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
Howard
J. Hoffman,
MA, Jehu C. Hunter,
BS, Karla Damus,
PhD,
Jean Pakter,
MD, Donald
A. Peterson,
MD, Gerald
van Belle, PhD, and
Eileen G. Hasselmeyer,
PhD
From the Epidemiology and Biometry Research Program, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland; Albert Einstein College of Medicine and Columbia University School of Public Health, New York City; and School of Public Health and Community Medicine, University of Washington, Seattle
ABSTRACT. The possible association between diphthe-ria-pertussis-tetanus (DTP) immunization and the sub-sequent occurrence of sudden infant death has been ex-amined using data from the National Institute of Child Health and Human Development (NICHD) Sudden In-fant Death Syndrome (SIDS) Cooperative Epidemiolog-ical Study, a large multicenter, population-based, case-control study. In a preliminary report based on the first 400 eligible singleton SIDS victims and 800 matched living control infants, no temporal association between SIDS and DTP immunization was found. From the final sample of 800 eligible singleton SIDS victims, 95% (n =
757) were defined as definitely or probably having died of SIDS on the basis of pathology data. Data from these
757 case infants and their corresponding control infants
(n = 1,514) are presented in this report. Two control infants, both living, were randomly selected for each case infant: an age-matched control A and an age-, race-, and low birth weight-matched control B. Overall, case infants were less likely to have received any DTP immunization. Only 39.8% of case infants had received at least one DTP immunization compared to 55.0% of control A infants and 53.2% of control B infants. Based on maternal inter-views and postnatal medical records, 1.8% of case infants (five infants) immunized with DTP died within the first 24 hours following immunization. Similarly, 5.0% of con-trol A infants (n = 21) and 2.2% of control B infants (n
= 9) had been immunized within 24 hours of the maternal interview, which represents the comparable time frame
Received for publication March 13, 1986; accepted Nov 26, 1986.
Reprint requests to (H.J.H.) Biometry Branch, NICHD,
Na-tional Institutes ofHealth, Landow-6C-09, Bethesda, MD 20892. PEDIATRICS (ISSN 0031 4005). Copyright © 1987 by the
American Academy of Pediatrics.
for the age-matched control infants. These results con-firm the earlier preliminary findings from the NICHD
SIDS Cooperative Epidemiological Study and suggest that DTP immunization is not a significant factor in the occurrence of SIDS. Pediatrics 1987;79:598-611; sudden
infant death syndrome, diphtheria-pertussis-tetanus vac-cine, risk factor, epidemiology.
No preventive or therapeutic measure, including pertussis vaccine, is completely safe or absolutely effective. Mortimer and Jones’ noted that pertussis vaccine occasionally produces severe reactions with
permanent sequelae or death. It may also produce some milder reactions that are of uncertain signif-icance. Three disturbing reactions to pertussis vac-cine, or perhaps to its combination with diphtheria and tetanus toxoids, are noteworthy. One of these is excessive somnolence, beginning within a few hours after the injection; another is an episode of one to several hours of high-pitched, persistent, uncontrollable screaming that also begins within a few hours following the injection. The third and rarest is an episode of one to several hours of shock with all of its manifestations. According to Morti-mer and Jones,’ death associated with this reaction
has not been recorded, and its pathogenesis has not
been determined. The occasional occurrence of ad-verse CNS reactions to pertussis vaccine is well
after injection and include convulsions and possibly
encephalopathy with permanent brain damage or death. Yet, despite the acknowledged risks, the view
that there is definitely more benefit than risk from
the vaccine has been upheld repeatedly.’4
Beginning with the reports of Hutcheson5’6 in
1979 from Tennessee, concern was raised that a
recent history of DTP immunization could be as-sociated with the occurrence of sudden infant death
syndrome (SIDS). Because of the major public
health implications of such an association, the
re-suits obtained from the first 200 SIDS case infants and their age-matched living control infants from
the National Institute of Child Health and Human
Development (NICHD) SIDS Cooperative
Epide-miological Study were examined while the study was still in progress and presented orally to an ad
hoc meeting sponsored by the US Public Health
Service.7 These early findings from the NICHD case-control study did not affirm an association
between SIDS and DTP immunization. Based on
these results, attention was then redirected to the
suspect lot A of the vaccine used in Tennessee,
which was voluntarily withdrawn from the market
by the manufacturer as a precautionary measure.
A paper presented by Torch’#{176}on April 7, 1982, also suggested an association between SIDS and DTP immunization, but this study had no control subjects and involved parental recall of information ranging from 6 months to 10 years in the past.
There was no systematic sampling frame for
re-cruitment of subjects. Because this study has re-mained unpublished, further details of study
meth-ods are not available.
As a result of Torch’s presentation, a press re-lease based on the first 400 eligible singleton SIDS victims (case infants) and 800 matched living
con-trol infants was prepared by the NICHD, confirm-ing that no positive association could be found in
the preliminary results of the NICHD SIDS
Coop-erative Epidemiological Study. These results were
then presented at the American Pediatric
Society-Society for Pediatric Research annual meeting on
May 12, 1982.” On May 18, 1982, a report based on the results from the first half of the study was presented and later published with the Proceedings of the 17th Immunization Conference by the Cen-ters for Disease Control.’2
This report presents results for DTP
immuniza-tion in relation to the occurrence of SIDS based on all singleton SIDS cases defined on the basis of
pathologic data and their corresponding matched
living control infants from the NICHD SIDS
Co-operative Epidemiological Study.
MATERIALS
AND METHODS
The NICHD SIDS Cooperative Epidemiological Study was designed to enable identification of risk
factors that could differentiate case infants from
noncase infants. The design is that of a multicenter, population-based, case-control study with a sample of 838 case infants (800 singleton and 38 multiple birth case infants) ascertained under a common necropsy protocol to establish SIDS during the 15-month period from October 1978 through December
1979. There were 1,600 age-matched living single-ton control infants and 40 co-multiple birth control
infants recruited into the study from six
geograph-ically defined study centers.
The study population derived from three
rela-tively large sites-Chicago, California (eight coun-ties), and New York City-with 31%, 21%, and 24% of the cases, respectively, and from three smaller sites-Seattle, Upstate New York (20
coun-ties), and St Louis-with 6%, 10%, and 8%,
respec-tively. Rural counties were included in the Califor-nia and Upstate New York study centers. The remaining study centers were primarily urban or suburban. The population of births included within the geographical areas of the six study centers represented approximately 10% of the total births annually in the United States.
