autism researcher, I often try to put myself in the shoes of parents who have
just been told that their child has autism. More and more families in the
United States and around the world are facing this difficult news. The families
that I’ve seen go through this often respond emotionally at first. Some go
through denial; others are sad or furious. But emotions soon give way to
questions. What caused my child’s autism? Was I to blame? Which treatments will
help? And what does the future hold?
Autism research has made tremendous progress over
the last 20 years, but yet we still can't provide definitive answers to most of
these questions. I find the autism community to be proactive, combative, and
opinionated. The complexity and ambiguity of autism has spawned myriad
speculations about causes—many of which have little supportive evidence. It
seems clear at this point, however, that when all is said and done, we will
find that autism has multiple causes that occur in diverse combinations.
begin with, many people struggle to understand the nature of a condition so
wide ranging in its severity. Autism Spectrum Disorder (ASD) or autism is a
behaviorally defined neurodevelopmental disorder characterized by 1)
deficits in social communication and interaction across multiple contexts, and
2) restricted, repetitive patterns of behavior, interests, or activities.
Few would dispute that the causes of ASD
include both genetic and environmental factors. Indeed, more than 100 genes are
known to confer risk
and 1,000 or more may ultimately be identified.
A wide range of potential environmental challenges have also been associated
with autism, although studies in this area lag behind genomics research. A
short overview of data supports genetic and environmental contributions to ASD
etiology. A focus on prenatal events will hopefully clarify that the cause of
autism, in the vast majority of cases, occurs prenatally, even if behavioral
signs first appear several years after birth.
Strong evidence against the unfounded view that autism results
from neglectful parenting came in 1977 from
and Rutter and the first systematic, detailed study
of twin pairs containing at least one child with autism.
In this study, 11 of the twin
pairs were monozygotic (nearly identical genetics) and 10 were dizygotic
(shared approximately half of their genome with each other). The major finding
was that four of the monozygotic twin pairs were concordant (both had autism),
whereas none of the dyzygotic twins were. Beyond autism, nine of the eleven monozygotic
pairs were concordant for some form of cognitive impairment, compared to one of
ten of the dyzygotic pairs.
The researchers concluded that autism and other
neurodevelopmental disorders have a strong genetic component. But environmental
factors must also contribute to autism etiology, they pointed out. For the 17
twin pairs that were discordant for autism—one child had a diagnosis and the
other did not—the authors speculated that direct damage to the brain might have
affected the diagnosed twin. They identified five features known to be
associated with brain damage, such as
hemolytic disease, a delay in breathing of at least five minutes after birth,
and neonatal convulsions. In six of the pairs, one twin—always the autistic
one—experienced one or more of these insults. Looking
further, they found that one of an expanded list of "biological
hazards" (e.g., discrepancies in birth weight, a pathologically
narrow umbilical cord) occurred in the autistic twin in 6 of the 11 remaining
discordant pairs and never in the non-autistic twin. The authors concluded that
“some form of biological impairment, usually in the perinatal period, strongly
predisposed to the development of autism.”
Since the Folstein and Rutter paper cited above, there have been a
total of 13 twin studies focused on autism. All find genetic and environmental
contributions to autism, although conclusions about the proportions of the two
factors and interpretations have varied substantially. One research team,
for example, concluded that a large proportion of the variance in liability (55
percent for strictly defined autism and 58 percent under a broader definition)
can be explained by shared environmental factors, whereas genetic heritability
accounts for 37 percent. This somewhat surprising finding—that environmental
factors contribute more substantially than genetics—has been challenged by a
more recent, large-scale twin study,
which found that the largest contribution to autism liability comes from
additive genetic effects. And, a recent meta-analysis
concludes that the causes of autism are due to strong genetic effects, and that
shared environmental influences are seen only if autism is very narrowly
defined. A brief synopsis of the history of autism twin studies
findsthat concordance for
monozygotic twins is roughly 45 percent, versus 16 percent for dizygotic twins.
The reason for this short review of autism twin studies is to
emphasize that even the best evidence for both genetic and environmental
etiologies of autism leads to inconsistent conclusions about their proportional
contributions. Moreover, twin studies do not typically consider that the cause
of autism may involve genetic and
environmental factors working together (the so-called gene by environment
effect); i.e., certain environmental exposures only cause autism in individuals
with a particular genetic composition. The second point is that if autism had a
completely genetic etiology, we would expect a much higher concordance rate in
monozygotic twins; the actual rate may reflect, in part, that even monozygotic
twins do not share an identical environment prenatally.
