Maternal diabetes and offspring autism risk... again

"In this large, multiethnic clinical cohort of singleton children born at 28 to 44 weeks’ gestation, exposure to maternal GDM [gestational diabetes mellitus] diagnosed by 26 weeks’ gestation was associated with risk of ASD [autism spectrum disorder] in offspring."

That was the conclusion reached by Anny Xiang and colleagues [1] (open-access) following their analysis of some 3300 children diagnosed with ASD as part of a wider cohort of over 300,000 children "born in 1995-2009 at Kaiser Permanente Southern California (KPSC) hospitals." Records of children with and without autism were examined according to the presence or not of maternal type 2 diabetes or maternal GDM during pregnancy. "Diagnosis of GDM was based on laboratory values confirming a plasma glucose level of 200 mg/dL or higher on the glucose challenge test or at least 2 plasma glucose values meeting or exceeding the following values on the 100-g or 75-g oral glucose tolerance test: fasting, 95 mg/dL; 1 hour, 180 mg/dL; 2 hours, 155 mg/dL; and 3 hours, 140 mg/dL." Autism diagnosis was based on "ICD-9 codes 299.x or equivalent KPSC codes" covering "autistic disorders, Asperger syndrome, or pervasive developmental disorder not otherwise specified (PDD-NOS) and excluded childhood disintegrative disorder and Rett syndrome."

Results: of the 3388 children diagnosed with an ASD, a large majority were deemed 'unexposed' to either maternal type 2 diabetes or GDM (87%). What this tells us is that ideas about exposure to maternal diabetes being 'universally' associated with a diagnosis of ASD in offspring are incorrect. That being said, some 115 children were exposed to maternal type 2 diabetes and 310 GDM exposed.

Taking into account the timing of exposure as per the analysis of gestational weeks at diagnosis of GDM - "26 weeks or earlier (mean of 16 weeks), after 26 weeks but prior to 30 weeks (mean of 28 weeks), and 30 weeks or later (mean of 32 weeks)" - and controlling for various potentially confounding variables such as maternal age, parity, education, household income, race/ethnicity, history of comorbidity, and sex of the child, some interesting results are reported. GDM exposure diagnosed by 26 weeks gestation was associated with something of an increased risk (hazard ratio) of offspring autism to the tune of about a 40% increased risk. At the same time, exposure to maternal pre-existing type 2 diabetes did not seem to significantly elevate the risk of offspring ASD. The Autism Speaks write-up of the Xiang trial offers this helpful statement: "the increased autism risk seen with early gestational diabetes translated into roughly seven additional cases per 1,000 pregnancies."

The reason why I titled this post 'maternal diabetes and offspring autism risk... again' is because it is not new news that maternal diabetes might have some kind of effect on offspring autism risk. I covered this research area previously on this blog (see here) based on findings such as those from Xu and colleagues [2] (open-access). Other peer-reviewed research has similarly hinted at the possibility of an association between maternal diabetes and offspring autism as part of a wider spectrum of 'effects' on the developing child [3].

"The mechanisms underlying the effects of maternal hyperglycemia on the developing fetus may involve increased oxidative stress, hypoxia, apoptosis, and epigenetic changes" according to that paper by Ornoy and colleagues [3]. With autism in mind, most of those concepts have been banded around as being linked to cases at one time or another, perhaps only missing out on the 'inflammatory' element mentioned by Xiang et al. I wouldn't like to speculate any further on what specific process might be going on (more likely a combination of effects) but given the seemingly important variable of timing, as in exposure to GDM by 26 weeks gestation, I'd suggest that epigenetics might be a front-runner [4]. Foetal programming hypothesis and all that palaver...

"Our results also suggest that screening for GDM and control of glucose levels early in pregnancy may be important in reducing ASD risk for offspring. Whether early diagnosis and treatment of GDM can reduce the risk of ASD remains to be determined." I struggle to disagree with the closing sentiments from Xiang and colleagues.

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[1] Xiang AH. et al. Association of Maternal Diabetes With Autism in Offspring. JAMA. 2015; 313: 1425-1434.

[2] Xu G. et al. Maternal diabetes and the risk of autism spectrum disorders in the offspring: a systematic review and meta-analysis. J Autism Dev Disord. 2014 Apr;44(4):766-75.

[3] Ornoy A. et al. Effect of maternal diabetes on the embryo, fetus, and children: Congenital anomalies, genetic and epigenetic changes and developmental outcomes. Birth Defects Res C Embryo Today. 2015 Mar;105(1):53-72.

[4] Lehnen H. et al. Epigenetics of gestational diabetes mellitus and offspring health: the time for action is in early stages of life. Mol Hum Reprod. 2013 Jul;19(7):415-22.

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Xiang, A., Wang, X., Martinez, M., Walthall, J., Curry, E., Page, K., Buchanan, T., Coleman, K., & Getahun, D. (2015). Association of Maternal Diabetes With Autism in Offspring JAMA, 313 (14) DOI: 10.1001/jama.2015.2707