Measles, mumps, and rubella vaccination and bowel problems or developmental regression in children with autism: population study

It seems to me that the statistician on this project has struggled
with a dataset which was not thoughtfully constructed for statistical
analysis.

(a) The timing data is weak. Figure 1 relies on date of birth as a proxy
for date of MMR vaccination. There is no discussion of how strong that
link is.

(b) The sizeable group with "atypical autism" is likely to disturb the
analysis. I believe this includes both borderline cases of childhood
autism and cases starting after age three. The latter are likely to
coincide with the “vaccine before parental concern” group and should have
been considered separately.

(c) Moreover, the vaccine timing chosen as the explanatory variable
(before, after, none) is not a proper variable, but two. Let me try to
separate them. If we disregard the "none" group and look at the timing
alone, we find that "before" group are more likely than the "after" group
to have bowel problems, 19% against 15%, not statistically significant
given the sample size but in the right direction to support Dr Wakefield’s
hypothesis. If we take vaccine (regardless of timing) versus no vaccine as
the key, the percentages are 18% and 16% which again gives weak support to
Wakefield.

Moving to regression, vaccine before gives 26% while vaccine after also
gives 26%. All vaccines give 26%, whereas with no vaccine we have 30%
suffering from regression. These figures for what they are worth go
against the Wakefield theory, though we should remember that since the
supposed causation is from MMR to regression via bowel troubles, the
statistical evidence on regression would be expected to be weaker than
that on bowel problems.

It seems to me that what comes out of the fog of proxy variables tends to
support, weakly, an association with bowel problems but not the causation
of regression which Dr Wakefield proposes.

I think it regrettable that the authors have not included any data for the
total incidence of autism in the catchment area as a time series, as
Amelia Hare and John Marsh have pointed out. Furthermore, since the
child’s response to the rubella component of the MMR vaccine is at the
centre of attention here, it is very regrettable that previous exposure to
rubella vaccine though breast-feeding has not been considered as a
variable.

Michael Yaffey PhD

Competing interests:  
None declared

Sir:

Recent rates for autism spectral disorders are estimated to be 3-4
times higher than 30 years ago (1). This increase is partly accounted for
by changes in methodological factors, but the influence of new
environmental exposures cannot be discounted.

A causal association with measles-mumps-rubella immunization is
discounted (2) and that with mercury-containing vaccines is weak (3).
However, is an association with the dramatic increase in immediate
clamping of the umbilical cord (ICC) at birth possible?

ICC is routinely applied during premature, operative and "at risk"
births, and increasingly during "normal" births following the
recommendation (4) that a segment of the cord should be retrieved
immediately after delivery for medico-legal purposes.

The immediate effect of ICC is to deprive the neonate of placental
respiration and transfusion resulting in complete asphyxia until the lungs
function, and 30%-50% loss of the neonate's natural blood volume; the
combined hypoxia and hypovolemia / ischemia is then conducive of hypoxic
ischemic brain injury. The neonate that receives a full placental
transfusion has enough iron to prevent anemia during the first year of
life(5), but blood loss in a neonate subjected to ICC becomes evident in
infancy as anemia.(5)

In grade school children, anemia correlates with all types of
autistic disorder (6) and the degree of anemia correlates with the degree
of mental deficiency; (7) correcting the anemia does not correct the
defect.

Kinmond et al. (8) showed that delayed cord clamping combined with
gravity assisted placental transfusion prevented anemia (the need for
blood transfusion) in preemies. Hack et al. (9) found a high incidence of
poor achievement in low birth weight babies.

The correlation between autism and birth complications is supported
by aother sudies. Hultman (10) reports a great increase in the risk of
autism in cesarean deliveries, deliveries with fetal distress and five
minute Apgar scores below seven. These obstetrical situations correlate
with ICC.

In extensive studies on brain damage from induced birth asphyxia (11)
in primates, ICC combined with pulmonary obstruction was used routinely to
produce asphyxia, brain damage and cerebral palsy. In milder cases of
asphyxia, memory defects were noted without any permanent neurological
defect; brain stem nuclear damage was noted at autopsy.(12)

Meyers (11) found. in monkeys, that when placental circulation was
left intact by delayed cord clamping, resuscitation of the depressed fetus
did not result in brain damage. In humans, Gunther (13) and Peltonen (14)
demostrated continued placental function (respiration and transfusion)
after birth, and concluded that "there is good reason in cases of
resuscitation to keep the placental circulation intact".

