This
article was written by William Parker, an Associate Professor at Duke
University, where he has worked in the Department of Surgery since 1993.
It was printed here with the permission of
Greenmedinfo.com. You can sign up for their newsletter
here.
A number of non-
peer-reviewed articles have
been written and published on the web claiming that there is literally
nothing to fear from acetaminophen during pregnancy. There are two types
of articles that fall into this category. First, reputable watchdog
organizations have weighed in on the issue, declaring acetaminophen use
during pregnancy and during childhood to be proven safe. In particular,
the National Health Service of the UK and the Center for Accountability
in Science have both strongly criticized the Spanish study from 2016
showing a link between
acetaminophen use during pregnancy and ADHD/autism.
The second type of article is generally
written by a science writer working for an organization that runs a
website. Often quoting one to three experts who claim that is perfectly
safe and that pregnant women and families should not be concerned, many
of these articles are published by reputable sources that are generally
trustworthy. Typically, an expert is being asked to comment on one
particular publication showing a link between acetaminophen use (usually
during pregnancy) and some sort of neuropsychiatric problem (
autism,
lowered IQ, hyperactivity, and/or social/behavioural problems,
depending on the study). There are several important things to consider
when evaluating these articles:
1. There are a number of University
Professors who have studied the use of acetaminophen on the developing
brain and who are keenly aware of the potential dangers. A partial list
of these individuals is provided below.
2. Being an expert in acetaminophen
neurotoxicity during development means that considerable time has been
invested in studying the issue. Any true expert in this issue will be
aware of basic facts regarding acetaminophen neurotoxicity. These facts
include the following:
(a) Studies in animal
models (both in mice and in rats) demonstrate that acetaminophen use
during a sensitive period of brain development causes long-term
alterations in the brain and is manifested as problems with social
function.
(b) Margaret
McCarthy, Chair of Pharmacology at the University of Maryland, has
worked out the probable mechanism by which acetaminophen-induced brain
damage occurs. Her research team has found that the male brain is
considerably more sensitive to acetaminophen than the female brain,
possibly accounting for the gender bias in autism.
(c) There are (as of
January 2017) a total of 8 published studies evaluating the long terms
effects on children of acetaminophen use during pregnancy or during
childhood. Two of these (one in 2014, one in 2016) were published in
JAMA Pediatrics, one of the most highly respected pediatric journals.
All studies point toward acetaminophen use being associated with
long-term problems with neurological function. Each study design has
included some attempt to control for indication. In all studies,
acetaminophen use rather than indication has been identified as the key
factor associated with cognitive problems. A formal meta-analysis is not
currently possible because of the varied outcome measures and study
designs, but all 8 studies point in the same direction: Acetaminophen is
neurotoxic to the developing brain. The studies are not “cherry
picked”, selecting only those which find an effect. All studies point
toward a neurotoxic effect of acetaminophen in the developing brain.
(d) Acetaminophen substantially alters brain chemistry and temporarily impairs awareness of social issues in adult humans.
(e) Testing of
acetaminophen safety in children did not include any evaluation of brain
function, and no long-term studies were ever conducted. The primary
manufacturer of acetaminophen in the US acknowledges that the drug has
never been shown to be safe for brain development when used during
pregnancy or in childhood. All safety tests were performed with the
assumption that any side effects would be acute in nature (e.g.,
bleeding or acute organ damage). This assumption was based on
observations made with acetaminophen in adults and with aspirin in
children. It was not based on any experience with acetaminophen use in
children.
3. Having prescribed tens of
thousands of doses of acetaminophen does not make anyone an expert on
the neurotoxicity of acetaminophen, any more than eating thousands of
pounds of chips makes somebody an expert in the effects of an
inflammatory diet. Credentials and certifications that allow physicians
to prescribe acetaminophen do not make them experts, and elevated
positions in the medical community do not qualify anybody as an expert
on the effects of acetaminophen. If somebody does not know those basic
facts listed above, then they are not an expert on the neurotoxicity of
acetaminophen. Usually, the experts will have published one or more
peer-reviewed manuscripts on the topic. Those are the people to ask when
an expert is needed.
