Maternal Metabolic Conditions and Risk for Autism and Other Neurodevelopmental Disorders

By Matt Carey

What factors are there that may influence a child being autistic? What might increase or lower the chances that any given child will be diagnosed with autism? These are obviously major questions within the autism stakeholder communities and the autism research community. There have been indications since the 1970’s that the prenatal environment might play a key role in some part of autism. The work of Stella Chess pointed to congenital rubella syndrome as a risk factor for autism. Since then other possible exposures during pregnancy have been identified, including thalidomide, valproic acid and others. But while these exposures point to gestation as the key period for environmental risks, there is no reason to expect that they are an exhaustive list.

The journal Pediatrics released a new autism study today which presents more possible risk factors: Maternal Metabolic Conditions and Risk for Autism and Other Neurodevelopmental Disorders.  The study by authors from the University of California, Davis (including the MIND Institute) and Vanderbilt University. One thing I like about Pediatrics is that they give good lay summaries of the papers they publish, with “what is known on this subject” and “what this study adds”. In this case:

WHAT’S KNOWN ON THIS SUBJECT: Diabetes during pregnancy has been associated with general development impairments in
offspring; however, associations between autism and maternal diabetes have been inconsistent. Few studies have examined
related conditions accompanied by underlying increased insulin resistance and their association with developmental outcomes.

WHAT THIS STUDY ADDS: This population-based study in young children provides evidence that maternal metabolic conditions
are a risk factor for autism, developmental delay without autistic symptoms, and impairments in several domains of development,
particularly expressive language, after adjusting for sociodemographic and other characteristics.

The study, part of the CHARGE Study, posed the question of whether metabolic conditions (MC’s) in pregnant women pose a risk for autism and other developmental disabilities. In specific, they looked at maternal diabetes, hypertension, and obesity as risk factors. They found that in their study group, mothers who reported that they had these MC’s were more likely to have children with autism or other developmental disabilities. For autism, the risk was 60% higher (odds ratio 1.61) while for developmental disabilities the risk was over double (odds ratio 2.35) when the mother had one of these metabolic condition.

If this sounds somewhat familiar, it’s worth noting that preliminary results from this study were presented at IMFAR last year and this study was highlighted at the press conference.

The CHARGE study draws families locally to the MIND Institute by way of the regional centers, recruitment efforts by MIND personnel (my family was recruited but was just outside the catchment area at 130 miles from MIND). One strength of the CHARGE study is that they don’t rely upon existing records; they test each child (ADOS, ADI-R, Mullen Scales of Early Learning, Vineland, etc.) in-house. Information on metabolic conditions during pregnancy were taken from structured interviews with some cross-checking of medical records to confirm the accuracy of the interviews:

Demographic and medical information was obtained from the CHARGE Environmental Exposure Questionnaire
(EEQ; available for 97.6% of participants), birthfiles, and medicalrecords (available for 57.7% of participants). The EEQ is a structured telephoneadministered interview with the biological mother and includes questions about demographic characteristics,
maternal medical history, and various environmental exposures. Trained study staff extracted data from medical records

The primary focus metabolic condition was diabetes (type 2 diabetes and gestational diabetes) with obesity (body mass index >30) and hypertension also studied.

Table 2 from the paper (click to enlarge) shows the odds ratio for autism spectrum disorders (ASD) and other developmental disorders (DD) vs. typically developing (TD) for children born to mothers with diabetes and other maternal metabolic conditions:

As noted above, the odds are about 50% higher (and more, depending on condition) for ASD, and even higher for other developmental disabilities. The authors didn’t stop there. They explored how these maternal metabolic conditions might affect language and other measures of development. Table 3 (click to enlarge) shows comparisons of test scores for children with and without ASD and whose mothers had or did not have diabetes. (MSEL: Mullen Scales of Early Learning. VABS: Vineland Adaptive Behavior Scales)

Maternal diabetes may result in lower language scores, for both ASD and non-ASD kids. The authors wrote:

Within the ASD group, children of mothers with diabetes performed 0.37 SD lower on the MSEL expressive language scale compared with children of nondiabetic mothers (P = .01; Table 3); MSEL receptive language and VABS communication scores were also lower among children of diabetic mothers, with differences approaching statistical significance. No significant differences in MSEL or VABS scores were observed regarding MCs collectively among children with ASD.