Data collection on all infants included a maternal interview and abstraction of all available maternal
(ante-, intra-, and postpartum) and infant postnatal medical records. The maternal interview was sched-uled for approximately 1 month after the infant
died of SIDS. The processing of all study data, including data editing, coding, and
computeriza-tion, was accomplished at the SIDS Data
Coordi-nating Center, Department of Biostatistics, Uni-versity of Washington in Seattle. In addition to the
interview and medical records data, pathology
re-ports were obtained on each case infant, and a
microscopic review of tissues was coordinated through a centralized facility located at the Office
of the Chief Medical Examiner and Coroner of the City and County of San Francisco.
SIDS
Case Infants
SIDS case infants were ultimately identified by pathologic classification of eligible sudden infant deaths. An eligible case infant was defined as any infant who died suddenly and unexpectedly, who
upon postmortem examination was designated as an eligible case infant by a medical examiner or
within the geographic region of a study center, (3)
designated as an eligible SIDS case infant by a
medical examiner or coroner using the standardized
necropsy protocol. Exclusion criteria were: (1) no autopsy performed, (2) major deviations from standardized necropsy protocol during postmortem
examination, (3) any death of an infant younger
than 14 days or older than 24 months of age, (4)
any death of an infant occurring in a hospital if the infant had been in the facility for more than 24 hours immediately prior to death. There were ap-proximately 25 infant deaths excluded from the study because permission was not granted by the
parents or other responsible adult for an autopsy
to be performed. Autopsies were performed in ac-cordance with a common necropsy protocol based on the Jones and Weston’3 report. Twenty-six
dif-ferent slides of tissues were preserved for detailed examination by a panel of three SIDS pathology
experts.
The pathologic classification of the eligible case infants was determined by the pathology study panel and was based on the results of a two-tiered independent review system plus a consensus meet-ing. For the double-blinded first pathology review, histologic findings were recorded. Only microscopic
slides and information regarding age at death and
gestational age and birth weight at delivery was
sent for the first independent review by each of the
panelists. Following the completion of the first review by all three pathologists, panelists independ-ently rereviewed each potential case using their
initial microscopic findings from the first review as
well as the death investigation and gross autopsy reports and any other information available from the local medical examiners’ or coroners’ offices.
Upon completion of the second review, a joint
ses-sion among the three pathologists was convened
during which significant discrepancies in individual assessments of eligible SIDS cases were evaluated and resolved.
The pathology study panel classified the eligible cases into either SIDS, further subgrouped as
“def-mite,” “probable,” or “possible,” or nonSIDS, with
death due to “known cause” or “indeterminate” findings. The algorithm used was based on both the probability of assigning the cause of death as due to SIDS or other cause, as well as the completeness of all data sources on a case infant. Therefore, missing data (eg, lack of a death investigative
re-port) would automatically reduce the highest level of classification from “definite” to “probable” for a case that was histologically compatible with SIDS. A “definite” SIDS meant that at least two of the
three pathology reviewers were in agreement that the infant had at least a 90% chance of having died
of SIDS. A similar two-thirds rule of agreement among pathologists was used to distinguish “prob-able” SIDS (reflecting a 50% to 89% chance of having died of SIDS) from “possible” SIDS (defined as having a 10% to 49% chance of having died of SIDS). All infants thought to have less than a 10%
chance of having died of SIDS were labeled as non-SIDS infants, either with “known cause” or
“inde-terminate cause.” The analysis of results presented
in this paper is restricted to singleton cases
deter-mined by the pathology study panel to be either a “definite” or a “probable” SIDS case. Additional
details regarding both the pathology review process
and some preliminary pathology results from this study have been reported.’4
Control Infants
Two living control infants were
contempora-neously selected for each case infant from the birth certificate-defined pool of eligible infants born in
the study center region. The first control, control
A, was randomly selected from the pool of
age-matched eligible infants. This allowed the age of the control infant at interview to be as close as possible to the age at death of the corresponding
case infant. If the interview could not be obtained within the required time frame (a window of 3 weeks), a new pool of birth certificates was
identi-fled for the selection of an alternate control A. Although this process led to some slippage in the
correspondence of exact month of birth between
case and control infants, it had the advantage of maintaining a close match on age. After written
and telephone contact, the majority of the mothers of control infants agreed to participate in the study. Approximately 20% of those initially identified were not interviewed for the following reasons: not home (6%), moved (7%), refused to be interviewed or to release medical records (4%), and other (4%). In all of these instances, alternate control mothers were selected for the study.
The second control, control B, was selected using
the same criteria for age matching as for control A but was additionally matched for birth weight and race. Birth weight was dichotomized (2,500 g or >2,500 g) and, to achieve a closer match on the low
birth weight infants (2,500 g or less), control B was
matched to within 250 g of the corresponding SIDS
case infant’s birth weight whenever possible. The
third matching criterion for control B, race, was also dichotomized (black or nonblack). The infant’s
race was defined as black if either parent was black, otherwise nonblack. This definition of race was
used because previous studies had indicated that
was associated primarily with the 90% of infants in
this category who were black.
DTP Immunization Status
The infant’s immunization status was considered positive if immunization was confirmed either by maternal interview or postnatal medical records.
For most infants, the immunization status for DTP
or oral polio vaccine was derived from the mother’s response as recorded on the interview schedule.
However, if the postnatal outpatient records
mdi-cated that the infant was immunized, even though the mother’s response was negative or unknown, then the infant was defined as having been immu-nized. There were 25 instances, including both case and control infants, in which the postnatal outpa-tient records indicated that a DTP immunization had occurred and, yet, the interview schedule failed to confirm the immunization. Similarly, there were 52 such instances for oral polio vaccine. It appeared
that the mothers were aware of the DTP immuni-zation more often than of the oral polio
immuni-zation, even though both were usually given at the same visit.
Statistical Methods
Statistical significance was determined using
x2
tests on the incidence data and fourfold tables. The
standard odds ratio estimate and the Mantel-Haen-zel weighted estimate of relative risk have been
used in the univariate comparisons. Also,
multivar-iate logistic regression models were used to estimate
adjusted relative risks in the presence of several variables simultaneously based on the computer subroutines from the General Linear Interactive Modelling System.’5 Matched analyses were
per-formed for some of the univariate comparisons and,
as expected, confirmed that significance levels
based on unmatched analyses were conservative.16
Although refined multivariate techniques for the
analysis of matched case-control studies now exist,
these techniques are complex and expensive and
may even reduce the efficiency of the estimated regression coefficients.’7 Therefore, in this paper we discuss only the unmatched analysis results, leaving to a later methodologic paper a detailed
comparison of matched v unmatched analyses.