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4. It is tempting to point accusing
fingers at physicians who say that acetaminophen is safe when they
literally have no grasp whatsoever of the relevant scientific
literature. However, this would be a mistake. I have tracked down a few
of these individuals who were quoted in a very public format, and one
individual, in particular, didn’t even remember having made a comment on
the topic. The most likely explanation is that a reporter asked them if
acetaminophen was safe, and their response based on their training (not
on the knowledge of the literature) was that it is safe. After all, if
they didn’t think it was safe, they would not be administering it dozens
of times per day. So, if a reporter asks a physician if something is
safe, and they provide their knowledge based on what they have been
taught and how they practice, then it is hard to blame them. The
reporter didn’t ask them to spend days or even weeks reviewing the
literature in detail, but rather assumed that any physician
administering something dozens of times per day would know the
literature. (This is a false assumption. No physician has the time to
study all current literature on every drug they administer.) So, in a
nutshell, a tragic propagation of incorrect information is occurring
despite the best of intentions of all parties involved.
5. Unless an organization such as
the National Health Service has the time to review a topic thoroughly,
they should remain silent on an issue. It took a team of us two years to
put together our summary of the evidence, both direct and
circumstantial, regarding the potential neurotoxicity of acetaminophen
during development. It took the NHS only days to publish their recent
criticism of the 2016 Spanish study. Offering questionable criticisms of
a single paper without reviewing the literature to see how that
publication fits into the big picture is a disservice to the public
being served.
6. Reading the published quotes from
many “experts” who exonerate acetaminophen, it is apparent that the
logic falls into one of two categories.
(a) Everybody is doing it, so it must be OK.
(b) This single study is not perfect, so no change in practice should be made.
Neither of these criticisms is logically
sound, of course. These two criticisms are often combined and were, in
fact, part of the critical comments directed toward the first paper
showing that acetaminophen probably has substantial neurotoxicity during
development (published in 2008 by Steve Shultz). Further, the
evaluation of study weaknesses is usually skewed and not entirely valid.
Since the idea that
acetaminophen is safe is
being embraced, then any merit in the paper is often undermined to make
the case. This is certainly true of the published (peer reviewed)
criticisms of the 2008 Shultz paper.
7. Many on-line sources support the
view that acetaminophen can be very dangerous to the developing brain.
Probably the most reliable source, the FDA, is remaining silent on the
topic until something more definitive is done. The FDA knows that this
is extremely urgent, but unfortunately, our FDA is not linked well (in a
practical manner) with our NIH, and thus they can’t dictate research
priorities.
8. Here is a list (not comprehensive) of experts regarding the neurotoxicity of acetaminophen during brain development.
(a) First, I’ll
thank the wonderful team of individuals who helped put together our
comprehensive review on this topic. Shu Lin, a professor with me in
Duke’s Surgery Department, is a very dear and long-time friend of mine
who has supported me through countless projects over the past 22 years.
Staci Bilbo, director for research on Autism at Harvard, is a friend and
collaborator who has helped me understand what causes inflammation and
the role of inflammation in brain dysfunction. Chi Dang Hornik, a
pediatric pharmacist at Duke, contributed greatly to our understanding
of the frequency of acetaminophen administration and the available
formulations of the drug. Many thanks to Martha Herbert. As a Harvard
professor and clinician, she has a great appreciation for the clinical
data obtained from patients with autism. Cindy Nevison, a professor at
the University of Colorado at Boulder, rounds out our team, providing
critical information about the epidemiology of autism. (Thanks also to
our interns (Rasika Rao and Lauren Gentry) and research analyst (Zoie
Holzknecht) who were a tremendous help in compiling information and
preparing that information for publication.)
