Promising forecast for autism spectrum disorders.

Abstract

Controversyseemstofollowautism like the tailonakite.From the earliest descriptions of autism, clinicians questioned whether this disorder was an independent entity. For instance, in 1959,Bender1 highlighted the imprecision of the term because many distinctly different etiological pathways could converge in the same disorder and concluded thatautismwasneitheranetiologicalnorclinical entity. Incontrast, in 1952 Van Krevelen’s skepticism about the existence of autismwas reversedwhenheencounteredhis firstpatientwho 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 diverseasmothering3orthereticular formation4couldbethecommon etiologic denominator. More recently, controversy continues and is reflected in changes in diagnostic criteria and theincreasingrecognitionofheterogeneitythat incorporatesthe word “spectrum” into the diagnosis. With each new prevalence estimate that suggests inexplicable and substantial increases in thenumberof childrendiagnosedwith thedisorder,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 age—a time inproximity to a scheduledMMR immunization. Itmade senseknowing this temporalwindow 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 claimsdatabase:does the incidence of ASD differ in younger siblings of affected children whoare immunizedwithMMRvs thosewhoarenot?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 siblingswhowere included in the study, 1929hadanolder siblingwith 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. Someparentsof childrenwithASDmayhavechosen todelay immunization in subsequent children until theywere certain any riskhadpassed. Suchbehavior,which arguably could enrich the immunization rate in thenonautismsubgroup relative to the group that may have been showing early atypical development,might create the impression thatMMRvaccine is actually reducing risk forASD. Indeed, Jain et al7 report relative risks of less than 1.0. Even so, short of arguing that MMR vaccine actually reduces the riskofASD in thosewhowere immunizedbyage 2years, theonly conclusion that canbedrawn 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, somedozen studieshavenowshown that theageofonsetofASDdoesnotdiffer betweenvaccinatedand unvaccinated children,8,9 the severity or course of ASD does notdifferbetweenvaccinatedandunvaccinatedchildren,10and 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 week’s issue of JAMA directs attention for autism risk elsewhere—to 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 manifest—informing 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. Related articles pages 1524 and 1534 Opinion