Therefore, one must seriously search for environmental factors that either
alone, or in combination with genetic predisposition, can increase autism risk.
What are these factors?
If twin studies provide the best evidence for a genetic basis of
autism, then naturally occurring pathogen exposures offer the strongest
evidence of environmental etiology. The best example is maternal rubella
(German measles) infection during pregnancy. Before development and widespread
dissemination of effective vaccines, major pandemics occurred every 10 to 30
The last of these was from 1963 to 1965 and infected an estimated
10 percent of pregnant women, resulting in more than 13,000 fetal or early
infant deaths; 20,000 infants born with major birth defects and 10,000 to
30,000 infants born with moderate to severe neurodevelopmental disorders.
Stella Chess, a child psychiatrist at New York University, studied 243 children
exposed to rubella during pregnancy
and found that the largest category of neurodevelopmental disorder was
intellectual disability, which affected 37 percent of the sample. Nine of these
children were also diagnosed with autism; another, without intellectual
disability, had a possible diagnosis; and eight a partial syndrome of autism.
These numbers would translate to an autism prevalence of 741 per 10,000
rubella-exposed children, just over seven percent. This is striking in
comparison to published prevalence rates, at the time of the study, of two to
three per 10,000 in the general population. Fortunately, rubella epidemics have
ended due to widespread dissemination of the measles, mumps and rubella
vaccines and the association of autism with other viral or bacterial infections
is weaker than with rubella.
Collier et al
have pointed out that nearly 64 percent of women surveyed in the
US have experienced an infection during their pregnancies. This obviously does
not lead to autism or any other neurodevelopmental disorder in most cases.
Examining prenatal environmental factors is best conducted in very
large cohorts of subjects that have excellent health care records. This can be
done in Scandinavian countries with their nationalized health care systems, and
in large health care providers in the US.
such study, conducted in Denmark, found no association between maternal
bacterial or viral infection during pregnancy and diagnosis of ASD in the
although viral infection during the first
trimester, or admission to the hospital due to infection during the second trimester
were associated with the diagnosis. In a more recent study
Atladottir and colleagues found little evidence, overall, that common
infectious diseases or fevers (lasting more than seven days) during pregnancy
increased the risk of autism—noting, however, that influenza increased the risk
of having an autistic child twofold. Use of antibiotics also increased risk.
The link between influenza exposure during fetal life and increased risk for
autism is in line with a series of animal studies
suggesting that the influenza virus activates the maternal immune system, which
may be harmful to fetal brain development. But the Danish researchers seem to
downplay even their statistically significant findings, suggesting that their
results do not indicate that either mild infection or the use of antibiotics
represent strong risk factors for autism.
parallel set of studies has been carried out by Zerbo and colleagues in
California. The first,
based on 1,122 children, found no association between maternal influenza and
ASD but (in contrast to Atladottir et al), the occurrence of maternal fever did
increase risk. A second study
of 2,482 children (407 with ASD) found that mothers of children with ASD were
diagnosed with viral infections during pregnancy no more often than mothers of
non-autistic children. Maternal bacterial infections during the second
trimester and the third trimester, however, were associated with a twofold
increase in ASD risk, and two or more infections diagnosed in the third
trimester with even higher risk, again suggesting a link with more severe
infection during pregnancy. The most recent study,
based on a large cohort of children (196,929)
born between 2000 and 2010,found that
neither maternal influenza infection
during pregnancy nor influenza vaccination were associated with
increased risk for ASD.
conclusion: Some infections during pregnancy, such as German measles, clearly
increase the risk of ASD. However, there seems relatively little evidence that
today’s widely experienced infectious illnesses, such as influenza, during
pregnancy substantially increase the risk of ASD. Perhaps the signal is weak
because of gene by environment effects [as seems to be the case for different
strains of mice
If so, evidence will need to come from studies that combine large scale
epidemiology with sophisticated genomic analyses.
diseases (in which immune cells erroneously identify cells in the body as
foreign and attack them)
mediated by circulating antibodies
currently affect as much as nine percent of the world’s population,
and the notion that autoimmunity may be associated with
neurological and psychiatric disorders goes back to the 1930s. Reviewing this
contentious area of research, Goldsmith and Rogers
conclude that the literature, though conflicting, “contains a
large amount of circumstantial, but not conclusive, evidence for immune
dysfunction in patients with schizophrenia.” Interestingly, an auto-immune
disorder with antibodies directed at the NMDA receptor causes an encephalopathy,
which in its early stages can be indistinguishable from schizophrenia.
