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immunological products and vaccines Other
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Peter J Fleming
a Institute of Child Health, Royal Hospital for Children, Bristol BS2 8BJ, b Newcastle Neonatal Service, Ward 35, Royal Victoria Infirmary, Newcastle upon Tyne NE1 4LP, c Department of Child Health, Postgraduate Medical School, Royal Devon and Exeter Hospital, Exeter EX2 5DW, d Nuffield Institute for Health Services, Leeds LS2 9PL
Correspondence to: P Fleming peter.fleming@bris.ac.uk
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Abstract |
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 Top  Abstract
 Introduction
Methods Results Discussion
References
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Objectives: To investigate whether the accelerated immunisation
programme in the United Kingdom is associated, after adjustment
for potential confounding, with the sudden infant death syndrome.
Design: Population based case-control study, February 1993 to
March 1996. Parental interviews were conducted for each death and for
four controls matched for age, locality, and time of sleep.
Immunisation status was taken from records held by the parents.
Setting: Five regions in England with a combined population of
over 17 million.
Subjects: Immunisation details were available for 93%
(303/325) of infants whose deaths were attributed to the sudden
infant death syndrome (SIDS); 90% (65/72) of infants with explained
sudden deaths; and 95% (1515/1588) of controls.
Results: After all potential confounding factors were
controlled for, immunisation uptake was strongly associated with a
lower risk of SIDS (odds ratio 0.45 (95% confidence interval 0.24 to
0.85)). This difference became non-significant (0.67 (0.31 to 1.43))
after further adjustment for other factors specific to the infant's
sleeping environment. Similar proportions of SIDS deaths and
reference sleeps (corresponding to the time of day during which the
index baby had died) among the controls occurred within 48 hours of
the last vaccination (5% (7/149) v 5% (41/822)) and within two
weeks (21% (31/149) v 27% (224/822)). No longer term temporal
association with immunisation was found (P=0.78). Of the SIDS infants
who died within two weeks of vaccination, 16% (5/31) had signs and
symptoms of illness that suggested that medical contact was required,
compared with 26% (16/61) of the non-immunised SIDS infants of
similar age. The findings for the infants who died suddenly and
unexpectedly but of explained causes mirrored those for SIDS
infants.
Conclusions: Immunisation does not lead to sudden unexpected
death in infancy, and the direction of the relation is towards
protection rather than risk.
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What is already known on this topic Potential bias in the studies includes lack of a comparative control group with similar low immunisation uptake and misclassification of cause of death What this study adds After confounding was controlled for, immunisation uptake was lowest among the infants who died, with no temporal relation or correlation with signs and symptoms of illness |
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Introduction |
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Top Abstract
Introduction
Methods Results Discussion
References
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The age at which infants receive their primary course of immunisation corresponds to the peak age for the incidence of the sudden infant death syndrome, promoting speculation that these two events might be related. During the past 20 years sporadic reports1-4 and some methodologically weak case-control studies 5 6 showed a possible association. However, a series of studies came to the opposite conclusion,7-11 and one raised the possibility that an accelerated immunisation programme directly contributed to a reduction in these deaths.12 All these studies share the weakness that they may be biased by residual confounding.13 In particular, an infant who is showing minor symptoms may have immunisation delayed, and infants from the most deprived and geographically mobile families are least likely to be immunised. As these factors may independently influence the risk of the sudden infant death syndrome it is essential that they feature in any analysis.
In 1990 the national immunisation programme in the United Kingdom was accelerated, with immunisation against diphtheria, tetanus and pertussis, and oral poliomyelitis given at ages 2, 3, and 4 months respectively instead of at ages 3, 5, and 9 months. Since 1992 immunisation against Haemophilus influenzae type b has also been given. The accelerated schedule was adopted after recognition that a common reason for low uptake of the vaccine was the mobility of young families who move out of districts before the children had completed the primary courses.14 Recent estimates suggest that 93% of infants complete the primary course by 1 year of age.15
We conducted a large case-control study of sudden unexpected death in infancy
as part of the Confidential Enquiry into Stillbirths and Deaths in
Infancy (CESDI SUDI study), after the changes in the immunisation
programme and the reduction in the rate of the sudden infant death
syndrome in the early 1990s. Findings previously reported from this
study suggested that infants dying of the syndrome and those dying of
explained causes share many of the same underlying factors, including
high levels of deprivation,16 increased
geographical mobility,17 and symptoms
of illness in the 24 hours before death.18
We examine here one of the primary hypotheses of the study
a
temporal relation between the accelerated immunisation programme and
time of death.
