Opinion

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EDITORIAL

Promising Forecast for Autism Spectrum Disorders

Bryan H. King, MD, MBA

Controversy seems to follow autism like the tail on a kite. From

the earliest descriptions of autism, clinicians questioned
whether this disorder was an independent entity. For instance, in 1959, Bender1 highlighted the imprecision of
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the term because many disand 1534
tinctly different etiological
pathways could converge in the same disorder and concluded
that autism was neither an etiological nor clinical entity. In contrast, in 1952 Van Krevelens skepticism about the existence of
autism was reversed when he encountered his first patient who
was as much like those described by Kanner as one raindrop
is like another.2 Others argued whether autism was psychogenic or hardwired in biology and suggested that factors as diverse as mothering3 or the reticular formation4 could be the common etiologic denominator. More recently, controversy
continues and is reflected in changes in diagnostic criteria and
the increasing recognition of heterogeneity that incorporates the
word spectrum into the diagnosis. With each new prevalence estimate that suggests inexplicable and substantial increases in the number of children diagnosed with the disorder,5
the urgency to better understand causation is amplified.
Although the evidence is already abundant that no relationship exists in the general population between measles,
mumps, and rubella (MMR) vaccine receipt and autism spectrum disorder (ASD) risk,6 immunization rates remain low in
certain populations and countries because of this inappropriate belief. Descriptions of autism contain histories of children who seemingly were suddenly affected by a catastrophic developmental event between 1 and 2 years of agea
time in proximity to a scheduled MMR immunization. It made
sense knowing this temporal window to ask, Could it be that,
if all of the requisite genetic and other risks are present, MMR
can lead to the development of autism? If so, the population
in which there might be such a signal would be families already affected by autism.
In this issue of JAMA, Jain and colleagues7 evaluated 2
questions in their large insurance claims database: does the incidence of ASD differ in younger siblings of affected children
who are immunized with MMR vs those who are not? And, for
the population as a whole, does the incidence of ASD vary as
a function of MMR immunization status? The answer to both
questions is no.
In the report by Jain et al,7 of 95 727 children with older
siblings who were included in the study, 1929 had an older sibling with ASD and 994 children had ASD diagnosed. The relative risk of ASD at age 2 years was 0.76 (95% CI, 0.49-1.18) for
children with older siblings with ASD and 0.91 (95% CI, 0.671.20) for children with older siblings without ASD.
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Some parents of children with ASD may have chosen to delay immunization in subsequent children until they were certain any risk had passed. Such behavior, which arguably could
enrich the immunization rate in the nonautism subgroup relative to the group that may have been showing early atypical
development, might create the impression that MMR vaccine
is actually reducing risk for ASD. Indeed, Jain et al7 report relative risks of less than 1.0. Even so, short of arguing that MMR
vaccine actually reduces the risk of ASD in those who were immunized by age 2 years, the only conclusion that can be drawn
from the study is that there is no signal to suggest a relationship between MMR and the development of autism in children with or without a sibling who has autism.
Taken together, some dozen studies have now shown that
the age of onset of ASD does not differ between vaccinated and
unvaccinated children,8,9 the severity or course of ASD does
not differ between vaccinated and unvaccinated children,10 and
now the risk of ASD recurrence in families does not differ between vaccinated and unvaccinated children.7
The study by Xiang and colleagues11 in last weeks issue
of JAMA directs attention for autism risk elsewhereto the
prenatal environment. Accumulating data from various different sources, including genetic, neuropathological, electrophysiological, and even infant eye gaze preference studies, have suggested that the developmental pathways for
autism are created much earlier than clinical symptoms are
manifestinforming both the timing and the types of environmental exposures on which research should focus. This
study leveraged the large Kaiser-Permanente database and
asked 2 questions, building on findings that maternal diabetes increases autism risk.12 First, is the risk for ASD increased
among offspring of mothers with type 2 diabetes during
pregnancy, and second, for those mothers who develop gestational diabetes, does the time of onset during the pregnancy influence that risk or provide clues about critical periods of vulnerability?
Of the 322 323 children studied, 3388 were diagnosed
with ASD, including 2963 unexposed, 115 exposed to preexisting maternal type 2 diabetes, and 310 exposed to gestational diabetes. The unadjusted incidences were 1.77, 3.26,
and 2.14 per 1000, respectively. More than 99% of infants
who were exposed to maternal diabetes in utero did not
develop ASD. However, in adjusted analyses, the authors
found an increased risk in the subgroup of children exposed
to gestational diabetes at 26 weeks or earlier. The hazard ratio
for preexisting type 2 diabetes was 1.21 (95% CI, 0.97-1.52)
and for gestational diabetes at 26 weeks or earlier, 1.42 (95%
CI, 1.15-1.74). Thus, the timing for this environmental exposure is isolated to early pregnancy.