The authors repeated the comparison, but for all metabolic conditions instead of just diabetes. Their Table 4 (click to enlarge) showed that there were no significant differences within the ASD group on maternal metabolic conditions. But for the non-ASD group, on every measure of the Mullens and Vineland tests, children of mothers with metabolic conditions scored lower than children whose parents did not have diabetes, obesity and/or hypertension.

This shouldn’t be surprising since the non-ASD group includes those with developmental disabilities other than ASD. So in some way this is basically telling that story in another way: maternal metabolic conditions increase the risk of developmental disabilities.

The study was relatively large, with 1004 subjects. Some of the subgroups were small, limiting the power of the study in those areas. These numbers can be found in Table 2. The most common maternal metabolic condition, by far, was obesity. The number of children whose mothers had hypertension were relatively few, leading to large confidence intervals for those odds ratios.

Another limitation is that they rely upon parent-reported medical conditions. The authors address this issue and tie together the conditions studied (diabetes, hypertension and obesity) in this paragraph:

Reliance on self-reported medical conditions was a limitation of this study. However, in the 56% of participants for
whom medical records were available, we found the 2 sources to be in good agreement. Thus, despite this limitation, we can have confidence in our results. Furthermore, although biological measurements (eg, glucose, insulin, lipids, immune biomarkers) before and during pregnancy would have been ideal, we chose conditions (T2D/GDM, hypertension, and obesity) highly indicative of increased insulin resistance as proxy measures of dysregulated metabolism and chronic inflammation because we lacked these biological measurements for most of the participants.

Without biological measurements during pregnancy the authors can’t draw specific conclusions about what behind these conditions might raise the risks of autism and developmental disorders. But they do pose some possibilities such as increased levels of glucose, fetal iron deficiency, increased levels of the cytokine interleukin-6 and others.

In the end, the authors conclude rather simply:

The prevalence of obesity and diabetes among US women of childbearing age is 34% and 8.7%, respectively. Our findings raise concerns that these maternal conditions may be associated with neurodevelopmental problems in children and therefore could have serious public health implications.

Until these results are replicated, these maternal metabolic conditions should be considered as strong potential candidates for autism risk factors. As the authors say, “these maternal conditions may be associated with neurodevelopmental problems in children”. But such a conservative conclusion takes nothing away from the potential impact of this study nor the fact that researchers can start to incorporate this new information into their models of autism etiology right away.

The paper: Maternal Metabolic Conditions and Risk for Autism and Other Neurodevelopmental Disorders
The authors: Paula Krakowiak, MS, Cheryl K. Walker, MD, Andrew A. Bremer, MD, PhD, Alice S. Baker, BA, Sally
Ozonoff, PhD, Robin L. Hansen, MD, and Irva HertzPicciotto, PhD

10 Replies to “Maternal Metabolic Conditions and Risk for Autism and Other Neurodevelopmental Disorders”

  1. Hello friends –

    With the caveats of the need for replication, when we consider the growing obese, diabetic, and hypertensive natures of our population, does this force us to requestion the degree to which our existing observations of an increasing number of children have autism can be attributed to widening diagnostic criteria?

    Nice write up.

    – pD

  2. A number of groups have been recruiting thousands of families for the purpose of analyzing environmental risk factors in pregnancy and in the newborn period. The groups include the CHARGE study group, SEED and there largest study group is the ABC (Autism Birth Cohort) collaboration between Norwegian researchers and Columbia University which so far has recruited over 100,000 pregnant women. The CHARGE group is the first to have begun publishing its findings.
    There is a fundamental logical flaw in all of these studies. The design of these studies assumes, as they should, that exposure to environmental pathogens may affect the developmental outcomes in the womb or in early childhood but that it is the only potential effect of environmental effects. These studies ignore the effects of environmental pathogens in reproductive health and take the medical histories and history of environmental effects from the mothers and largely ignore the fathers.