RESULTS
The incidences (number of SIDS case infants per
1,000 live births) by race are shown in Table 1.
Information on births and infant deaths for 1979 were provided by the National Center for Health Statistics (R. B. Hartford, personal communica-tion, 1986) so that the incidence in our study areas could be compared with national figures. As shown
in this table, the incidence of SIDS among nonbiack infants is nearly the same as the national data, at
1.10 to 1.25 per 1,000 live births. However, the incidence of SIDS among black infants in the study areas was 29% higher than indicated by the national
data. Although variations in incidences between the different study centers occurred among both black and nonblack infants who died of SIDS, only among black infants was there an overall significant
dif-ference between the cooperative study and national data.
Ofthe 838 eligible case infants, 800 singleton and
38 multiple births, the majority were judged to be
either “definite” or “probable” SIDS case infants
by the pathology study panel. Thus, 757 singleton
case infants (94.6%) and 35 multiple birth case
infants (92.1%) were determined by the pathology
study panel to be either a “definite” or “probable” SIDS case as shown in Table 2.
The distributions of age at death for infants who died of SIDS, and age at interview for control A
TABLE 1. Live Births and Infant, Neonatal, Postneonatal, and Sudden Infant Death Syndrome (SIDS) Mortality Rates by Race for the Geographical Area Encompassed by the National Institute of Child Health and Human Development SIDS Cooperative Epidemiological Study and for Total United States in 1979
Live Infant Neonatal Postneonatal SIDS
Births Mortality Mortality Mortality Mortality
Rate* Rate Rate Rate
Black race
Cooperative study 87,371 22.6 14.8 7.8 3.65
Total United States 577,855 21.8 14.3 7.5 2.82
Nonblack race
Cooperative study 259,909 11.6 8.0 3.5 1.10
Total United States 2,916,543 11.3 7.8 3.6 1.25
Total race
Cooperative study 347,280 14.3 9.7 4.6 1.75
Total United States 3,494,398 13.1 8.9 4.2 1.51
* Infant mortality rate equals the number of infant deaths per 1,000 live births. The
TABLE 2. Eligible Sudden Infant Death Syndrome
(SIDS) Cases (Singleton and Multiple Births) by Final
SIDS Pathology Classification 15
10
5
SIDS C
-Non scs c
2 4 6 8 10 12 14 16 18 20 22 24
AGE IN WEEKS Final Pathology Singleton Multiple
Classificationt Births Births
No. % No. %
“Definite” SIDS 627 78.4 29 76.3
“Probable” SIDS 130 16.3 6 15.8
“Possible” SIDS 18 2.3 0 0.0
“Known Cause” 14 1.8 1 2.6
“Indeterminate” 11 1.4 2 5.3
15
10
U
- -ControA
2 4 6 8 10 12 14 16 18 20 22 24 AGE IN WEEKS
Fig 1. Distributions of age at death for singleton sudden infant death syndrome (SIDS) case infants and age at interview for matched control infants. Percentage distri-butions are plotted by 2-week intervals and shown only through first 24 weeks of life.
and B infants, are shown in Fig 1. There is a slight tendency for more case infants, compared with either set of control infants, to be younger than 6 weeks of age. In general, the three distributions are closely matched, reflecting the successful age-matching for both control groups. The median age at death for case infants was 11.0 weeks (77 days).
The median age at interview for control A infants
was 11.4 weeks (79 days) and for control B infants was 11.5 weeks (80 days). The study finding that the preponderance (80%) of deaths due to SIDS occurred before 5 months of age conforms to a
well-known feature of SIDS epidemiology.2#{176} The peak
incidence between 2 and 3 months of age and the
gradual decline in incidence after 4 months of age
was also demonstrated. Only 16 case infants (2.1%) were more than 12 months of age at death.
The distribution of age at death is shown sepa-rately for black and nonblack case infants in Fig 2. On average, black infants died of SIDS at an earlier age (by approximately 1 week) than nonblack in-fants. The median age at death for black infants was 10.6 weeks (73 days), but for nonblack infants, it was 11.6 weeks (81 days). Because control B
infants were matched for race and birth weight in
I
,,
,I- ,I’-1. -
I-I---.
ConoIB
- SIDS Cas
Fig 2. Distributions of age at death for black and
non-black singleton sudden infant death syndrome (SIDS)
case infants. Median age at death for black SIDS case
infants was 10.6 weeks (73 days), which was 1 week earlier than median age at death of nonblack SIDS case infants, which was 11.6 weeks (81 days) in the National Institute of Child Health and Human Development SIDS Coop-erative Epidemiological Study.
addition to age, this effect is automatically adjusted for in the comparison between case and control B
infants.
Selected
SIDS Risk Factors
The percentages of selected potential risk factors for case and control A and B infants are given in Table 3. Most of these SIDS risk factors of the
newborn, delivery, and postnatal periods have been reported previously based on the findings from the
first half of the study.223 Relative risk estimates
and significance levels, based on the entire sample of 757 singleton pathologically defined case infants and the corresponding number of control A and
control B infants, are shown in Table 3. Because of
the matching on race and low birth weight among
control B infants, most of the newborn and delivery
factors are not significant for that comparison. The
exception was that male sex was significantly
ele-vated among case infants compared with control B
infants.
The comparison of newborn and delivery factors
between case infants and randomly selected control A infants illustrates the strong relationship
be-tween low birth weight and/or preterm birth and
SIDS risk. Black race and low Apgar scores were also significantly associated with SIDS risk.
How-ever, cesarean delivery was not associated with risk
of SIDS.
