Wednesday, October 20, 2010

Jaundice And Autism

Earlier this month, a study was published in Pediatrics that suggested that there might be a relationship between neonatal jaundice and autism.  After reading the study several times, I think I can best sum it up as a little weak and very confusing.

In this study, researchers examined the electronic health records of at all 733,826 children born in Denmark between 1994 and 2004 and collected data on a variety of factors.  These factors not only included whether the child had jaundice or one of several developmental disorders but also included data on their birth weight, gestational age, fetal presentation, apgar score, demographic information about the parents, and other factors.  Or, in short, they collected a lot of data.

The researchers found that almost 5% of the children in the study had a diagnosis of neonatal jaundice noted in their medical records.  As would be expected, these children were more likely to be born premature (36 weeks or earlier) by a margin of 43% to 4.4%, more likely to be underweight - 53% to 14%, and more likely to have an irregular fetal presentation - 29% to 17%.  I don't know if any of these relationships are statistically significant as the study does not say, but I don't think that really matters as none of these relationships are controversial.

Moving onto the autism side of things, the study found a total of 1,721 children who had a diagnosis "in the spectrum of disorders of psychological development".  This spectrum included disorders of speech, motor, and social development as well as autism and intellectual disability (ID).  In this group, there were 577 children that had a diagnosis that put them on the autism spectrum and 1,239 children that had intellectual disability.  There were 74 children in this group that had both intellectual disability and autism.

The researchers crunched the numbers and found some rather peculiar results.  Jaundice was found to be associated with autism but only in full term infants.  To make matters more confusing, this association partially disappeared when the children were separated out by the time of year that they were born (summer vs winter) and whether they were first born or not.  Children with jaundice who were born in the summer or who were first born did not have an increased risk of autism, while children born in the winter or were not first born did.

As I said, I find this result to be rather confusing.

The lack of association between jaundice and autism in premature children is odd.  Children with jaundice are much more likely to be premature and premature children are more likely to have autism.  The numbers found in this study bear that out - 43% of the children with jaundice were premature and prematurity is more common in the children with autism (7.8%) than the general population (6.3%, 4.4% in those without jaundice).  Intuitively it seems like there should have been a relation there, but there wasn't.

The authors try and explain away the time year effect by exposure to sunlight and hence vitamin D levels, but, while that sounds good, there is no demonstrated correlation between vitamin D and autism.  Similarly, they try to explain the order of birth effect by differences in hospital discharge policies and maternal antibodies in second and later pregnancies.  I don't find any of these reasons convincing as I like to see actual data behind assertions rather than just magical thinking.  Although, to be fair, some studies have hinted that there might be a seasonal bias with autism.

I have to question how significant the association found is.  It is one thing to say that there is an increased risk but the actual significance of the association rests on the count of cases.  So I would have liked to see the actual number of children who had autism and jaundice but the only figures provided are hazard ratios (HR).

Not to get too technical, but this hazard ratio, which is basically a relative risk, provides an estimate of how much higher the (relative) risk of the outcome (autism in this case) is if the child had exposure to what was being measured (jaundice) when compared to those who were not.  So in this case, an HR of 1 would mean equal risk while an HR of 2 would mean that the children with jaundice were twice as likely to have autism than the children who didn't have autism.

The overall unadjusted HR for all children with autism was found to be 1.84 while that number dropped to 1.56 after being adjusted for maternal smoking, apgar scores, mother's citizenship, birth weight, and congenital malformations.  So we aren't talking about a large increase of risk.  But perhaps more telling is the ranges of these values.

At the risk of getting a bit technical again, the study says that the 95% confidence intervals for these figures are 1.05 to 2.69 and 1.05 to 2.30, respectively.  This confidence interval basically means that we would be 95% certain that the "real" value of the HR would be between these values.  These values represent a rather large range - from no increased risk to about 2.5 times the risk - which suggests that the increased risk are based on relatively few cases.  A result based on a fewer cases or, more appropriately, on a a small difference in the relative number of cases, would be weaker than a result based on a larger number of cases or a larger difference.

A crude example here would be if the unexposed group had 1 case in a group of 10 while the exposed group had 2 cases in a group of ten.  In theory, the exposure group would have twice the risk but in practice that risk could shift drastically if you looked at a larger sample.

And, speaking of relatively few cases, consider the total number of children with autism in the study.  In ten years only 577 children with autism were born in Denmark?  That would equate to a rate of about 7.8 per 10,000 which is extremely low when compared to the 91 per 10,000 recently found in this country.  This isn't data from the 80s or early 90s when you would expect to see this rate of autism, this data was from the late 90s and almost halfway through the 2000's.  It it possible that the 577 number would increase over time as the children aged (the youngest children in the study would have only been a little over 3 when the data was collected), but still, if you considered all of the children found to have a disability included in this study, we are still only talking about 23.5 per 10,000.

Either there are simply fewer cases in this country or the majority of children with autism have been missed.  If it is the first reason, then I would have to wonder at how applicable these results would be the world and, more importantly, why researchers aren't trying to figure out what is different about this country.  If it is second, then the association found would likely be flawed as well.

