Monday, January 31, 2011

Too Many, Too Soon?

EXECUTIVE SUMMARY: One of the misgivings about current early-childhood vaccination recommendations is that they involve exposing infants to so many infectious agents. While there's already been research into the effect of multiple vaccines on the immune system, Smith and Woods (2010) are the first to look at whether getting lots of vaccinations very early in life might have any effect on the nervous system.

Using the vaccination records and neuropsychological data on a group of children born between 1993 and 1997 that were gathered and made publicly available for an earlier vaccine-safety study, they did two different group comparisons between children who had received all the recommended vaccines on time and children who hadn't. They found no ill effects of exposure to lots of different vaccines within the first seven months of life; the only effects of earlier vaccination on neuropsychological development that they found were beneficial ones, but these mostly did not survive controlling for other demographic variables.

ResearchBlogging.orgIn an interview with The Thinking Person's Guide to Autism editor Shannon Des Roches Rosa, Autism's False Prophets and Deadly Choices author Dr. Paul Offitt mentioned a study published last May in Pediatrics that addresses the "too many, too soon" version of the vaccines-cause-autism hypothesis.

Some parents of very young children, while they might not believe that any single vaccine is dangerous, notice that a lot more vaccines are recommended within the first six years of life now than there used to be, and wonder whether it might damage a child's immune system to expose that child to so many antigens within such a short period of time*.

While there was already evidence that the current vaccine schedule is safe from an immunological standpoint, Smith and Woods (2010) are the first researchers to look at its potential impact on the developing nervous system.

Their study re-analyzes data gathered for an earlier study looking at neuropsychological outcomes in 7-to-10-year-old children exposed to thimerosal in vaccines; those researchers recruited children from four HMOs participating in the CDC's Vaccine Safety Datalink project, tested them on 42 measures of neuropsychological outcomes (which broadly fell into seven domains --- speech and language, verbal memory, fine motor coordination, attention/executive functioning, behavioral regulation, tics, and general intelligence --- and also included two other tests, one of visuospatial ability and another of letter and word identification; see Table C, or pages 9-11 of this document, for a complete listing), and looked for relationships between a child's performance on those tests and the amount of thimerosal that child had been exposed to, as estimated from vaccination records.

That study didn't find much of an effect for early thimerosal exposure --- it found a small scattering of statistically significant effects, but those effects were 1) often not the same in boys and girls, or in children belonging to different HMO groups, 2) evenly divided between higher mercury exposure --> better outcome and higher mercury exposure --> worse outcome, and 3) very small. That suggests to me that many of those associations might simply have been noise.

What's more important in terms of whether the "too many, too soon" hypothesis holds water is the raw data those researchers collected --- complete vaccination records and neuropsychological test results for 1,047 children. The existence of those data allowed Drs. Michael J. Smith and Charles R. Woods to look for relationships between timing of vaccination in early infancy and later neuropsychological outcomes.

They compared outcome data for the 491 children who got all the recommended vaccines on time (which they defined as within 30 days of the recommended age, given in months, on the CDC's vaccination schedules for 1993-1997) with the data for the rest of the children (who fell into two categories: those who had gotten all of the recommended vaccines, but just didn't get them at the recommended time, and those who hadn't gotten all the shots by the time they participated in Thompson et al.'s study), finding that children who got all their recommended shots on time performed better than the other children on 12 of the 42 outcome measures --- the Boston Naming Test, the grooved pegboard (a test of fine-motor coordination), the metacognition subscale of the Behavior Rating Inventory of Executive Function, teacher ratings for inattention and hyperactivity, parent rating for stuttering, and verbal, performance and full-scale Wechsler IQ. There was no measure on which they performed worse than the less-vaccinated group.

Because there were demographic differences between the families of children who were vaccinated on time vs. children who weren't, the researchers also did a multivariable analysis to try and control for those factors. That analysis found only two (small) between-group differences, but both of these were also in the fully-vaccinated kids' favor. (They scored 1 point higher on the speeded-naming subtest of the Developmental Neuropsychological Assessment's Language and Communication domain, and also tended to have slightly higher performance IQs).