    The recent spate of studies has identified a growing number of cases in simplex families that are associated with gene mutations that are not present in either parent (de novo mutations). In simplex families a paternal age effect was also seen in girls in with autism associated with de novo mutations. De novo gene mutations are associated with sperm or egg mutations. What has not been recognized is that in many genetic syndromes (Rhett Syndrome, Downs Syndrome, Prader-Willi Syndrome, Klinefelter Syndrome and many more) most cases are caused by reproductive errors (sperm or egg) and are not inherited.

    Two recent studies come to mind, the CHARGE study discussed here which found that obesity and diabetes in mothers were associated increased risk for autism in newborns. The CHARGE group also recently found that living in close proximity (less than 100 yards) to heavily congested and polluted freeways in densely populated urban cities in California was associated with increased autism risk.

    One study found that exposure to SSRI’s in males was also associated with the production of sperm mutations. Another study found that obesity and diabetes type 2 in males has also been associated with infertility and sperm damage. Another study, the Chinese–Benzene Sperm Study (C-BASS), found that workplace exposure to benzene generated sperm mutations, including 1p36 sperm deletions and reported that workplace exposure to benzene is a risk factor for the 1p36 deletion syndrome. The 1p36 deletion syndrome is one of the most devastating genetic syndromes associated with autism:

    http://ghr.nlm.nih.gov/condition/1p36-deletion-syndrome

    Given the growing number of sub-groups whose etiology involves de novo gene mutations derived from reproductive errors in egg or sperm it has become imperative that these groups begin to take the medical history and history of environmental exposure of the fathers as well as the mothers and investigate the underlying causes that may generate de novo sperm or egg mutations.

    One of these groups has become convinced of the importance of taking extensive medical histories and the fathers exposure to workplace environmental pathogens and of the importance of collecting sperm specimens from the fathers for further analysis and I expect the other studies to follow their lead.

    REFERENCES

    Bishop & Scerif (2011). Klinefelter syndrome as a window on the aetiology of language and communication impairments in children: the neuroligin–neurexin hypothesis. Acta Pediatr. 2011 June 100(6):903-907.
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3107947/

    Bosch et al (2003). Linear increase of structural and numerical chromosome 9 abnormalities in human sperm regarding age. European Journal of Human Genetics (2003) 11, 754–759. doi:10.1038/sj.ejhg.5201049
    http://www.ncbi.nlm.nih.gov/pubmed/14512965

    Du Plessis et al 2010. The effect of obesity on sperm disorders and male infertility. Nature reviews Urology 7 153-161

    Click to access agradoc356.pdf

    Lowe et al (2001). Frequency of XY Sperm Increases with Age in Fathers of Boys with Klinefelter Syndrome. American Journal of Human Genetics 69(5) Nov 2001 1046-1054.
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1274351/?tool=pubmed

    Marchetti F, Eskanazi B, Weldon RH et al (2011). Occupational exposure to benzene and chromosomal structural aberrations in the sperm of Chinese men. Environ Health Perspect
    Doi:10.1289/ehp.1103921.
    http://ehp03.niehs.nih.gov/article/info:doi/10.1289/ehp.1103921

    Molina et al (2011). Sperm rates of 7q11.23, 15q11q13 and 22q11.2 deletions and duplications: a FISH approach. Hum Genet. 2011 Jan;129(1):35-44. Epub 2010 Oct 8.
    http://www.ncbi.nlm.nih.gov/pubmed/20931230

    Sarafinejad M (2008). Sperm DNA damage and semen quality impairment after treatment with selective serotonin reuptake inhibitors detected using semen analysis and sperm chromatin structure assay. J Urology. 2008 Nov;180(5):2124-8. Epub 2008 Sep 18.
    http://www.ncbi.nlm.nih.gov/pubmed/18804223

    Sloter ED et al (2007). Frequency of human sperm carrying structural aberrations of chromosome 1 increases with advancing age. Fertil Steril. 2007 May;87(5):1077-86. Epub 2007 Apr 11.
    http://www.ncbi.nlm.nih.gov/pubmed/17433321

    Volk HE, Hertz-Picciotto I et al (2010). Residential proximity to freeways and autism in the CHARGE study. Environ Health Perspect 119(6):
    Doi:10.1289/ehp.1002835 full text available at:
    http://ehp03.niehs.nih.gov/article/info%3Adoi%2F10.1289%2Fehp.1002835

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