We examined whether metabolic conditions (MCs) during pregnancy (diabetes, hypertension, and obesity) are associated with autism spectrum disorder (ASD), developmental delays (DD), or impairments in specific domains of development in the offspring.
Children aged 2 to 5 years (517 ASD, 172 DD, and 315 controls) were enrolled in the CHARGE (Childhood Autism Risks from Genetics and the Environment) study, a population-based, case-control investigation between January 2003 and June 2010. Eligible children were born in California, had parents who spoke English or Spanish, and were living with a biological parent in selected regions of California. Children’s diagnoses were confirmed by using standardized assessments. Information regarding maternal conditions was ascertained from medical records or structured interview with the mother.
All MCs were more prevalent among case mothers compared with controls. Collectively, these conditions were associated with a higher likelihood of ASD and DD relative to controls (odds ratio: 1.61 [95% confidence interval: 1.10–2.37; odds ratio: 2.35 [95% confidence interval: 1.43–3.88], respectively). Among ASD cases, children of women with diabetes had Mullen Scales of Early Learning (MSEL) expressive language scores 0.4 SD lower than children of mothers without MCs (P < .01). Among children without ASD, those exposed to any MC scored lower on all MSEL and Vineland Adaptive Behavior Scales (VABS) subscales and composites by at least 0.4 SD (P < .01 for each subscale/composite).
Maternal MCs may be broadly associated with neurodevelopmental problems in children. With obesity rising steadily, these results appear to raise serious public health concerns.
The recent paper by Krakowiak et al.1 reported that maternal diabetes, obesity and other metabolic conditions were significantly associated with risk of the infant developing autism.
It was proposed in 2008 that vitamin D deficiency was an important risk factor for development of autism.2 The question addressed in this eletter is whether the paper by Krakowiak provides additional support for that hypothesis.
Vitamin D deficiency is associated with increased risk of diabetes as seen in numerous observational studies.3 The mechanisms whereby vitamin D deficiency can increase the risk of diabetes mellitus include "increasing insulin resistance, reducing insulin secretion and increasing autoimmune or inflammatory damage to pancreatic islets".4
Vitamin D deficiency is associated with obesity. For example, obese women have increased risk of vitamin D deficiency, as do their offspring.5 The likely reason for the linkage between obesity and vitamin D deficiency is dilution of 25(OH)D in a large body.6
Vitamin D deficiency is associated with increased risk of the metabolic syndrome.7,8
A recent randomized controlled trial found that supplementing pregnant and nursing women with 4000 IU/d vitamin D3 (10 times the amount in most prenatal vitamins) was effective in raising serum 25(OH)D concentrations to where 1,25-dihydroxyvitamin D concentrations were in substantial equilibrium with 25(OH)D; there were no adverse effects.9 Since 1,25-dihydroxyvitamin D controls expression of many genes, this finding supports the hypothesis that high serum 25(OH)D concentrations during pregnancy could modulate brain development.
This hypothesis is further supported by two recent papers indicating that point mutations are risk factors for autism10,11 along with a paper suggesting that vitamin D reduces the risk of autism by reducing the risk of such mutations.12
Further studies are needed to assess the role vitamin D deficiency plays in autism.
References 1. Krakowiak P, Walker CK, Bremer AA, et al. Maternal metabolic conditions and risk for autism and other meurodevelopmental cisorders. Pediatrics peds. 2011-2583; published ahead of print April 9, 2012, doi:10.1542/peds.2011-2583 2. Cannell JJ. Autism and vitamin D. Med Hypotheses. 2008;70:750-759. 3. Parker J, Hashmi O, Dutton D, et al. Levels of vitamin D and cardiometabolic disorders: systematic review and meta-analysis. Maturitas. 2010;65(3):225-236. 4. Boucher BJ. Vitamin D insufficiency and diabetes risks. Curr Drug Targets. 2011;12(1):61-87. 5. Bodnar LM, Catov JM, Roberts JM, Simhan HN. Prepregnancy obesity predicts poor vitamin D status in mothers and their neonates. J Nutr. 2007;137(11):2437-2442. 6. Drincic AT, Armas LA, Van Diest EE, Heaney RP. Volumetric dilution, rather than sequestration best explains the low vitamin D status of obesity. Obesity (Silver Spring). 2012 Jan 19. doi: 10.1038/oby.2011.404. [Epub ahead of print] 7. Hypp?nen E, Boucher BJ, Berry DJ, Power C. 25-hydroxyvitamin D, IGF-1, and metabolic syndrome at 45 years of age: a cross-sectional study in the 1958 British Birth Cohort. Diabetes. 2008;57(2):298-305. 8. Ganji V, Zhang X, Shaikh N, Tangpricha V. Serum 25-hydroxyvitamin D concentrations are associated with prevalence of metabolic syndrome and various cardiometabolic risk factors in US children and adolescents based on assay-adjusted serum 25-hydroxyvitamin D data from NHANES 2001-2006. Am J Clin Nutr. 2011;94(1):225-233. 9. Hollis BW, Johnson D, Hulsey TC, Ebeling M, Wagner CL. Vitamin D supplementation during pregnancy: double-blind, randomized clinical trial of safety and effectiveness. J Bone Miner Res. 2011;26(10):2341-2357. 10. Neale BM, et al. Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature http://dx.doi.org/10.1038/nature11011 11. Sanders SJ, et al. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature http://dx.doi.org/10.1038/nature10945 12. Kinney DK, Barch DH, Chayka B, Napoleon S, Munir KM. Environmental risk factors for autism: do they help cause de novo genetic mutations that contribute to the disorder? Med Hypotheses. 2010;74:102-106.