Precedents for antibody-related CNS disorders include Rasmussen
encephalitis, stiff-person syndrome, neuromyelitis optica, post streptococcal
movement disorders (Sydenham’s chorea and PANDAS), and systemic lupus
Judy Van de Water, of UC Davis, the main proponent of the idea
that circulating antibodies may cause some forms of autism, first reported in
2008 that 12 percent of mothers of children with ASD have unusual antibodies
directed at fetal brain proteins.
Based on more specific assays for these antibodies, she has since proposed that
Maternal Antibody-Related (MAR) causes may be associated with as many as 22
percent of autism cases, suggesting that this may be a preventable form of ASD.
This area of research is exciting because it suggests potential therapeutic
targets. Although many questions remain (e.g., how antibodies would enter the
fetal brain, what neurodevelopmental processes they may alter), it is entirely
possible that circulating antibodies represent prenatal environmental risk
factors for ASD.
Efforts to understand the increased prevalence of autism spectrum
disorder have led some to wonder whether the use of various drugs during
pregnancy might be partly responsible. Historically, a strong case could be
made for an association between autism and thalidomide, a potent sedative that
was used (for several years around 1960) during pregnancy for the relief of
nausea. A study of 100 adult Swedish patients whose mothers had taken
thalidomide while pregnant
found that at least four had clear autistic characteristics. This
was the first evidence that a drug ingested during pregnancy could
substantially increase autism risk. More recently, concerns have been raised
about valproic acid and serotonin reuptake inhibitors.
Valproic acid, an approved drug since the early 1960s, is
primarily prescribed for epilepsy and seizure control, but also used for
ailments ranging from migraine headaches to bipolar disorder. Both animal and
human epidemiological studies have raised concerns that valproic acid is a
teratogen. The largest epidemiological study to date
tracked 415 children, 201 of whom were born to mothers who took antiepileptic
medication during their pregnancies. Nearly 7.5 percent of the children of the
treated women had a neurodevelopmental disorder, primarily some form of autism,
versus 1.9 percent in the non-epileptic women.
A recent concern has been the use of serotonin reuptake inhibitors
(SSRIs) for the treatment of depression during pregnancy. Serotonin is an
important brain neurotransmitter that plays a significant role in functions
ranging from sleep to mood to appetite, and whose dysregulation during early
fetal life can have serious negative consequences for brain development.
As the name implies, SSRIs, which have been in use since the late
1980s, delay the reuptake of serotonin from the synaptic cleft into the
presynaptic terminal and thus enhances its effect on the postsynaptic
receptors. A recent review and meta-analysis of six case-control studies and
four cohort studies concluded that SSRI use during pregnancy
was significantly associated with increased risk of ASD in offspring.
The effect was most prominent with use of the drugs during the
first and second trimesters of pregnancy. Interestingly, the researchers found
that preconceptual exposure to SSRIs was also associated with increased ASD
risk—as was the use of non-SSRI antidepressants. They note that a large cohort
study found that, while ASD rates in the SSRI-exposed group were significantly
higher than in the unexposed group, the rates in the SSRI-exposed group did not
significantly differ from those among mothers with unmedicated psychiatric
disorder and those who had discontinued SSRIs. It currently appears impossible
to disentangle the deleterious effect of SSRIs from the fact of a maternal
condition that necessitates the drug. Many authors also comment on the
potentially worse effect on pregnancies of untreated maternal depression.
In sum, a brief review of the literature indicates that ingesting
some drugs during pregnancy increases the risk of ASD, suggesting the need for
more careful evaluation of drug safety during fetal development prior to
widespread medical use.
Beyond viral and bacterial pathogens and medically prescribed
drugs, researchers have begun investigating environmental toxicants. These
range from automobile-produced air pollution to cigarette smoke to heavy metals
Small increases in autism risk have been reported if, for example, a family
lives closer to a freeway or to an agricultural area during pregnancy. The
field of autism environmental epidemiology is still in its infancy and
techniques to comprehensively establish a prenatal "exposome" (i.e.,
all environmental factors affecting a
fetus during pregnancy) are still under development. That said, given the
unlikelihood that all autism will be explained by genetic factors, the
determination of environmental causes, some of which might be avoided or
minimized, may have far greater translational impact than the much better
funded genetic studies. Strategies for exploring gene-by-environment
interactions need to be enhanced with haste.