They also did a secondary analysis, dividing the study participants into three groups, based on "timeliness" of vaccine receipt. The "most timely" group (n = 310) was created by dividing all the children who'd gotten all 10 of the vaccines recommended for the first year of life into quintiles based on how old they were when they completed the schedule. The first two quintiles, or the 40% of children who completed the schedule earliest (i.e., within the first seven months of life), constituted the most timely group, while the children who had gotten six or fewer of the ten recommended vaccines by the time they were seven months old made up the "least timely" group (n = 112).

(The rationale for doing this secondary analysis was to look for any effect of spacing all the vaccinations really close together --- the children in the "most timely" group had crammed the ten first-year vaccines into the smallest window of time. Similarly, the group they're being contrasted with represents the opposite extreme in terms of vaccine compliance --- these are the children who've gotten the fewest shots within that same seven-month window of time. If there is a spacing effect, it ought to show up in a comparison between those two groups, if it shows up anywhere.)

The results of the secondary analysis were a lot like those of the primary analysis: univariate analysis turned up fifteen outcome measures on which the most-vaccinated children outperformed the least-vaccinated ones (including most of the same measures identified as showing a difference between groups in the primary analysis), while multivariate analysis found no difference between the groups. Overall, this study failed to find evidence of any deleterious effects of multiple vaccinations on neuropsychological development, even when those vaccines are spaced very close together very early in life.

(One of the potential objections the authors deal with in their Discussion section involves the fact that the vaccination schedule has changed since the mid-1990s, but they figure that, since most of the children in their study received the version of the combined diphtheria, tetanus and pertussis vaccine that includes whole-cell pertussis, their overall antigenic load would be heavier, not lighter, than what children are exposed to today. See my note below for more explanation about changes in the pertussis vaccine.)

Smith, M., & Woods, C. (2010). On-time Vaccine Receipt in the First Year Does Not Adversely Affect Neuropsychological Outcomes PEDIATRICS, 125 (6), 1134-1141 DOI: 10.1542/peds.2009-2489

Thompson WW, Price C, Goodson B, Shay DK, Benson P, Hinrichsen VL, Lewis E, Eriksen E, Ray P, Marcy SM, Dunn J, Jackson LA, Lieu TA, Black S, Stewart G, Weintraub ES, Davis RL, DeStefano F, & Vaccine Safety Datalink Team (2007). Early thimerosal exposure and neuropsychological outcomes at 7 to 10 years. The New England journal of medicine, 357 (13), 1281-92 PMID: 17898097

*Actually, while it looks like we're throwing more things at young children's immune systems now than before, when you just look at the number of vaccines children receive now versus thirty years ago, the composition of vaccines has changed, too, so that each vaccine now contains fewer antigens than they used to. Looking at this table in a 2002 review on vaccine safety by Paul Offitt and colleagues, the switch from using the whole bacterium that causes whooping cough, Bordetella pertussis, to just using the toxin it secretes cut the number of distinct antigens in the pertussis vaccine from around 3,000 to just two to five (depending on how many other bacterial cell components are still mixed with the active ingredient, the toxin). That whole-cell pertussis vaccine looks like the proverbial pig in the python, swelling the total number of antigens in all the recommended vaccines to 3,000+ during the time period in which it was used. Now, with the adoption of the acellular pertussis vaccine, the total number of antigens in all the early-childhood vaccines is about 125, give or take a few. So the question of antigen overload is actually a lot more complicated than just comparing the number of vaccines recommended at different points in time, and, if anything, a closer look seems to tell us that young children's developing immune systems are less overloaded by the current vaccine schedule, not more.


Eema-le said...

Thanks for posting this information. It's really nice to see a rational analysis of research data when it comes to vaccines. There's so much hand wringing and fear mongering out there, and sadly it causing many children to be ill and many other to be at risk for serious illness.

Matt said...

thanks for posting this. Now I think it's very clear that unvaccinated kids are at a higher risk for developing illnesses that have neuropsychological sequellae [Haemophilus influenzae meningitis being the major one].