I therefore conclude that ICC, especially when imposed on existitng
birth asphyxia, can cause mental impairment without obvious neurological
impairment, and therefore may well be a significant contributory cause of
the current autism epidemic.

Erasmus Darwin predicted the autism epidemic 200 years ago, and left
instructions for its prevention and its correction (15)

"Another thing very injurious to the child, is the tying and cutting
of the navel string too soon; which whould always be left till the child
has not only repeatedly breathed but till all pulsation in the cord
ceases. As otherwise, the child is much weaker than it ought to be, a
portion of the blood being left in the placenta, which ought to have been
in the child."

References:

1. Fombonne E The Prevalence of autism. JAMA 2003;289:87-89

2. Taylor B. et al. Measles, mumps and rubella vaccination ... in
children with autism. BMJ 2002;324:393-396

3. Pichichero ME et al. Mercury concentration and metabolism in
infants receiving vaccines containing thiomersal: Lancet 2002;360:1737-
1741

4. ACOG COmmittee Opinion on Obstetric Practice. Number 138. Int J.
Gyn Obs 1994:45:303-304

5. Linderkamp O. Placental transfusion: determinants and effects.
Clinics in Perinatology 1982;9:559-592

6. Lozoff et al. Iron deficiency anemia and Iron therap[y effects on
infant development test performance. Pediatrics 1987;79:981-995

7. HurtadoEK et al. Early childhood anemia and mild to moderate
mental retardation. Am J Clin Nut 1999; 69(1): 115-9

8. Kinmond et al. Umbilical Cord Clamping and Preterm Infants: a
Randomized Trial. BMJ 1993; 306: 172-175

9. Hack M, et al. Outcomes in Young adulthood for very low birth
weight infants. New Eng J Med Vol. 346, NO. 3 Jan, 2002:149-157

10. Department of Medical Epidemiology, Karolinska institutet, S-
17277 Stockholm, Sweden. Christina Hultman@mep.ki.se

11. Myers,RE (1972) Two patterns of perinatal brain danmage.
American J Obst and Gynec. 112:246-276

12. Windle et al. Brain Damage by Asphyxia at Birth. Scientific
American 1969 Oct;221(4):76-84

13. Gunther M The transfer of blood between the baby and the
placenta in the minutes after birth. Lancet 1957; I:1277-1280

14. Peltonen T. Placental transfusion, Advantage - Disadvantage.
Eur J Pediatr. 1981;137:141-146

15 Darwin E. Zoonomia 1801; Vol III, p301

Further references at www.cordclamping.com

Competing interests:  
None declared

Re Article Measles, mumps, & rubella vaccination...Is there
a problem with giving the vaccines separately, while this
controversy swirls around a possible causal relationship
with childhood autism? At one time in medicine and still if
there is a question, How can medicine condone continuing to
give this combination vaccine to our most vulnerable
population?

In California there is a ' 273 per cent increase in Autism',
according to a University of California Davis M.I.N.D,
study by Dr. Robert Byrd. Furthermore Dr. Byrd state "this
could not be attributed to a loosening of criteria for
diagnosis, also he states, " more than 90% of the children
were native".

Figures like these cannot be ignored, somewhere there is a
problem.

Thank you for allowin

I have no particular interest in the MMR vaccine, but found myself
reading the paper by Taylor et al. (BMJ 2002:324:393-6) with some
incredulity. A primary assertion of the paper appears to be that bowel
problems in children with autism is not associated with MMR vaccination.

Data shown in the first line of the table is relevant to this assertion.

The authors provide no confidence limits in relation to several pertinent
findings. Logistic regression of a binary response variable (Y) on a
binary independent variable (X = MMR prior to parental concern of bowel
problems)with a sample size of 443 observations (of which 58% are in the
group X=0 and 42% are in the group X=1) achieves only 15% power at the
0.05 level of significance to detect a change in the probability of bowel
problems from a baseline value of 0.180 to 0.215. This change corresponds
to an odds ratio of 1.25. It is stated that only single variable results
are shown because "adjustment for potential confounders did not
substantially affect the results". Although it is possible that adjustment
for the seven listed confounders would not alter point estimates of the
predictive relationships, confidence intervals would undoubtedly be
altered. The authors assert that MMR is not predictive of bowel problems
when N is reduced further to include only 28 cases of bowel problems
thought most likely to reflect "autistic enterocolitis".

Even if a
predictive relationship does exist, such apparent non association is
hardly surprising. Given the controversy surrounding this issue, the
authors would do well to provide their raw data so that others can repeat
their analysis.

Aubrey Blumsohn

Senior Lecturer, University of Sheffield