Since autism is a neurological disorder that undoubtedly reflects
altered brain function, it is possible that the insult to the brain occurs
after birth. There is currently very little evidence for this. One historical
concern was that vaccines, such as the measles, mumps, and rubella (MMR)
vaccine, administered initially when the child is about one-year old, might
transform a healthy child into one with autism. This fear was fueled by
regressive onset in some cases—a child seems fine for the first year or so,
then loses social and language function and regresses into a classical autistic
syndrome. But we have found that even in children who demonstrate this
regressive form of autism, brain changes begin by four to six months, long
before behavior changes.
Moreover, many large-scale epidemiologic studies have unequivocally
demonstrated no link between MMR administration and the risk of ASD (summarized
the same conclusion that the US National Academy of Sciences reached in a
thorough review carried out in 2011.
The only other postnatal experience that has been linked to the
onset of ASD is profound social isolation in institution-reared children, such
as those in the Romanian orphanage system.
Rutter and colleagues
found that nearly 10 percent of children raised in Romanian orphanages and
adopted by British families showed some features of autism. These children were
very poorly treated in the orphanage (most were underweight and had
intellectual disability and various medical problems). While fully qualifying
for an autism diagnosis at age 4, they showed substantial improvement and less
severe autism symptoms by age 6. Is this truly autism? The authors conclude:
"The characteristics of these children with autistic features, although
phenomenologically similar in some respects to those found in
"ordinary" autism, differed sharply in the marked improvement evident
between 4 and 6 years of age and in the degree of social interest... The
quasi-autistic pattern seemed to be associated with a prolonged experience of
perceptual and experiential privation, with a lack of opportunity to develop
attachment relationships, and with cognitive impairment."
This sad epoch demonstrates both the potential for severely
abnormal rearing practices to influence brain regions that are affected by
typical causes of autism, and the resilience of the brain in compensating and
restoring once the individual is placed in a more normal environment. But it
does not provide evidence for the postnatal genesis of autism.
research picture regarding the causes for Autism Spectrum Disorder remains
complex, although there is certainly a very strong genetic component. While
there are some genes, such as CHD8, the mutation of which almost always cause
autism in a very low percentage of cases
most mutations seem to confer small increases in risk. Similarly, while some
environmental factors, such as rubella infection or fetal exposure to valproic
acid, have been highly associated with autism risk, the increase in risk
associated with others, such as living close to a highway, is small. It is very
likely that the answer to what causes autism will not reside solely in genetics
or in environment but in a combination of the two. Whatever factors go into the
mix, they most likelyhave their effect
during fetal life: a person with autism is born with autism.
View Financial Disclosure
Rubeis, S., et al., (2014) Synaptic, transcriptional and chromatin genes
disrupted in autism. Nature, 515(7526):
D.H. and M.W. State, (2015) Gene hunting in autism spectrum disorder: on the
path to precision medicine. Lancet Neurol,
14(11): p. 1109-20.
Rubeis, S. and J.D. Buxbaum, (2015) Genetics and genomics of autism spectrum
disorder: embracing complexity. Hum Mol Genet,
24(R1): p. R24-31.
S. and M. Rutter, (1977) Infantile autism: a genetic study of 21 twin pairs. J
Child Psychol Psychiatry, 18(4): p.
J., et al., (2011) Genetic heritability and shared environmental factors among
twin pairs with autism. Arch Gen Psychiatry,
68(11): p. 1095-102.
E., et al., (2015) Heritability of Autism Spectrum Disorder in a UK
Population-Based Twin Sample. JAMA Psychiatry,
72(5): p. 415-23.
B., et al., (2016) Autism Spectrum Disorders and Other Mental Health Problems:
Exploring Etiological Overlaps and Phenotypic Causal Associations. J Am Acad
Child Adolesc Psychiatry, 55(2): p.
T., (2016) The genetics and neurobiology of ESSENCE: The third Birgit Olsson
lecture. Nord J Psychiatry, 70(1): p.
K. and S. Norgate, (2005) The equal environments assumption of classical twin
studies may not hold. Br J Educ Psychol,
75(Pt 3): p. 339-50.
W., et al., (2012) Genetic, environmental and stochastic factors in monozygotic
twin discordance with a focus on epigenetic differences. BMC Med, 10: p. 93.
R.S., (2009) Congenital rubella syndrome--major review. Optometry, 80(1): p. 36-43.
S., (1971) Autism in children with congenital rubella. J Autism Child
Schizophr, 1(1): p. 33-47.
S., (1977) Follow-up report on autism in congenital rubella. J Autism Child
Schizophr, 7(1): p. 69-81.
J.E., et al., (2005) Autistic disorder and viral infections. J Neurovirol, 11(1): p. 1-10.