Most of the maternal factors shown were signif-icant for case infants v the randomly selected
con-trol A infants. Notable exceptions were alcohol use
TABLE 3. Frequency and Associated Estimated Relative Risk for Selected Ne for Sudden Infant Death Syndrome (SIDS) Case and Control Infants
wborn, Del ivery, and Maternal Factors
Risk Factors Infant Group (%) Relative Risk
SIDS Case Control A Control B Control A Control B
Newborn and delivery
Low birth wt (2,500 g) 24.0 6.5 23.9 4.6*
Very low birth wt (1,500 g) 4.5 0.3 4.5 17.8*
Preterm birth (<37 wk) 18.2 4.6 16.4 4.6* 1.1
Very preterm birth (<33 wk) 5.8 0.4 4.6 15.6* 1.3
Cesarean section delivery 16.8 16.3 14.7 1.0 1.2
Apgar score at 1 mm <7 12.7 6.7 12.3 2.0* 1.0
Apgar score at 5 mm <7 4.1 1.2 4.3 35*
o9
Male sex 59.7 51.9 50.2 1.4t 1.5*
Black race 53.6 32.0 53.2 2.5*
Maternal
Parity 0 26.6 39.2 41.4 0.6* #{216}#{149}5*
Parity 2+ 38.1 28.8 26.7 1.5* 1.7*
Maternal age <20 yr 31.5 17.2 21.7 2.2* 1.7*
Maternal age <20 yr at 1st pregnancy 75.4 44.9 53.2 3.8* 2.7*
Maternal education <12 yr 56.7 34.1 35.0 2.5* 2.4*
Cigarette smoking during pregnancy 69.6 37.9 42.0 3.8* 3.2*
Alcohol use during pregnancy 61.2 59.1 62.0 1.1 1.0
Late (26 wk) or no prenatal care 22.5 11.0 11.4 2.4* 2.3*
Low prepregnancy wt (<49.5 kg [<110 lb]) 15.8 13.5 13.1 1.2 1.2
Low pregnancy wt gain (9 kg [20 lb]) 42.3 25.9 30.1 2.1* 1.7*
*P< .001.
tP< .005.
:1:
Because of matching on this factor in the control B infants, result of the study design.the relative risk estimate is inappropriate, ie, 1.0 as a
TABLE 4. Immunization Frequency and Estimate nus-Pertussis (DTP) and Oral Polio Vaccine (OPV) (SIDS) Case and Control Infants
d Relative Risk for Diphtheria-Teta-for Sudden Infant Death Syndrome
Infant Group (%) Relative Risk
SIDS Case Control A Control B Control A Control B
DTP immunization
Yes 39.8 55.0
No 60.2 45.0
No. of infants 716t 757
OPV immunization
Yes 39.5 53.5
No 60.5 46.5
No. of infants 717 757
53.2 #{216}#{149}54* 0.58* 46.8
757
51.8 #{216}#{149}57* 0.61* 48.2
757
*P< .001.
t Information regarding DTP immunization status was unknown for 41 SIDS case infants.
:1:
Information regarding OPV immunization status was unknown for 40 SIDS case infants.with the highest relative risks, with respect to both controls A and B, were: (1) maternal smoking dur-ing pregnancy (A, relative risk 3.8; B, 3.2); (2)
maternal age at first pregnancy less than 20 years
(A, 3.8; B, 2.7), and (3) maternal education less
than 12 years (A, 2.5; B, 2.4).
DTP Immunization and SIDS Risk Factors
The percentages of case and control infants
im-munized with DTP and oral polio vaccine (OPV)
are shown in Table 4. Only 39.8% of case infants
were immunized with DTP compared with 55.0% and 53.2% of control A and B infants, respectively.
The odds ratio estimates of relative risk of a case
infant being immunized with DTP were 0.54 and 0.58 for case infants v control A and B infants, respectively, a highly significant difference
(P
< .001). Nearly identical estimates were obtained for immunization with oral polio vaccine.The percentages of case and control infants im-munized with DTP by race and birth weight cate-gories are shown in Table 5. A significantly larger
percentage of nonbiack infants, 54.6%, were
im-munized with DTP than black infants, 43.5%
(P
<.01). For nonblack infants there was no birth weight
TABLE 5. Diphtheria-Tetanus-Pertussis (DTP) Immunization Frequency and Esti-mated Relative Risk by Race and Birth Weight for Sudden Infant Death Syndrome (SIDS) Case and Control Infants*
Infants Im munized With DTP (%) Relativ e Risk
SIDS Case Control A Control B Control A Control B
Black race 2,500 g >2,500 g
27.1 37.0
45.4 51.4
40.7
51.4 0.54 0.55
No. of infantst (118:265) (22:220) (123:280) Nonblack race
2,500 g >2,500 g
48.2 46.0
59.3 56.8
58.6
59.1 0.65 0.60
No. of infantst (54:278) (27:488) (58:296)
Total immunized (%) 39.8 55.0 53.2
* Relative risk was derived using the Mantel-Haenszel summary odds ratio estimate. t Number of low birth weight (2,500 g) infants is shown first in the parentheses, followed by the number of not low birth weight (>2,500 g) infants.
:I:P<.001. §P<.01.
TABLE 6. Diphtheria-Tetanus-Pertussis (DTP) Immunization Frequency and
Esti-mated Relative Risk for Selected Maternal Factors for Sudden Infant Death Syndrome (SIDS) Case and Control Infants*
Maternal Risk Factors Infants 1mm unized Wit h DTP (%) Relativ
Control A e Risk
Control B SIDS Case Control A Control B
Maternal age (yr)
<20 38.0 50.0 47.0
20-24 39.8 57.4 55.0 0.55t 0.60t
25+ 41.8 55.3 54.9
Parity
0 52.6 58.9 58.9
1 38.0 54.6 48.1 0.57t 0.63t
2+ 32.4 50.0 51.5
Maternal education (yr)
<12 34.7 47.7 47.6
12 39.4 56.8 53.5 0.62t 0.65t
>12 59.6 60.5 59.3
Smoking during pregnancy
Yes 36.2 50.2 48.4
No 47.7 57.4 56.7 .
Time prenatal care began 25 wk gestation Late or no care
42.3 30.1
56.4 43.4
53.7
48.8 o.57 0 60.
* Relative risk was derived using the Mantel-Haenszel summary odds ratio estimate.
tP<.001.
among black infants, only 27.1 % oflow birth weight
case infants were immunized with DTP compared
with 37.0% of the case infants who were not of low
birth weight. Among black control infants, there
was a similar birth weight effect with less DTP
immunization among the low birth weight infants.