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Methods |
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Top Abstract
Introduction
Methods
Results Discussion
References
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The methods of the study are described elsewhere.16-20 Briefly, it was a large, population based, case-control study initially conducted in three former health regions (the South West, Northern, and Yorkshire regions) for two years (February 1993 to January 1995) and expanded (Wessex and Northern regions) for a third year (April 1995 to March 1996). Ethical approval was obtained in each region from the local research ethics committees. The study aimed to include all sudden unexpected deaths (both explained and unexplained) of infants aged 1 week to 1 year from a total study population of 17.7 million people. Four age matched controls for each case were selected.
An interviewer visited each control family (matched for locality) within a week of the death to collect the same data as for the index case. A period of sleep (the "reference sleep") corresponding to the time of day during which the index baby had died was identified in the 24 hours before the interviews of the control families.
Data were collected on a questionnaire by research interviewers and from medical records, including details of immunisation from records held by parents. A multidisciplinary committee established cause of death after a full paediatric postmortem examination to a standard protocol.
A modified form of the Cambridge Baby Check was included to capture signs and symptoms of illness in the final 24 hours before death or reference sleep.18 This is a check system to help to quantify illness in babies; medical contact is suggested if infants score more than 7.
An infant was considered immunised if he or she had received any component of the programme before the last or reference sleep. A conservative estimate of the uptake of the immunisation programme was calculated as the proportion of infants who began the programme by age 90 days.
Statistical methodology
Data that were not normally distributed were described by using
medians and interquartile ranges. Correlation was conducted using
Pearson's coefficient. The Mantel-Haenszel
2 test was used to test
individual confounders. Odds ratios, 95% confidence intervals, and P
values for the univariate and multivariate analyses were calculatedwith
the matching taken into account by using conditional logistic
regressionwith the SAS
statistical package.21 Models were
constructed with the stepwise procedure for variables significant at
the 5% level in the univariate analysis.
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Results |
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Top Abstract
Introduction
Methods Results
Discussion
References
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Ascertainment
Over the three years there were over 470 000 births in the study area
and 456 sudden unexpected deaths in infancy, of which 363 were
attributed to the sudden infant death syndrome. Interviews were
conducted for 325 deaths attributed to the sudden infant death
syndrome (90%), 72 of the 93 explained deaths (77%), and the
controls. Immunisation details were available for 93% (303/325) of
the infants whose deaths were attributed to the sudden infant death
syndrome, 90% (65/72) of the infants with explained deaths, and 95%
(1515/1588) of controls.
The major causes of death among the 72 explained deaths were unrecognised infection (46% (33)), accidental (15% (11)), congenital anomalies (14% (10)), and non-accidental injury (13% (9)). The causes of the remaining deaths included metabolic disorders, bowel obstruction, bronchopulmonary dysplasia, and cardiomyopathy.
Proportion immunised and potential confounding
Sudden infant death syndrome
Just under half (149/303) of the SIDS infants (infants whose deaths
were attributed to the sudden infant death syndrome) had begun or
completed the immunisation programme, compared with two thirds
(822/1234) of the controls for the SIDS infantsa
significant univariate difference (odds ratio 0.48 (95% confidence
interval 0.37 to 0.63)). When adjusted for matching, this significance
increased (0.23 (0.14 to 0.37)). The uptake of the programme,
based on infants aged 3 months or older, was 93% (638/688) among the
control infants and 79% (116/146) among the index infants. The table
stratifies immunisation rates for confounding factors that might
explain the lower uptake among SIDS infants. The difference between
the SIDS infants and the control infants was consistent across the
different age groups. The proportion immunised was similar across the
social classes among the controls, with reduced uptake among the
index families in both the highest and lowest social strata. Moving
house was associated with reduced uptake of immunisation for both
groups. The uptake was slightly higher among the younger index
mothers but not among the younger control mothers, and lower among
larger families in both index and control families. Slightly fewer of
the control infants with low birth weight or short gestation had been
immunised, although this was not observed among the index infants.