S.A., et al., (2009) Prevalence of self-reported infection during pregnancy
among control mothers in the National Birth Defects Prevention Study. Birth
Defects Res A Clin Mol Teratol, 85(3):
H.O., et al., (2010) Maternal infection requiring hospitalization during
pregnancy and autism spectrum disorders. J Autism Dev Disord, 40(12): p. 1423-30.
H.O., et al., (2012) Autism after infection, febrile episodes, and antibiotic
use during pregnancy: an exploratory study. Pediatrics, 130(6): p. e1447-54.
P.H., (2011) Maternal infection and immune involvement in autism. Trends Mol
Med, 17(7): p. 389-94.
L., et al., (2003) Maternal influenza infection causes marked behavioral and
pharmacological changes in the offspring. J Neurosci, 23(1): p. 297-302.
O., et al., (2013) Is maternal influenza or fever during pregnancy associated
with autism or developmental delays? Results from the CHARGE (CHildhood Autism
Risks from Genetics and Environment) study. J Autism Dev Disord, 43(1): p. 25-33.
O., et al., (2015) Maternal Infection During Pregnancy and Autism Spectrum
Disorders. J Autism Dev Disord, 45(12):
O., et al., (2016) Association Between Influenza Infection and Vaccination
During Pregnancy and Risk of Autism Spectrum Disorder. JAMA Pediatr.
J.J., et al., (2016) Behavioral impact of maternal allergic-asthma in two
genetically distinct mouse strains. Brain Behav Immun.
J.J., et al., (2013) Maternal immune activation and strain specific interactions
in the development of autism-like behaviors in mice. Transl Psychiatry, 3: p. e240.
G.S., M.L. Bynum, and E.C. Somers, (2009) Recent insights in the epidemiology
of autoimmune diseases: improved prevalence estimates and understanding of clustering
of diseases. J Autoimmun, 33(3-4): p.
C.A. and D.P. Rogers, (2008) The case for autoimmunity in the etiology of
schizophrenia. Pharmacotherapy, 28(6):
J., et al., (2008) Anti-NMDA-receptor encephalitis: case series and analysis of
the effects of antibodies. Lancet Neurol,
7(12): p. 1091-8.
B., et al., (2013) Brain-reactive antibodies and disease. Annu Rev
Immunol, 31: p. 345-85.
D., et al., (2008) Autism: maternally derived antibodies specific for fetal
brain proteins. Neurotoxicology, 29(2):
E. and J. Van de Water, (2015) Maternal Anti-Fetal Brain IgG Autoantibodies and
Autism Spectrum Disorder: Current Knowledge and its Implications for Potential
Therapeutics. CNS Drugs, 29(9): p.
K., et al., (1994) Autism in thalidomide embryopathy: a population study. Dev
Med Child Neurol, 36(4): p. 351-6.
R.L., et al., (2013) The prevalence of neurodevelopmental disorders in children
prenatally exposed to antiepileptic drugs. J Neurol Neurosurg Psychiatry, 84(6): p. 637-43.
P., (2011) Serotonin and the autisms: a red flag or a red herring? Arch Gen
Psychiatry, 68(11): p. 1093-4.
Y.C., et al., (2016) Prenatal selective serotonin reuptake inhibitor use and
the risk of autism spectrum disorder in children: A systematic review and
meta-analysis. Reprod Toxicol, 66: p.
A., L. Weinstein-Fudim, and Z. Ergaz, (2015) Prenatal factors associated with
autism spectrum disorder (ASD). Reprod Toxicol,
56: p. 155-69.
W. and M.C. Lai, (2016) Annual Research Review: The role of the environment in
the developmental psychopathology of autism spectrum condition. J Child Psychol
Psychiatry, 57(3): p. 271-92.
C.W., et al., (2011) Brain enlargement is associated with regression in
preschool-age boys with autism spectrum disorders. Proc Natl Acad Sci U S
A, 108(50): p. 20195-200.
V., et al., (2012) Vaccines for measles, mumps and rubella in children.
Cochrane Database Syst Rev, (2): p. CD004407.
I.o., Adverse effects of vaccines: Evidence and Causality, K. Stratton, et al.,
C.A., N.A. Fox, and C.H. Zeanah, Romania's abandoned children. 2014, Cambridge
MA: Harvard University Press.
M., et al., (1999) Quasi-autistic patterns following severe early global
privation. English and Romanian Adoptees (ERA) Study Team. J Child Psychol
Psychiatry, 40(4): p. 537-49.
R., et al., (2014) Disruptive CHD8 mutations define a subtype of autism early
in development. Cell, 158(2): p. 263-76.