A comparison of DTP immunization frequencies by five maternal factors (age, parity, education,
smoking, and prenatal care status) for case and
control infants is given in Table 6. Regardless of
the factor examined, significantly fewer case than
control infants had received the DTP
immuniza-tion, as reflected by the overall Mantel-Haenzel
odds ratio estimates of relative risk which control
for the different levels of each factor. The
obser-vation that infants of young mothers (less than 20 years old) have lower rates of DTP immunization is much more apparent for mothers of control
in-fants than for mothers of case infants. With respect
to mother’s parity at time of the index pregnancy (either for the case or control infant), an inverse relationship was identified for DTP immunization frequency. That is, the first child was more likely to have received DTP immunizations than were infants born later. The most striking result is the
high and similar rate of DTP immunization among
TABLE 7. Multivariate Logistic Regression Estimated Relative Risk for Diphtheria-Tetanus-Pertussis (DTP) Immunization and for 11 Other Potential Sudden Infant Death Syndrome (SIDS) Risk Factors
Control A
Relative Risk
vSIDS
P Value
Control B
Relative Risk
v SIDS
P Value
DPT immunization 0.7 .003 0.7 .016
Low birth wt (2,500 g) 2.8 <.001
Male sex 1.4 .002 1.5 .001
Black race 1.5 .002
Parity 1+ 1.6 .001 2.0 <.001
Maternal age <20 yr 1.6 .004 1.4 .030
Maternal education <12 yr 1.4 .022 1.6 <.001
Cigarette smoking during pregnancy 2.7 <.001 2.8 <.001
Alcohol use during pregnancy 1.1 .353 1.1* .337
Late (26 wk) or no prenatal care 1.3* .088 1.5 .017
Low prepregnancy wt (<49.5 kg [<110 lb]) 1.0w .755 1.2* .268
Low pregnancy wt (9 kg [20 lb]) 1.3 .033 1.2* .096
* Relative risk estimate not significantly different from r.o.
60.5% of control A infants and 59.3% of control B
infants). If mothers had not completed high school,
the rate of DTP immunization was lower for both
case and control infants. Controlling for the effect of maternal smoking during pregnancy and for late
or no prenatal care as well provides similar differ-ences in the rates of DTP immunization for the
groups at high risk for SIDS compared to those at
low risk. The low frequency of DTP immunization
in case infants of mothers with late or no prenatal care (30.1%) is even lower for black case infants, among whom only 24.8% had been immunized.
Although controlling for different levels of SIDS risk factors failed to modify the significantly
re-duced relative risk of DTP immunization among
case and control infants, a multivariate adjustment procedure which takes into account several SIDS
risk factors simultaneously was performed to
ascer-tam whether the significance of the reduced relative
risk for DTP immunization would be affected. The
results indicate that the significantly lower rate of
DTP immunization holds, even when a multivariate
logistic regression is used to account for differences between case and control infants. All eleven factors shown in Table 7 are either positively or not signif-icantly associated with the occurrence of SIDS,
except DTP immunization (relative risk, .7) which is negatively associated with SIDS occurrence.
DTP Immunizations and Postnatal Age
The relationship between DTP immunization and age at death due to SIDS for case infants, or age at interview for control infants, is shown in
Table 8. Only four infants had received a DTP
immunization before 6 weeks of age (42 days). This result is in accordance with the recommendation in
the United States that DTP be administered in
three doses at 2, 4, and 6 months of age during the first year of life.24 At each of the age intervals after
6 weeks, however, case infants were less likely to have been immunized than were control infants.
For example, 77% ofblack control infants (controls
A and B combined) between the ages of 84 and 167 days had received at least one immunization,
com-pared with only 47% of the black case infants. The comparable rates for nonblack infants were 85% of
control infants with at least one DTP immuniza-tion, compared with only 68% of case infants in the
age range of 84 to 167 days. After 6 months of age,
97% of the control infants had been immunized
compared with 85% of the case infants (both races combined).
Although fewer case infants were immunized
with DTP (or oral polio vaccine), the question remains whether the infants who were immunized
TABLE 8. Sudden Infant Death Syndrome (SIDS)
Case and Control Infants Immunized With Diphtheria-Tetanus-Pertussis (DTP) by Race and Age at Death or Interview
Age (d) at Death/Interview
Infants Immunized W ith DTP QTflQ
Case Control A Control B
No. % No. % No. %
Black race
<42 1 1.6 1 3.6 1 2.0
42-83 40 23.8 37 34.6 52 28.4
84-167 50 47.2 58 73.4 95 78.5
168-365 37 88.1 26 100.0 42 93.3
366+ 3 75.0 1 100.0 4 100.0
Nonblack race
<42 0 0.0 0 0.0 1 2.3
42-83 39 31.7 76 37.1 48 38.7
84-167 81 68.1 150 86.7 114 82.6
168-365 23 79.4 52 100.0 33 94.3
366+ 11 91.7 15 93.8 13 100.0
TABLE 10. Distribution of Sudden Infant Death
Syn-drome (SIDS) Case and Control Infants by Number of
Diphtheria-Tetanus-Pertussis (DTP) Immunizations
and by Time Interval Between Last DTP Immunization and Death or Interview
had either more or fewer vaccinations compared
with control infants. The respective conditional
distributions of infants having either 1, 2, or 3 or more DTP vaccinations are shown in Table 9. Slightly more than two thirds of the case infants received a single DTP immunization. The distri-bution of the number of DTP vaccinations for the control B infants was not significantly different
from that of the case infants. However, more con-trol A infants had three or more vaccinations,
18.0%, compared with only 12.3% of case infants who had received three or more DTP vaccinations
(P=.06).
Temporal Association With DTP Immunization
A comparison of the time interval frQm DTP
immunization to death due to SIDS for case infants, or to interview date for control infants, is shown in
Table 10. The most critical comparison in this table
is the percentage of case infants dying of SIDS compared with the percentage of control interviews obtained within 24 hours of receiving a DTP
im-munization. These percentages were 1.8% for case infants, 5.0% for control A infants, and 2.2% for
control B infants. There is no suggestion of an
excess of deaths due to SIDS within the first 24
hours after DTP immunization; in fact, the critical percentage for case infants was the lowest of all
three groups, and nearly identical with that for
control B infants. For the majority of infants,
re-gardless of whether or not the infant died of SIDS or was a living control, the interval since DTP immunization was more than 2 weeks (65.6% of
case infants, 62.5% of control A infants, and 72.5%
of control B infants).