Increased medical contact either by admission to a special care baby
unit or by subsequent hospital admission was associated with an
increased uptake of immunisation for both groups; similarly, uptake
was highest for the infants who had experienced a life threatening
event, many of whom were seen by their doctor. Few infants had a five
minute Apgar score less than 8; of those who did, a higher proportion
of the controls were immunised.
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After all of the above confounders were controlled for, immunisation uptake
remained strongly associated with a lower risk of the sudden infant
death syndrome (multivariate odds ratio 0.45 (0.24 to 0.85)).
However, when we also controlled for highly significant risk factors
in the infant's sleeping environment for the last or reference sleepsuch
as placing the infant prone or finding the infant with bedclothes
over the headthe
difference became non-significant (0.67 (0.31 to 1.43)).
We also analysed the immunisation uptake for a subgroup of infants
subsequently matched for potential confounding. We selected the
infants with normal birth weight (>2500 g) and gestational age (
37
completed weeks) who had had a normal Apgar score (>7), no history of
an apparent life threatening event, never been admitted to either a
special care baby unit or hospital, and not moved house more than
once in the past year. Preserving the age matching, we chose one
control infant matched for social class (within one stratum),
maternal age (within five years), and parity (within one child). The
resultant comparison yielded 60 SIDS infants and 60 closely matched
controls. In this subgroup 58% (35) of the SIDS infants were
immunised, compared with 63% (38) of the controls. At age 3 months or
older, the corresponding figures were 86% (25/29) and 97% (31/32).
Explained deaths
Of the infants who died of explained causes, 54% (35/65) began or
completed the immunisation programme, compared with 61% (172/281) of
controls (univariate odds ratio 0.51 (0.21 to 1.26)). The uptake of
the programme was 86% (159/184) among the control infants and 82%
(32/39) among the infants who died of explained causes. Of those who
died of infection, 48% (15/31) were immunised, compared with 58%
(74/128) of controls (0.44 (0.11 to 1.65)).
Temporal comparison
Sudden infant death syndrome
The median age at which the first immunisation was given was 61 (interquartile
range 56-71) days for SIDS infants and 59 (36-63) days for controls.
The observed higher proportion of immunised controls was consistent
over age (figure).
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The median time from last immunisation to death was 27 (16-68) days, similar to the 29 (13-70) days until interview for controls. Five per cent (7/149) of the immunised SIDS infants had received a vaccination in the 48 hours before death; 5% (41/822) of immunised control infants had received a vaccination in the 48 hours before the reference sleep. With the period extended to two weeks, the corresponding values were 21% (31/149) and 27% (224/822). The distribution of the interval between the last vaccination and death or reference sleep did not seem to yield a particular interval in which a higher proportion of deaths occurred than expected (P=0.78).
Explained deaths
Of the infants whose death was explained and who had begun or
completed the immunisation programme, 6% (2/35) died within 48 hours
of a vaccination; 3% (6/172) of the age matched immunised controls
had been vaccinated within 48 hours of the reference sleep. With the
interval extended to two weeks, the corresponding values were 17%
(6/35) and 16% (28/172). Of the immunised infants who died of
infection, 7% (1/15) had received a vaccination within two weeks of
death, compared with 9% (12/128) of the immunised controls within two
weeks of their reference sleep.
Signs and symptoms of illness
Sudden infant death syndrome
In the overall study 21% (68/318) of the SIDS infants scored >7 on
the Baby Check (suggesting that medical advice or attention would
have been required) in the 24 hours before death, compared with 7%
(97/1299) of the controls in the 24 hours before the reference sleep
(univariate odds ratio 4.18 (95% confidence interval 2.73 to 6.39)).
