Dear all:

My background is awash in epidemiology.  An emphasis in epidemiology for my Master of Health 
Science from Johns Hopkins & a minor in epidemiology & program evaluation from Cornell.  If I 
babble on, its because this background is kicking in right now. So, I"m sorry - you all may find 
this a bit boring, but I can't help myself.  The extrapolation from one study that shows no effect 
on NEC to whole-scale policy decisions on hospital practices I find to be premature based on this 
epidemiology background and it is spurring me to pick over everything about premies and donor 
milk with a fine tooth comb.  It probably will take me a while to plow through all this literature 
even though it is totally irrelevant to my private practice that consists of seeing moms after they 
come out of the hospital and trying to finesse my relationshps with the baby nurses who probably 
have more influence over these mothers, but my curiousity has been aroused.
 
When there is a lack of an effect - one should look VERY carefully at the data.  Thinking about the 
criteria in Thomas Hale, I have to say that he does not use as strict criteria as I would probably 
apply - and relies more on plausibility much than probability.  BOTH of these are necessary to 
establish the chain of causality.  This cannot and should not really be established by one study 
alone.  My example of the one study phenomenon is one of "positive" results and has a different 
outcome, but I do believe it is relevant because the reason why the study wasn't beleived was 
because they found no effect on morbity and a huge effect on mortality.

There was once a wonderful study done on vitamin A deficiency that showed a 30% reduction in 
mortality.  The study was excellently randomized.  Sufficient sample size.  Carefully done 
statistics.  People criticized the study for being poorly designed, which really was quite incorrect.  
While this study was actually excellently designed, it was insufficient to provide a chain of 
causality. Why?  Because the plausible steps between the treatment and the reduction in mortaltiy 
were not established.  The study showed NO EFFECT ON MORBIDITY.   They did not pick up any 
effect of the treatment on diarrhea and respiratory infections.  People simply just could not believe 
it without the plausible steps in between.

Tens of millions of dollars later, it turns out that this 30% reduction in mortality was entirely right.  
The reason why "no effect" was shown for morbidity was because the wrong question was being 
asked about diarrhea and respiratory infections.  When studies looked at the severity and duration 
of the diarrhea rather than the incidence alone, they showed an effect of a 25% reduction.  The 
reduction in severe measles was even greater - about 50%.   Respiratory infections were a bit 
tricky - having some contradictory results - most of which were due to symptoms that may have 
been part of the healthy function of the immune system combatting the respiratory infection 

Furthermore, a metaanalysis of all the the mortality studies showed a range of a 24-30% reduction 
in childhood mortality when vitamin A was provided to children who were mildly to moderately 
deficient.  Some of those studies did show no effect but the overall balance showed the effect and 
when you looked at issues of sample size, effectiveness of the treatment, etc you could find the 
reason why there was no effect.  The originator of the initial study was awarded the Lasker prize in 
medicine (he was the Dean of Johns Hopkins School of Hygiene and Public Health).  It could just 
have easily turned out the other way.  Or, if the inital study had showed no effect on mortality 
because of a too small sample size or a contamination effect,  and no one followed up with further 
studies --- we would never have been able to save as many lives in developing countries.

So, moving on:

While intention to treat may be one was to evaluate the "effectiveness" of an intervention it is not 
the gold standard for evaluating the "efficacy of a treatment".  Efficacy of a particular treatment 
requires a much higher standard.  On this point, my major dissertation advisor would pound us 
over the head and woe to the poor graduate student who forgot this lesson.  To really determine 
whether a study or (always better) a group of studies establish causality that a treatment is NOT 
efficacious, one of the first on the list of most of my former professors is:  


1) Did the treatment actually occur?  which has several parts:
a) Did the subjects need the treatment to begin with? (this pertains to nutrition in that many 
studies are done on those who are not deficient or may even have a surfeit of the nutrient in 
question)
b) Was the dose adequate to cause a response?
c) Did the subjects actually receive the treatment?
d) Did the control subjects receive the treatment through a contamination effect? 

A no to any of the above would negate the conclusion that one has clearly established causality 
that the treatment was not efficacious.  

For example, there was one weird study in Bolivia where iodine deficient school children were 
treated with iodine.   Again, a superbly designed study.  Randomized placebo trial.  No difference 
in performance on cognitive tests after treatment between the groups. The clincher in this case - 
all of the children showed increases in their iodine levels and there was virtually no difference 
between the groups.  So, both groups essentially had the same "treatment"  

A dose-response was shown however to urinary iodine levels to performance on cognitive tests 
after treatment.   This plausibly suggests that there was a response to the improvement in iodine 
levels - BUT because it was an association only, did not establish the "probability" that this was 
the case.   More studies were clearly needed to look into this because the "probability" trial failed 
because of contamination and the "plausibility" of the evidence in favor of the effect is insufficient 
to establish causality.



A second important issue when no effect is found is whether or not the sample size was large 
enough to detect a biologically important difference.  The vitamin A studies were enormously 
expensive because mortality is a rare event.  You need to have a large sample size to really pick 
up statistically and biologically relevant differences.  

I could go on and on.  The study in Pediatrics shows that the particular "intervention" provided was 
not effective.  I don't find that it established the full chain of causaility to determine that the 
"treatment" was not efficacious.  That still remains to be established with further studies.

Plus - as in the vitamin A trials, one must look at more than one outcome of a treatment.  And 
that can be the difference between definitions of disease such as "incidence" versus "severity" 
versus "prevalence".  And as you can see - vitamin A had multiple impacts on many different types 
of morbidity any one of which would have been worth the treatment even had the mortality effect 
been negated by further studies.

Remember, that NEC is not the only issue when it comes to breast milk.  We do know that there 
are plenty of risks of formula that have been well-established in an overwhelming body of 
research for full-term babies.  Much more research needs to be done before we dump human 
donor milk as a potentially viable intervention.  And certainly, as with any intervention we have to 
define the parameters for its effective use.  Populations vary.  What happens in an environment 
where most very low birth weight or very premature infants simply don't survive, but where 
kangaroo care works beautifully among the survivors is very different from the environment where 
50 year old women are able to have egg donors and IVF and have their triplets or quadruplets 
survive even at very low birth weights.  

I have Nancy Wight to thank for spurring me on to look with a much more critical eye at the IQ 
studies which may have used much more "mother's own milk" in their results than "pooled human 
donor milk".  A detail which must be considered.

Best regards, 
Susan E. Burger, MHS, PhD, IBCLC

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