A more detailed examination of the time interval
between DTP immunization and death due to SIDS or control interview date, according to the last DTP
immunization (either first, second, third, or higher), is shown in Table 10. There is no indication of any increased risk for SIDS for infants with DTP im-munization within the past 24 hours as a function of the increasing number of DTP vaccinations. The majority of infants who received a DTP immuni-zation within the past 24 hours had received only
TABLE 9. Distribution of Sudden Infant Death
Syn-drome (SIDS) Case and Control Infants by Number of
Diphtheria-Tetanus-Pertussis (DTP) Immunizations
No. of DTP Immunizations
Infants Immunized With DTP
SIDS Case Control A Control B
No. % No. % No. %
1 195 68.4 249 59.9 257 63.8
2 55 19.3 92 22.1 87 21.6
3+ 35 12.3 75 18.0 59 14.6
Time Interval No. of Infants and No.
of DTP Immunizations
Im munized With DTP
SIDS Case
Control A
Control B
>2 wk
1 126 153 183
2 32 51 59
3+ 29 56 50
No. of infants 187 260 292
%
immunized 65.6 62.5 72.5<2 wk but >24 h
1 65 80 69
2 22 37 26
3+ 6 18 7
No.ofinfants 93 135 102
%
immunized 32.6 32.5 25.3<24 h
1 4 16 5
2 . 1 4 2
3+ 0 1 2
No. of infants 5 21 9
%
immunized 1.8 5.0 2.2one immunization, and there were no differences
between case, control A, or control B infants on
this variable.
Postnatal
Outpatient
Visits
and DTP
Immunization
The relationship between postnatal outpatient
visits and DTP immunization was examined for
case and control infants. More case infants than
control A or B infants had no regular visits (26.1% of case infants, 15.6% of control A infants, and 15.3% of control B infants), with significantly more black than nonblack infants of all groups receiving no well-baby care. In contrast, case infants were
more likely to be seen for a sick visit; overall, 33.8% of case infants, compared with 44.9% of control A
and 44.0% of control B infants, had not been seen for a sick visit since birth. Despite these findings, the percentage of infants immunized with DTP was
lower for case infants than for both groups of
con-trol infants, regardless of the type of visit. These data appear in Table 1 1, where the percentage of infants immunized are presented according to the
type and number of postnatal outpatient visits. For
case infants who had at least one well-baby checkup, 52.3% were immunized with DTP. The rates of DTP immunization for control infants with
one or more well-baby visits were higher: 63.5% for
control A and 62.1% for control B infants. Simi-larly, case infants seen for at least one sick visit
infants-only 46.3% ofcase infants, compared with
63.6% of control A and 62.7% of control B infants,
had been immunized.
A high majority of all infants immunized received
the DTP injection during a well-baby visit (84.5%
of case infants, 90.6% of control A infants, and 89.9% of control B infants). Immunization took
place during the initial follow-up of a sick-baby visit for 13.2% of immunized case infants and about
8% each of immunized control A and B infants. The mean age at time of first and last DTP immunization for case infants and control infants
by gestational age at birth was also examined.
Among term births, there were no differences in
mean age at either first or last DTP immunization
for case and control infants. Among preterm births, there was a tendency for later mean age at both
first and last DTP immunization for case and
con-trol infants. This difference was significant, with a
mean age of 95 days at first DTP immunization for
TABLE I 1. Sudden Infant Death Syndrome (SIDS) Case and Control Infants Immunized With Diphtheria-Tetanus-Pertussis (DTP) by Number of Well- or
Sick-Baby Postnatal Outpatient Visits
Type of Infants Immunized With DTP Postnatal Outpatient
Visit(s) SIDS Case Control A Control B
No. % No. % No. %
Well-baby visit(s)
0 14 7.1 10 8.5 5 4.3
1+ 271 52.3 406 63.5 398 62.1
Sick-baby visit(s)
0 76 28.7 151 44.4 137 41.1
1+ 209 46.3 265 63.5 266 62.7
preterm case infants, compared with a mean age of 68 days for term case infants.
DTP Immunization and Maternal Reports of
Illness or Other Conditions
The relationship between specific illnesses or
conditions, as reported by mothers during the in-terview, and the time interval following the last
DTP immunization was examined for case and
control infants. Four specific conditions were
ex-amined that have been noted as possible reactions
to DTP immunization in prior studies, fever, being
listless or droopy, vomiting, and seizures.25’26 In each instance, the mother was asked whether her
child had had these conditions and, if so, whether it occurred within any of three time intervals
(greater than 2 weeks, less than 2 weeks but greater than 24 hours, or less than 24 hours) since death or interview. The percentage of infants with these conditions has been analyzed in relation to the same time intervals since DTP immunization (Table 12). Of the four conditions, only vomiting shows an
increased rate for case infants compared with con-trol infants. The increase in rates of vomiting was
apparent regardless of whether DTP immunization had occurred within the last 2 weeks, or before, and
did not reach statistical significance.
The numbers of infants who received DTP
vac-cinations during the last 24 hours before death or interview was quite small and there were no
signif-icant differences found. There was, however, a tendency for fever to have been noted more fre-quently within the last 24 hours for control than for case infants. Because only five case infants had
TABLE 12. Sudden Infant Death Syndrome (SIDS) Case and Control Infants by
Moth-er’s Report of Illnesses or Conditions According to Time Interval Since Last Diphtheria-Tetanus-Pertussis (DTP) Immunization
Selected Illnesses or Conditions and No. of Infants
Infants Immunized With DTP (%) SIDS Case Control A Control B Last DTP immunization >2 wk
Fever 33.2 34.2 35.3
Listless or droopy 8.0 6.2 5.8
Vomiting 19.3 15.0 12.7
Seizures 1.1 0.4 0.3
No.ofinfants 187 260 290
Last DTP immunization <2 wk but >24 h
Fever 15.1 19.3 15.8
Listless or droopy 1.1 4.4 2.0
Vomiting 6.5 3.7 2.9
Seizures 0.0 0.0 0.0
No.ofinfants 93 135 101
Last DTP immunization <24 h
Fever 0.0 33.3 22.2
Listless or droopy 0.0 4.8 11.1
Vomiting 0.0 0.0 11.1
Seizures 0.0 0.0 0.0
been immunized within the last 24 hours, if even only one had had a fever reported, there would have
been no apparent difference. The absence of any of
the four conditions being noted among the case infants is probably due to the small number of
them, five, compared with a total of 30 control
infants who were immunized within the last 24 hours.