Of the SIDS infants who died within two weeks of immunisation, 16%
(5/31) scored >7 on the Baby Check, compared with 26% (16/61) of the
non-immunised SIDS infants who were older than 2 months (babies under
this age would rarely be immunised).
Analysing only the infants aged 2 months or older, we found no correlation, for either the index or the control group or overall, between the interval from the last immunisation to death or reference sleep and the Baby Check score measured in this latter period (Pearson's correlation coefficient 0.01, P=0.70).
Of the 12 signs and symptoms of illness, only two were more common among the SIDS infants (but not controls) who were immunised within two weeks of the reference sleep than among all the SIDS infants in the study. Of these 31 immunised infants, 6 were less alert than usual and 2 had blue fingernails or toenails, but these proportions were not significantly more than expected when compared with the non-immunised infants older than 2 months or with all the SIDS infants.
Among the infants who scored >7 on the Baby Check, 3% (2/68) of the SIDS infants had been immunised within the previous 48 hours, compared with 5% (5/97) of the controls. The composite Baby Check score was similar in these two small groups, as were the signs and symptoms of illness.
Explained deaths
Of the infants who died of explained causes, the proportion of
infants with a high Baby Check score was even more marked: 65%
(20/31) scored >7, compared with 8% (11/132) of the age matched
controls (univariate odds ratio 22.87 (5.46 to 95.83)). Only one
infant died of an infection within two weeks of immunisation (within
10 days), and this infant had no signs or symptoms of illness in the
24 hours before death. Again, we found no correlation between the
interval from the last immunisation to death or reference sleep and
the Baby Check score measured in this period (Pearson's correlation
coefficient 0.07, P=0.50).
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Discussion |
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Top Abstract
Introduction
Methods Results Discussion
References
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More than a third of the deaths attributed to the sudden infant death syndrome in this study occurred between the ages of 2 and 4 months, around the time that most infants in the United Kingdom were receiving all three primary immunisations against Haemophilus influenza type b, diphtheria, tetanus and pertussis, and oral poliomyelitis. For this to be more than coincidental one would expect a higher immunisation uptake among the infants who died than among age matched surviving infants, or at least some temporal pattern compatible with a reaction to immunisation. The findings from this study suggest the opposite: fewer infants whose deaths were attributed to the sudden infant death syndrome were immunised, and fewer deaths occurred than expected, both within two days and two weeks of the last vaccination, with no particular pattern beyond this time period. The findings for the infants who died suddenly and unexpectedly but of explained causes, particularly infections, mirrored those for the infants whose deaths were attributed to the sudden infant death syndrome: lower compliance, no temporal effect, and no correlation between recent immunisation and signs or symptoms of illness. Our data suggest that even when potentially confounding factors, such as family mobility, are taken into account, immunisation does not contribute to the risk of the sudden infant death syndrome and may protect against it.
Possible reactions to immunisation against diphtheria and tetanus and pertussis include fever, vomiting, and listlessness.7 Only listlessness was more common among the infants immunised within two weeks of death, and this was not significantly more than expected. In fact, among the infants whose deaths were attributed to the sudden infant death syndrome and who were older than 2 months, a greater proportion of those not immunised showed signs and symptoms of illness in the 24 hours before death that suggest medical attention would have been required.
Adjustment for confounding
Previously we have found similar characteristics among infants whose
deaths were attributed to the sudden infant death syndrome and among
those who died unexpectedly but of explained causes, with social
deprivation and infant illness shortly before death being strong
markers. 16 18 A
greater proportion of infants whose deaths were attributed to the
sudden infant death syndrome were from socially deprived households
and from younger, larger families, who tended to move home more
often. These infants were also vulnerable in terms of problems at
birth and further hospital admissions. However, these potential
confounders did not explain, either individually or collectively, the
lower than expected immunisation uptake among infants whose deaths
were attributed to the sudden infant death syndrome. The uptake among
the control infants reflected the national average (93%) but the
uptake among the infants who died of the syndrome was 10-15% below
this. After further adjustment for other particularly strong
associations related to the infants' sleeping environment, the
difference in immunisation uptake was not significant but was still
in the direction of immunisation being protective.