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Editorial Opinion

Inasmuch as a number of the genes implicated in autism

map to the insulin-signaling pathway,13 the finding is intriguing. Although insulin does not cross the placenta, elevation of
fetal blood glucose levels as a consequence of maternal diabetes could increase fetal insulin secretion and perhaps inappropriately stimulate the fetal PI3K/Tor pathway at a critical
period in development.14
It will be interesting to determine whether such genetic
abnormalities are overrepresented in this subgroup of children with autism associated with an abnormal metabolic environment during pregnancy compared with the majority of
similarly exposed but unaffected children. Given the increasing prevalence of obesity among women of child-bearing age,
understanding the effect of insulin and maternal diabetes on
pregnancy outcomes becomes more important.
In this issue of JAMA, Bearss and colleagues15 present the
results of a multisite, 24-week randomized trial comparing 89
parents of children with ASD with behavioral problems who
received parent training to reduce disruptive behavior with 91
parents who received simple education about ASD. In light of
the controversial parent blaming that is a legacy in the field,
the term parent training is arguably a misnomer and ought
to be retired. In effect, the training helps promote becoming a
better behavioral interventionist, not a better parent.
In this study, the largest of its kind to date, the parentrated primary outcomes improved more in the training group
than the education group, although neither met the prespecified statistical threshold for a clinically important difference.
The secondary outcome based on clinician ratings found that
68.5% of children of parents who received behavior training
and 39.6% of those who received autism education were rated
ARTICLE INFORMATION
Author Affiliations: Department of Psychiatry and
Behavioral Sciences, University of Washington,
Seattle; Seattle Childrens Hospital, Seattle,
Washington.
Corresponding Author: Bryan H. King, MD, MBA,
Seattle Childrens Autism Center, University of
Washington and Seattle Childrens Hospital, PO Box
5371/M1-1, Seattle, WA 98145-5005 (bryan.king
@seattlechildrens.org).
Conflict of Interest Disclosures: The author has
completed and submitted the ICMJE Form for
Disclosure of Potential Conflicts of Interest and
none were reported.
REFERENCES
1. Bender L. Autism in children with mental
deficiency. Am J Ment Defic. 1959;64(1):81-86.
2. Van Krevelen DA. Early infantile autism
[Z Kinderpsychiat. 1952;19(2):81-97]. In: Rimland B.
Infantile Autism: The Syndrome and Its Implications
for a Neural Theory of Behavior. Englewood Cliffs, NJ:
Prentice-Hall; 1966:17.
3. Bettleheim B. The Empty Fortress: Infantile
Autism and the Birth of the Self. New York, NY: The
Free Press; 1967.

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much or very much improved at the completion of the trial,

an outcome that rivals any medication studied to date. It is difficult to assess the clinical significance of parent-reported
changes in problem behaviors ascertained through rating scales
because parents could not be blinded to their group assignments. However, the use of clinician-rated global improvement measures and the maintenance of improvement at
follow-up at 48 weeks are noteworthy.
Although specific behavioral training was superior, both
groups reported considerable improvement over baseline,
suggesting that even regular intensive education about
autism provided value to parents and translated to perceived
behavioral improvements in their children. Some challenges
for the future include what can be learned about the children
who did not respond to behavioral intervention and why
some children of parents who were not educated about
behavioral principles also improved. Autism is a diverse condition, and a better understanding of how psychosocial interventions work will be critical for determining how to personalize treatment.
As long as there are swirling winds, the kite will have a
tail, and to be fair, controversy can be a stimulus for progress. These studies move the field forward toward a more
focused and productive search for temporal and environmental factors that contribute to autism risk. They also provide information to support families affected by autism
either by allaying concern that MMR vaccine might be
harmful or giving parents the knowledge and tools to better
understand their childs condition and manage his or her
behavior. The field is long overdue for calm weather, and
the forecast is increasingly promising.

4. Rimland B. Infantile Autism: The Syndrome and

Its Implications for a Neural Theory of Behavior.
Englewood Cliffs, NJ: Prentice-Hall; 1966.
5. Developmental Disabilities Monitoring Network
Surveillance Year 2010 Principal Investigators;
Centers for Disease Control and Prevention (CDC).
Prevalence of autism spectrum disorder among
children aged 8 years: autism and developmental
disabilities monitoring network, 11 sites,
United States, 2010. MMWR Surveill Summ. 2014;
63(2):1-21.
6. Demicheli V, Rivetti A, Debalini MG, Di
Pietrantonj C. Vaccines for measles, mumps and
rubella in children. Cochrane Database Syst Rev.
2012;2:CD004407.
7. Jain A, Marshall J, Buikema A, Bancroft T, Kelly
JP, Newschaffer CJ. Autism occurrence by MMR
vaccine status among US children with older
siblings with and without autism. JAMA. doi:10.1001
/jama.2015.3077.
8. Taylor B, Miller E, Farrington CP, et al. Autism
and measles, mumps, and rubella vaccine: no
epidemiological evidence for a causal association.
Lancet. 1999;353(9169):2026-2029.
9. Madsen KM, Hviid A, Vestergaard M, et al.
A population-based study of measles, mumps, and

rubella vaccination and autism. N Engl J Med. 2002;

347(19):1477-1482.
10. Fombonne E, Chakrabarti S. No evidence for a
new variant of measles-mumps-rubella-induced
autism. Pediatrics. 2001;108(4):58.
11. Xiang AH, Wang X, Martinez MP, et al.
Association of maternal diabetes with autism in
offspring. JAMA. doi:10.1001/jama.2015.2707.
12. Xu G, Jing J, Bowers K, Liu B, Bao W. Maternal
diabetes and the risk of autism spectrum disorders
in the offspring: a systematic review and
meta-analysis. J Autism Dev Disord. 2014;44(4):
766-775.
13. Chen J, Alberts I, Li X. Dysregulation of the
IGF-I/PI3K/AKT/mTOR signaling pathway in
autism spectrum disorders. Int J Dev Neurosci.
2014;35:35-41.
14. Stern M. Insulin signaling and autism. Front
Endocrinol (Lausanne). 2011;2:54.
15. Bearss K, Johnson C, Smith T, et al. Effect of
parent training vs parent education on behavioral
problems in children with autism spectrum
disorder: a randomized clinical trial. JAMA.
doi:10.1001/jama.2015.3150.

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