limit of a 28% relative risk increase reported by these authors for whole cell vaccine (over a baseline risk of 22.5%) corresponds approximately to a two-sided upper limit of a 50% increase in the odds of asthma.

The authors concluded that there was no evidence supporting an increase in allergic disease after pertussis immunization of the magnitude reported in some other studies, and if there was any increased risk, they thought it was most likely to be associated with the acellular pertussis vaccines. However, limitations included wide confidence intervals restriction to symptom development before 2.5 years of age, the unclear and nonstandard statistical approach, and the focus only on the pertussis component of the immunization schedule. Strengths included the randomized, prospective design and small (<5%) loss to follow-up.

Causality Argument

The committee reviewed five studies that utilized controls (Farooqi and Hopkin, 1998; Hurwitz and Morgenstern, 2000; Kemp et al., 1997; Wickens et al., 2001), including a randomized controlled trial (Nilsson et al., 1998) (see Table 4) and one ecological study (Anderson et al., 2001). Outcomes assessed included allergic symptoms (wheezing) and allergic disorders (hay fever and asthma). All the studies examined exposure to DTaP or DTwP, and other vaccines given concurrently, such as MMR and polio vaccines, but no two studies examined exactly the same exposure.

While many of these studies reported elevated odds ratios linking immunizations to some allergic outcome, some of which were statistically significant, methodological weaknesses within individual studies, as well as the pattern of results across studies diminish the confidence that the observed associations reflect causal relationships. In the two studies that reported a significant positive effect of DTP or tetanus immunization or the pertussis component of DTwP (Farooqi and Hopkin, 1998; Hurwitz and Morgenstern, 2000), potential sampling bias, caused by substantial losses to follow-up or restriction to subjects with regular medical care, could have distorted the relationship between immunization and allergies.

A problem in most of the studies was that the number of unvaccinated children was small, limiting the ability to control for potentially confounding factors, which are numerous and strong for the outcomes of asthma and atopy, and particularly complex when considering risk over an entire childhood. Adequate control of confounding is a serious issue for observational designs, particularly in this domain, as nonimmunized children typically differ on baseline characteristics from immunized children in ways that are not always measurable. Control can be compromised by imperfect and possibly biased confounder and outcome measurement introduced by retrospective, unblinded review of records or parental report of outcomes or exposures that occurred in the past.



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