Some studies have suggested that immunisation may bring an increased risk for certain subgroups of the infant population. A case series conducted by Walker and colleagues from 1972 to 1983 in the United States suggested an increased risk of the sudden infant death syndrome within three days of primary immunisation for healthy children with normal birth weights,22 although these findings were not subsequently confirmed,23 and a study in France suggested an increased risk among infants under 3 months old.24 In our study, only a fifth of infants aged under 3 months whose deaths were attributed to the sudden infant death syndrome had begun the immunisation programme, compared with a third of the surviving infants. The subgroup analysis of these infants, closely matched for socioeconomic and clinical characteristics with surviving infants, still showed a lower uptake than expected.
Implications
One possible source of error in previous studies would be if the
effect of immunisation were to increase the risk of sudden unexpected
deaths that were subsequently attributed to infection or other
specific causes and thus not registered as the sudden infant death
syndrome. We avoided this bias by including all infants who died
suddenly of identified causes.
Shann has suggested, on the basis of observations from trials in developing countries, that measles vaccination may confer protection from death due to causes other than measles itself.25 Our data are consistent with the hypothesis that the standard primary course of immunisation may also have a non-specific protective effect on the risk of death in infancy, or alternatively that failure to begin the course may be a marker of family organisation where the sudden infant death syndrome may be more frequent.
We therefore conclude that the accelerated immunisation programme in the
United Kingdom is not associated with sudden unexpected death in
infancy, whether the death is explained or unexplained. These data
re-emphasise the importance of rigorous analysis of temporal
associations of apparent significance.
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Acknowledgments |
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Contributors: PJF, PSB, MWP, JT, IJS, and JG were all involved in the concepts and design from the beginning of the study. The analysis was conducted by PSB under the supervision of the others, and all authors were involved in the interpretation of the data, drafting, and revisions. PJF, PSB, JT, and IJS supervised data collection for the whole study period within their particular regions, MWP for the final year of the study.
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Footnotes |
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Funding: The study was supported by research grants from the National Advisory Body for Confidential Enquiry into Stillbirths and Deaths in Infancy, the Foundation for the Study of Infant Deaths, and the Babes in Arms charity.
Competing interests: None declared.
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References |
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Top Abstract
Introduction
Methods Results Discussion
References
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| 1. | Hutcheson R. DTP immunization and sudden infant deathTennessee.
Morb Mortal Wkly Rep 1979; 28: 131-132.
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| 2. | Solberg LK. DTP vaccination, visit to child care health centre and sudden infant death syndrome (SIDS); evaluation of DPT vaccination. In: Oslo: Health Council, 1985:1-19. |
| 3. | Roberts SC. Vaccination and cot deaths in perspective. Arch Dis Child 1987; 62: 754-759[Abstract]. |
| 4. | Flahault A, Messiah A, Jougla E, Bouvet E, Perin J, Hatton F. Sudden infant death syndrome and diphtheria/tetanus toxoid/pertussis/poliomyelitis immunisation [letter]. Lancet 1988; 1: 582-583. |