During the interview, mothers were also asked whether or not their child had any changes in sleep (more sleep, less sleep, or more restless sleep) dur-ing either day or night within the last 2 weeks.
Changes in sleep were not asked about that were
observed only within the last 24 hours prior to death or interview, or for the time period of more than 2 weeks prior to death or interview. The results of the reported sleep changes in relation to time in-terval since the last DTP immunization are shown
in Table 13. No significant differences were ob-served in the percentage of case or control infants with recent sleep changes if the last DTP
immuni-zation had occurred more than 2 weeks previously.
However, if the last DTP immunization occurred within the past 2 weeks prior to death or interview,
fewer case infants were reported by their mothers to have had sleep changes compared with control infants. The percentage of infants with reported
sleep changes was lower among case than control
infants, but reached statistical significance only for control B infants who slept more restlessly. Com-parison of case with control B infants in terms of the other two sleep categories showed no significant differences
(P
< .08).DISCUSSION
The most significant difference with respect to
TABLE 13. Sudden Infant Death Syndrome (SIDS)
Case and Control Infants by Mother’s Report of Changes in Sleep During the Last 2 Weeks Before Death or Interview and Time Since Last
Diphtheria-Tetanus-Per-tussis (DTP) Immunization
Sleep Changes In fants Immunized During Last 2 Wk
and No. of Infants
With DTP (%)
SIDS Case
Control Control
A B
Last DTP immunization >2 wk
Slept more 26.1 25.4 25.8
Slept less 22.0 28.5 25.4
Slept more restlessly 21.2 26.0 24.7
No. of infants 187 260 292
Last DTP immunization within last 2 wk
Slept more 24.7 32.7 36.9
Slept less 20.4 23.7 33.3
Slept more restlessly 17.3 27.6 37.8*
No.ofinfants 98 156 111
*P< .005.
DTP and SIDS found in the NICHD SIDS
Coop-erative Epidemiological Study was the significantly lower incidence of immunization among case in-fants (39.8%) compared with both control A infants
(55.0%) and control B infants (53.2%). Rates of
immunization with oral polio vaccine in this study were nearly identical: 39.5% for case infants, 53.5%
for control A infants, and 51.8% for control B infants. Although some differences have been shown in the patterns of postnatal outpatient visits for case and control infants, it appears unlikely that
such patterns explain the lower rate of immuniza-tion for case infants. All potential sources of
med-ical records were systematically checked for the abstraction of data on postnatal outpatient visits,
and, although more of the care of the case infants
occurred in public clinics, our experience was that the public clinic records were often more complete than data from other sources. Also, when both the maternal questionnaire and postnatal visit records indicated that immunization had occurred, close
agreement was found in terms of the time interval
elapsed since last DTP or oral polio immunization
and either the date of death due to SIDS for case
infants or the date of interview for control infants.
In the rare instances when disagreements did occur, they were understandable; eg, when 15 days were
calculated based on postnatal outpatient visit
rec-ords and, yet, the mother answered “within 2
weeks” instead of “greater than 2 weeks.” Also, the exclusion of 43 infants (5.4%) from the total of 800 infants originally considered as “eligible” singleton
case infants does not affect these immunization
rates. The 43 excluded infants and their corre-sponding control infants had immunization rates indistinguishable from the infants judged by the
pathologists to be either “definite” or “probable” case infants (36.8% for case infants v 60.5% for control A and 55.3% for control B infants).
The most probable explanation for the observed
differences in rates of immunization between case and control infants incorporates the differences found with respect to maternal and infant factors. For example, differences in socioeconomic status
are associated with parental use of the health care system, which directly affects the number of
well-baby checkups.27 Almost 90% of DTP and oral polio immunizations were given during well-baby check-ups. Other explanations that could account for some portion of the observed differences in immu-nization rates include the finding that case infants
experienced more postnatal illness than control
infants, which could contribute to a delay in being
immunized for DTP and polio. The lower
immuni-zation rate of low birth weight black infants
in or no DTP immunization. Nevertheless, it is clear that exposure to DTP immunization does not correlate positively with these two major risk
fac-tors for SIDS, low birth weight and black race.
The observed discrepancy between the incidence
of SIDS in black infants from the NICHD SIDS Cooperative Epidemiological Study and national data (3.65 and 2.82 per 1,000 live births,
respec-tively) probably reflects underreporting of SIDS as
a cause of postneonatal infant death among black infants nationally. This interpretation is supported by the much closer agreement in total postneonatal
mortality rates among black infants between the cooperative study (7.8 per 1,000 live births) and from the national data (7.5 per 1,000 live births). A
recent report based on trends in US vital statistics
data indicates an increasing rate of SIDS during
the past 15 years.28 This evidence of an evolving standard in the assignation of SIDS deaths in the
United States further suggests that there may be underreporting of SIDS as a cause of death in the national data.
It is highly unlikely that infants who died sud-denly and unexpectedly following DTP
immuniza-tion would have been excluded from the study be-cause of selection bias. The cooperative study
in-vestigators did not attempt to dictate the mode of
diagnosis used by participating medical examiners. All potential occurrences of SIDS among infants between 2 weeks and 24 months of age were eligible for inclusion in the study. This definition also con-formed with preexisting protocols at several of the
offices of participating coroners or medical exam-iners. The mode of operation at each such office was not changed. The only constraint was the use
of a standardized autopsy protocol based on the
report by Jones and Weston. This report resulted from recommendations by an experienced panel of
forensic, pediatric, and other pathologists.’3 This minimal protocol was designed to err on the side of
inclusivity rather than exclusivity. The study was fortunate to have two members of the earlier au-topsy protocol panel as members of the pathology
study panel and a third member as director of the pathology coordinating laboratory.