So, as I said at the beginning, the results from this study are confusing.  If I had to guess, I would think that the association found wasn't real, but that is just my opinion.  The only way to know for certain would be to do more studies.


Maimburg RD, Bech BH, Væth M, Møller-Madsen B, Olsen J. Neonatal Jaundice, Autism, and Other Disorders of Psychological Development. Pediatrics. 2010 Oct 11. [Epub ahead of print] PubMed PMID: 20937652. doi: 10.1542/peds.2010-0052


  1. Hi MJ -

    The lack of association between jaundice and autism in premature children is odd.

    Perhaps there are multiple risk factors associated with prematurity such that prematurity was enough to noise out the effect of jaundice.

    The authors try and explain away the time year effect by exposure to sunlight and hence vitamin D levels, but, while that sounds good, there is no demonstrated correlation between vitamin D and autism.

    I do not believe this is accurate. For some examples, try:

    From a personal annectode standpoint, I can tell you that one of the most jaw dropping findings we saw from a blood draw from Kid Autism was his bottom of the cellar vitamin D levels. This was a kid that was spending two hours a day in the Florida sun, M-F and six hours S-S and still was in the bottom percent of vitamin D levels. Have you ever had your chlidren checked? I'd bet they are low.

    Other related metabolites that you need to have operational in order to utilize vitamin D are affected in autism quite frequently as well. My wife is a bit more up to speed on that area than me, so I can post some more on that later if you'd like.

    That being said, we also have evidence that pretty much everyone is low in vitamin D. People evolved in a world without cubicles and I'm not so sure we are clever enough to understand the ramification of living our lives indoors.

    The order of birth finding is pretty curious and I don't have any idea what is going on there, except the possibility of noise.

    The Danes have a damn good record keeping system as a result of their centralized (re: socialized) medical system. Great stuff for studies like this.

    Nice write up. Thank you, I've been meaning to get to it but keep getting stuck on something else.

    - pD

  2. Hi MJ -

    Sorry for double posting, I meant to come back and then posted instead.

    Anyway, I also thought you might be interested in knowing that jaundice we have other reasons to suspect jaundice as a particpatory player in autism.

    Specifically billirubin is known to be toxic to Purkinje brain cells, disturbances to which are among the most replicated of all neuroanatomical findings in autism.

    Jaundice is also known to be associated with increased oxidative stress, something which we absolutely know goes hand in hand with autism.

    I don't know if they touched on these parallels in the study or not, but there are ties between what we know about a jaundiced neonate, and what we know about a child with autism, biochemically, to make the findings be plausible.

    - pD

  3. Hi pD,

    Maybe I said that line about vitamin D a little badly.

    What I was trying to get across is that I don't find convenient explanations for the facts to be that satisfying. The way that the paper read it sounded like the authors were throwing out a line as a possible explanation for the seasonal results because they didn't have an answer.

    I think the thing that clinched that impression for me is that they made some mention about standard 400 IU vitamins not raising hydroxyvitamin D concentrations but their citation for it was strange. They cited this 'Cannell J. Vitamin D “advertisement.” Am J Obstet Gynecol. 2010;202(5):e9–e10' which is an author's rebutal letter to the journal that published his original "ad" where he was defending himself against the journal attacking him. But the real source of the citation was a report published by the American Academy of Pediatics where they talked specifically about preventing vitamin D deficiency. I would have thought that the authors would have gone with the much stronger citation.

    Maybe I am reading into it a little too much, but it seemed like they went looking for the first citation that fit what they were looking for without bothering to dig deeper which lead me to believe that they were just engaged in hand waving.

    Another thing that bothers me is that every time a seasonal effect like that comes up, the first thing that someone jumps on (right or wrong) is vitamin D and I don't think that is always the answer.

    For example, I was reading a paper about seasonal variations in ADHD the other day where the authors found/suggested that the reason for the season effect was maturity level and school enrollment cycles. The idea was that the youngest children in a given classroom were more likely to be diagnosed with ADHD because they were less mature than their peers. I am not sure if I believe that idea, but the data in the paper lined up pretty well with the idea.

    I have seen (and forgot about) some of the papers about vitamin D that you cited before but I will have go through and read (reread) the rest. I hadn't seen the ones about the effects of jaundice and billirubin before but I thought there might have been something like that out there. The paper didn't really go into a mechanism too much.

    The problem that I keep coming back to is the strangeness in the relation found. I would have thought that premature kids would have been far more vulnerable to the effects of jaundice than kids carried to term. Maybe the premature kids were treated faster and more effectively since they were most likely to be under medical care. The paper didn't have any measure for treatments, so perhaps that is the confounder.

    But thanks for the links, I appreciate the pointers.

    And having said all of that, I would completely agree with you that vitamin D is likely to play role in autism. I would just like to see someone nail down the relationship but, as you pointed out, that is hard when the majority of people are vitamin D deficient (at least in this country).

    As for the kids, we have never measured their vitamin D level but I wouldn't be surprised in the least if their levels were low. The twins have low levels of just about everything else and our youngest isn't much better. We have all three taking a good amount of vitamin D everyday in an effort to head off potential problem and because of their restricted diet. Well that and the twins seem to have a co-morid seasonal depression thing in the winter and vitamin D can help with that too, but that is a topic for another time.