| 5. | Torch WA. Diphtheria-pertussis-tetanus (DTP) immunization; a potential cause of sudden infant death syndrome (SIDS) [abstract]. Neurology 1982; 32: A169. |
| 6. | Baraff LJ, Ablon WJ, Weiss RC. Possible temporal association between diphtheria-tetanus toxoid-pertussis vaccination and sudden infant death syndrome. Pediatr Infect Dis 1983; 2: 7-11[Medline]. |
| 7. | Hoffman HJ, Hunter JC, Damus K, Pakter J, Peterson D, van Belle G, et al. Diphtheria-tetanus-pertussis immunization and sudden infant death: results of the National Institute of Child Health and Human Development Co-operative epidemiological study of sudden infant death syndrome risk factors. Pediatrics 1987; 79: 598-611[Abstract]. |
| 8. | Taylor EM, Emery JL. Immunisation and cot deaths [letter]. Lancet 1982; ii: 721. |
| 9. | Cameron MH, Williams AL. Development and testing of scoring systems for predicting infants with high-risk of sudden infant death syndrome in Melbourne. Aust Paediatr J 1986; 22(suppl 1): 37-45. |
| 10. | McGlashan ND. Sudden infant deaths in Tasmania, 1980-1986: A seven year prospective study. Soc Sci Med 1989; 29: 1015-1026[Medline]. |
| 11. | Mitchell EA, Stewart AW, Clements M, Ford RPK. Immunisation and the sudden infant deaths syndrome. Arch Dis Child 1995; 73: 498-501[Abstract]. |
| 12. | Dwyer T, Ponsonby A-L, Blizzard L, Newman N, Cochrane JA. The contribution of changes in the prevalence of prone sleeping position to the decline in sudden infant death syndrome in Tasmania. JAMA 1995; 273: 783-789[Medline]. |
| 13. | Fine PE, Chen RT. Confounding in studies of adverse reactions to vaccines. Am J Epidemiol 1992; 136: 121-135[Abstract]. |
| 14. | Jeffries S, McShane S, Oerton J, Victor SR, Beardow R. Low immunization uptake rates in an inner-city health district: fact or fiction? J Public Health 1991; 13: 312-317. |
| 15. | Platt MJ. Child health statistics review. Arch Dis Child 1998; 79: 523-527[Full Text]. |
| 16. | Leach CEA, Blair PS, Fleming PJ, Smith IJ, Ward Platt M, Berry PJ, et al. Sudden unexpected deaths in infancy: similarities and differences in the epidemiology of SIDS and explained deaths [abstract]. Pediatrics 1999; 104: 953. (Entire article available at www.pediatrics.org/cgi/content/full/104/4/e43) |
| 17. | Fleming PJ, Blair PS, Bacon C, Berry J, eds. Sudden unexpected death in infancy. The CESDI SUDI studies. London: Stationery Office, 2000. |
| 18. | Ward Platt M, Blair PS, Fleming PJ, Smith IJ, Cole TJ, Leach CEA, et al. A clinical comparison of SIDS and explained sudden infant deaths. How healthy and how normal? Arch Dis Child 2000; 82: 98-106[Abstract/Full Text]. |
| 19. | Blair PS, Fleming PJ, Smith IJ, Ward Platt M, Young J, Nadin P, et al. Babies sleeping with parents: case-control study of factors influencing the risk of sudden infant death syndrome. BMJ 1999; 319: 1457-1462[Abstract/Full Text]. |
| 20. | Blair PS, Nadin P, Cole TJ, Fleming PJ, Smith IJ, Ward Platt M, et al. Weight gain and sudden infant death syndrome. Changes in weight z-scores may identify infants at increased risk. Arch Dis Child 2000; 82: 462-468[Abstract/Full Text]. |
| 21. | SAS Institute. SAS technical report P-229, SAS/STAT software: changes and enhancements. Release 6.07. Cary, NC: SAS Institute, 1992. |
| 22. | Walker AM, Jick H, Perera DR, Thompson RS, Knauss TA. Diphtheria-tetanus-pertussis immunisation and sudden infant death syndrome. Am J Public Health 1987; 77: 945-951[Abstract]. |
| 23. | Griffin MR, Ray WA, Livengood JR, Schaffner W. Risk of sudden infant death syndrome after immunisation with the diphtheria-tetanus-pertussis vaccine. N Engl J Med 1988; 319: 618-623[Abstract]. |
| 24. | Jonville-Bera AP, Autret E, Laugier J. Sudden infant death syndrome and diphtheria-tetanus-pertussis-poliomyelitis vaccination status. Fundam Clin Pharmacol 1995; 9: 263-270[Medline]. |
| 25. | Shann S. A little bit of measles does you good. BMJ 1999; 319: 4-5[Full Text]. |
(Accepted 16 January 2001)
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