee on
Infectious Diseases, 20th edition. Peter G, ed. Elk Grove, IL:
American Academy of Pediatrics.
Baraff LJ, Ablon WJ,
Weiss RC. 1983. Possible temporal association between
diphtheriatetanus toxoid-pertussis vaccination and sudden infant
death syndrome. Pediatric Infectious Disease Journal
2:7-11.
Page 142
Bergman AB, Beckwith JB, Ray CG, eds.
1970. Sudden Infant Death Syndrome: Proceedings of the Second
International Conference on Causes of Sudden Death in Infants.
Seattle: University of Washington Press.
Bernier RH, Frank JA, Dondero TJ, Turner
P. 1982. Diphtheria-tetanus toxoids-pertussis vaccination and
sudden infant deaths in Tennessee. Journal of Pediatrics
101:419-421.
Bouvier-Colle MH, Flahaut A, Messiah A,
Jougla E, Hatton F. 1989. Sudden infant death and immunization: an
extensive epidemiological approach to the problem in
France—Winter 1986. International Journal of Epidemiology
18:121-126.
Bryan H. 1988. Home monitoring in infants
at risk for SIDS. In: Harper RM, Hoffman HJ, eds. Sudden Infant
Death Syndrome Risk Factors and Basic Mechanisms. New York: PMA
Publishing Corp.
Centers for Disease Control. 1985.
Diphtheria, tetanus, and pertussis: guidelines for vaccine
prophylaxis and other preventive measures. Morbidity and Mortality
Weekly Report 34:405-414, 419-426.
Coulter HL, Fisher BL. 1985. DPT: A Shot
in the Dark. New York: Harcourt Brace Jovanovich.
Damus K, Pakter J, Krongrad E, Standfast
SJ, Hoffman HJ. 1988. Postnatal medical and epidemiological risk
factors for the sudden infant death syndrome. In: Harper RM,
Hoffman HJ, eds. Sudden Infant Death Syndrome Risk Factors and
Basic Mechanisms. New York: PMA Publishing Corp.
DerSimonian R, Laird N. 1986.
Meta-analysis in clinical trials. Statistics in Medicine
6:351-358.
Fine PEM, Chen RT. 1991. Confounding in
studies of adverse reactions to vaccines. Unpublished.
Fleiss JL, Gross AJ. 1991. Meta-analysis
in epidemiology, with special reference to studies of the
association between exposure to environmental tobacco smoke and
lung cancer: a critique. Journal of Clinical Epidemiology
44:127-139.
Gilbert RE, Fleming PJ, Azaz Y, Rudd PT.
1990. Signs of illness preceding sudden unexpected death in
infants. British Medical Journal 300:1237-1239.
Golding J, Limerick S, Macfarlane A. 1985.
Sudden Infant Death: Patterns, Puzzles and Problems. Seattle:
University of Washington Press.
Griffin MR, Ray WA, Livengood JR,
Schaffner W. 1988. Risk of sudden infant death syndrome after
immunization with the diphtheria-tetanus-pertussis vaccine. New
England Journal of Medicine 319:618-623.
Haglund B, Cnattingius S. 1990. Cigarette
smoking as a risk factor for sudden infant death syndrome: a
population-based study. American Journal of Public Health
80:29-32.
Hoffman HJ, Hunter JC, Damus K, Pakter J,
Peterson DR, van Belle G, Hasselmeyer EG. 1987.
Diphtheria-tetanus-pertussis immunization and sudden infant death:
results of the National Institute of Child Health and Human
Development Cooperative Epidemiological Study of Sudden Infant
Death Syndrome Risk Factors. Pediatrics 79:598-611.
Hoffman HJ, Damus K, Hillman L, Krongrad
E. 1988. Risk factors for SIDS: results of the National Institute
of Child Health and Human Development SIDS Cooperative
Epidemiologic Study. Annals of New York Academy of Sciences
533:13-30.