The DTP immunization status for 41 case
in-fants, 5.4%, was undetermined, either because of a failure to obtain a maternal interview or, occasion-ally, because the mother did not know the immu-nization status of her child and no postnatal records were available. It is unlikely that the DTP immu-nization rate for these 5.4% of case infants would be significantly higher than the rate of 39.8% for
case infants with known immunization status. It seems more likely, based on the other known risk
factors for these 41 case infants, that their
immu-nization rate would be less than that of 39.8% for case infants with known DTP immunization status. Nevertheless, the difference in rate of immuniza-tion between case and control infants would remain
highly significant
(P
< .001) even if all 41 case infants with unknown status had been immunized.The effects of DTP immunization on a group of infants and children from birth to 6 years of age
who had been routinely scheduled for DTP immu-nization between Jan 1, 1978, and Dec 15, 1979,
was studied by Cody and colleagues.25 A total of 15,752 DTP immunizations were given. These
chil-dren were followed for 48 hours following immuni-zation by parents who recorded temperatures at 3, 6, 24, and 48 hours and noted the following reac-tions within the follow-up period: redness, swelling, or pain at the injection site; drowsiness; fretfulness;
vomiting; anorexia; persistent or unusual crying;
convulsion; and hypotonic hyporesponsive episode.
No children who had previously experienced severe
adverse reactions following DTP immunizations
were included. Nine convulsions and nine
hypo-tonic hyporesponsive episodes were reported. No
deaths occurred in the study population within 48
hours of immunization. All convulsions occurred
within 24 hours of immunization, with a median time of 14 hours. Hypotonic hyporesponsive
epi-sodes occurred within ten hours of immunization and usually within four hours. From this study it
appears that the more serious reactions of infants to DTP occur within 24 hours after immunization. Because fewer than 2% of case infants enrolled in
the NICHD SIDS Cooperative Epidemiological
Study occurred within 24 hours following immuni-zation, it is difficult to accept that a temporal relationship exists between DTP immunization and SIDS.
A few other reports since 1982 have discussed an association, or a lack of one, between DTP immu-nization and SIDS. Baraff et a129 presented prelim-mary data suggesting a temporal association be-tween DTP immunization, physician visits without DTP immunization, and SIDS. However, a critical
evaluation by Mortimer and colleagues30 of the
methods used in that study concluded that, because of several methodologic biases, the study did not
obtain enough valid information on DTP and SIDS
to clearly establish the purported association. Fulginiti3’ pleaded for further scientific research and publication of relevant data on the issue of
DTP immunization and SIDS. A study reported
from England failed to find any association between
SIDS and DTP immunization.32 A 1985 report from Norway has reached a similar conclusion regarding
an unusual cluster of SIDS cases occurring four to
nine days after DTP immunization in the region
surrounding Oslo between January 1979 and June 1982. From this carefully controlled study, the
in-vestigator concluded that it was extremely unlikely
that the cluster of SIDS cases could be attributed either to the vaccine or to a specific lot of vaccine.
The possible relationship between DTP immu-nization and SIDS is of great importance to par-ents, their families, health care providers, health policymakers, and public health officials. To
ad-dress this important concern, we have provided results from the total set of singleton pathologically defined SIDS case infants and matched living con-trol infants from the NICHD SIDS Cooperative Epidemiological Study. Based on this large multi-center, population-based, case-control study, DTP immunization does not appear to be a significant factor in the occurrence of SIDS.
ACKNOWLEDGMENTS
A large number of individuals contributed to the suc-cess of this study. In particular, we wish to acknowledge the principal investigators and project coordinators from each of the study centers plus other project staff and consultants: Julius Goldberg, PhD, Ronald Hornung, MS, Loyola University of Chicago; Jess Kraus, PhD,
Marilyn Misczynski, MA, University of California at Davis; Donald Peterson, MD, Nina Chinn, RN,
Univer-sity of Washington; Jean Pakter, MD, Ehud Krongrad, MD, Patricia Hanson, RN, Medical Health Research Association of New York; Dwight Janerich, DDS, Susan Standfast, MD, Diane Aliferis, MA, New York State
Health Department; Laura Hillman, MD, Barbara Puder, RRA, Sharon Hollander, MA, Maternal and Child Health Council of St Louis; Data Coordinating Center Gerald
van Belle, PhD (Director), Marjorie Jones, MA,
Cather-me Nanney, MS, Mary Jane Almes, MA, Donald Kunz,
BS, University of Washington; Pathology Coordinating Laboratory: Boyd G. Stephens, MD, Donna J. Allison,
PhD, San Francisco Office of the Chief Medical
Exam-iner and Coroner; Pathology Study Panel Members: Marie A. Valdes-Dapena, MD, University of Miami School of
Medicine; Russell Fisher, MD, Maryland Office of the
Chief Medical Examiner, and Johns Hopkins University Medical School; James Weston, MD, Patricia McFeeley,
MD, New Mexico Office of the Chief Medical Examiner, and University of New Mexico Medical Center; Advisory Committee: Henry L. Barnett, MD (Chairman), Albert Einstein College of Medicine, and Children’s Aid Society, New York City; Ralph R. Franciosi, MD, Children’s
Health Center Laboratory, Minneapolis; William L. Harkness, PhD, Pennsylvania State University, Univer-sity Park; G. Eric Knox, MD, Abbott Northwest Hospital, Minneapolis; Richard R. Naeye, MD, Milton S. Hershey Medical Center, Pennsylvania State University, Hersey; James D. Neaton, MS, University of Minnesota, Mm-neapolis; Zena Stein, MB, New York State Psychiatric Institute, New York City; Consultants: Glen Bartlett,
MD, PhD, Milton S. Hershey Medical Center,
Pennsyl-vania State University, Hershey; David C. Hoaglin, PhD,
Harvard University, Cambridge, MA; William C. Orr, PhD, Presbyterian Hospital and University of Oklahoma Health Sciences Center, Oklahoma City; Philip E. Sar-twell, MD, Harvard School of Public Health, Boston;
Harold Morgenstern, PhD, Yale University, New Haven,
CT; NICHD Staff Eileen G. Hasselmeyer, PhD, RN, Howard J. Hoffman, MA, Charles R. Stark, MD, DPH, Project Officers; Jehu C. Hunter, BS, Study Coordinator; Harvey Shifrin, BA, Contracting Officer; Karla Damus,
PhD, Epidemiology Consultant; Heinz W. Berendes, MD,
Chairman, SIDS Study Review Panel.
In addition, we would like to thank all of the interview-ers, public health nurses, medical records abstractors,
and other staff at each of the participating centers.
Fi-nally, we are indebted to the many local coroners, medical examiners, and pathologists who contributed SIDS cases for this cooperative study.
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MEDICINE’S
DILEMMA
Since medicine, unlike religion, aspires to be a science, it is torn by conflict between the need for criticism and the fear of it.
From Skrabanek P: Demarcation of the absurd. Lancet 1986;1:960-961.