(b) Margaret
McCarthy, chair of Pharmacology at the University of Maryland, it the
most knowledgeable person I know regarding the biochemistry of the human
brain and how that is affected by acetaminophen and other drugs in that
class.
(c) Chittaranjan
Andrade, Chair of Psychopharmacology at the National Institute of Mental
Health and Neurosciences, Bangalore, India, has written a peer-reviewed
paper on the topic of acetaminophen-induced brain damage. He nicely
summarized a number of studies looking at the connection between
acetaminophen and neurological damage. His final conclusion is that the
drug is probably more associated with ADHD than autism, but the
conclusion was limited to exposure during pregnancy and his work was
conducted before some critical studies were published in 2016.
(d) Henrik Viberg is
a professor in the Department of Organismal Biology at Uppsala
University in Sweden. He has studied how exposure of mice to
acetaminophen during development can cause long-term brain damage.
(e) In 2015, a
group of scientists working with Laurence de Fays at the Federal Agency
for Medicines and Health Products in Brussels acknowledged the clinical
studies and the studies in animal models which indicated that
acetaminophen could be dangerous to the developing fetus, but concluded
that paracetamol is “still to be considered safe in pregnancy”. At the
same time, they state that “additional carefully designed studies are
necessary to confirm or disprove the association (between acetaminophen
and brain damage to children)”, and that “care should be taken to avoid
raising poorly founded concerns among pregnant females”. We very
strongly agree with the conclusion that more studies are needed, but
very strongly disagree with the conclusion that women should be kept in
the dark about the matter. It is important to point out that several
more studies have come out since Laurence de Fays’ report. One of those
is a 2016 manuscript in JAMA Pediatrics (see the next expert), a highly
reputable peer-reviewed journal, which addresses the concerns raised by
de Fays, so it is possible that de Fays’ group may now have a different
opinion.
(f) A team of
scientists and doctors working with Evie Stergiakouli at the University
of Bristol analyzed data from a prospective birth cohort, and concluded
that “children exposed to acetaminophen prenatally are at increased risk
of multiple behavioral difficulties”. They found considerable evidence
indicating that the association was not due to the confounding factors
that concerned de Fays’ group (previous expert).
(g) Jordi Julvez at
the Centre for Research in Environmental Epidemiology in Barcelona,
Spain worked with a team of a dozen clinicians and scientists to publish
their 2016 study linking acetaminophen with autism and ADHD.
(h) Amany A. Abdin, a
professor in the Department of Pharmacology, Tanta University, Egypt,
wrote a review of the acetaminophen/autism connection and published it
in the journal
Biochemistry and Pharmacology: Open Access. Her conclusion in 2013 was that the drug is not safe and that the
acetaminophen/autism connection should receive attention.
(i) The original
paper that identified a connection between neuropsychiatric disorders
and acetaminophen was published by Steve Shultz while at the University
of California at San Diego. Coauthors on the paper included Hillary
Klonoff-Cohen, currently an Endowed Professor and Director of the MPH
program at the University of Illinois.
(j) Four
scientists, including research scientist Ragnhild Eek Brandlistuen and
professors Hedvig Nordeng and Eivind Ystrom in the Department of
Pharmacy at the University of Oslo, coauthored a study showing a
connection between adverse neurodevelopment and acetaminophen use during
pregnancy.
(k) Jorn Olsen,
Professor and Chair of the Department of Epidemiology at UCLA, published
one of the more recent papers (2016) showing a connection between
autism and acetaminophen use during pregnancy.
(l) Five
professors (John M. D. Thompson, Karen E. Waldie, Clare R. Wall, Rinky
Murphy, and Edwin A. Mitchell) from four different departments at The
University of Auckland published their findings in PLOSone in 2014 which
“strengthen the contention that acetaminophen exposure in pregnancy
increases the risk of ADHD-like behaviours. Our study also supports
earlier claims that findings are specific to acetaminophen.”
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