Hutcheson R. 1979a. DTP immunization and
sudden infant death—Tennessee. Morbidity and Mortality Weekly
Report 28:131-132.
Hutcheson R. 1979b. Follow-up on DTP
immunization and sudden infant deaths—Tennessee. Morbidity and
Mortality Weekly Report 28:134-135.
Keens TG, Davidson 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. American Journal of Diseases of
Children 139:991-994.
Kraus JF, Greenland S, Bulterys M. 1989.
Risk factors for sudden infant death syndrome in the US
Collaborative Perinatal Project. International Journal of
Epidemiology 18:113-120.
Page 143
Madsen T. 1933. Vaccination against
whooping cough. Journal of the American Medical Association
101:187-188.
Mortimer EA, Jones PK, Adelson L. 1983.
DTP and SIDS (letter). Pediatric Infectious Diseases 2:492-493.
Peterson DR. 1980. Evolution of the
epidemiology of sudden infant death syndrome. Epidemiologic Reviews
2:97-112.
Pollock TM, Mortimer JY, Miller E, Smith
G. 1984. Symptoms after primary immunisation with DTP and with DT
vaccine. Lancet 2:146-149.
Roberts SC. 1987. Vaccination and cot
deaths in perspective. Archives of Disease in Childhood
62:754-759.
Solberg LK. 1985. DPT vaccination, visit
to child health center and sudden infant death syndrome (SIDS):
evaluation of DPT vaccination. Report to the Oslo Health Council
1985. (Available as NIH Library translation 85-152, Food and Drug
Administration, Bethesda, MD.)
Spitzer WO. 1991. Meta-meta-analysis:
unanswered questions about aggregating data. Journal of Clinical
Epidemiology 44:103-107.
Stanton AN, Downham MAPS, Oakley JR, Emery
JL, Knowelden J. 1978. Terminal symptoms in children dying suddenly
and unexpectedly at home: preliminary report of the DHSS
multicentre study of postneonatal mortality. British Medical
Journal 2:1249-1251.
Stetler HC, Mullen JR, Brennan JP,
Orenstein WA, Bart KJ, Hinman AR. 1985. Adverse events following
immunization with DTP vaccine. Developments in Biological
Standardization 61:411-421.
Sullivan CE. 1988. Upper airway function
and sleep apnea: relevance for unexpected death in infancy. In:
Harper RM, Hoffman HJ, eds. Sudden Infant Death Syndrome Risk
Factors and Basic Mechanisms. New York: PMA Publishing Corp.
Taylor EM, Emery JL. 1982. Immunisation
and cot deaths (letter). Lancet 2:721.
Thach BT. 1986. Sudden infant death
syndrome: old causes rediscovered? (letter). New England Journal of
Medicine 315:126-128.
Torch WC. 1982.
Diphtheria-pertussis-tetanus (DPT) immunization: a potential cause
of the sudden infant death syndrome (SIDS) (abstract). American
Academy of Neurology, 34th Annual Meeting, April 25-May 1, 1982.
Neurology 32(4, part 2):A169-170.
Torch WC. 1986. Characteristics of
diphtheria-pertussis-tetanus (DPT) postvaccinal deaths and
DPT-caused sudden infant death syndrome (SIDS): a review
(abstract). Neurology 36(Suppl. 1):148.
Walker AM. 1990. Does pertussis vaccine
cause sudden infant death? Presentation for Institute of Medicine
Workshop on Possible Adverse Consequences of Pertussis and Rubella
Vaccines, Washington, DC, May 14, 1990. Unpublished.
Walker AM, Jick H, Perera DR, Thompson RS,
Knauss TA. 1987. Diphtheria-tetanus-pertussis immunization and
sudden infant death syndrome. American Journal of Public Health
77:945-951.
Werne J, Garrow I. 1946. Fatal
anaphylactic shock: occurrence in identical twins following second
injection of diphtheria toxoid and pertussis antigen. Journal of
the American Medical Association 131:730-735.
Items in cart [0]