Conflict of Interest:
WBG receives funding from the UV Foundation (McLean, VA), Bio-Tech Pharmacal (Fayetteville, AR), the Vitamin D Council (San Luis Obispo, CA), and the Vitamin D Society (Canada). JJC is founder and Executive Director of the Vitamin D Council and receives royalties from Purity Products.
I would like to applaud the authors on an effective, thorough, and clinically relevant study design.
This study's primary finding, that metabolic conditions (MCs) are significantly associated with autism spectrum disorder (ASD) and developmental delays (DD), raises profound questions regarding their interrelated pathogeneses, but the manuscript fails to address the potential direct impact of hyperglycemia and dyslipidemia on the extracellular signaling mechanisms that may underlie such a common developmental embroyonic neuropathogenetic pathway.
Firstly, embryogenesis is highly dependent on intercellular signaling, a significant degree of which is regulated by cell surface glycoproteins, glycolipids, or glycans (1,2). MCs, by virtue of definition, are more likely to maintain pathologically prolonged states of hyperglycemia in addition to their concurrent dyslipidemia and inflammatory states, thereby predisposing them to states in which cell surface signaling molecules may more likely be glycosylated or unintentionally modified. Neuropathological disease processes involving aberrant glycosylation have described for decades (i.e. diabetic neuropathy (3)) but, more recently, other neurological pathologies such the mechanisms underlying glioblastoma differentiation and metastases have also implicated aberrant cell surface receptor modification (4).
Other fields of medicine have also demonstrated the importance of glycosylation of cell surface markers in developmental processes (5), but the significant link between all these findings points towards a combined metabolic disease effect involving cell surface modulation (likely in addition to other pathologic or physiologic modalities) as a mechanism for disrupting healthy neurodevelopment.
True, the evidence is not yet available to substantiate a theory that obesity and/or diabetes mellitus during pregnancy may result in aberrant glycosylation of cell surface signaling molecules, thereby leading to disruption in intercellular signaling cascades integral to healthy neurodevelopmental pathways and, ultimately, ASD or DD. Futhermore, as this manuscripts identifies, there is concurrent epidemiological data between an increasing incidence of ASD and DD in the USA concurrently with an increasing incidence of obesity and diabetes over the last several decades (6).
Thus, it is relatively clear that in addition to the epidemiological data presented in this manuscript, supportive evidence in other fields suggests that cell surface glyco-modulation is, at least, a plausible explanation for ASD and/or DD neurodevelopment, and likely a worthwhile avenue for further research.
Ognjen Visnjevac, MD Anesthesiology State University of NY, University at Buffalo.
1. Luther KB, Haltiwanger RS. Role of Unusual O-Glycans in Intercellular Signaling. Int J Biochem Cell Biol. 2009 May; 41(5): 1011- 1024.
2. Parker RB, Kohler JJ. Regulation of intracellular signaling by extracellular glycan remodeling. ACS Chem Biol. 2010 January 15; 5(1): 35- 46.
3. Greene DA, et al. Glucose-induced Alterations in Nerve Metabolism: Current Perspective on the Pathogenesis of Diabetic Neuropathy and Future Directions for Research and Therapy. Diabetes Care May 1985 vol. 8 no. 3 290-299
4. Cheraya M, et al. Glycosylation-related gene expression is linked to differentiation status in glioblastomas undifferentiated cells. Cancer Letters. Volume 312, Issue 1, 15 December 2011, Pages 24-32
5. Hemmorantaa H, et al. N-glycan structures and associated gene expression reflect the characteristic N-glycosylation pattern of human hematopoietic stem and progenitor cells. Experimental Hematology. Volume 35, Issue 8, August 2007, Pages 1279-1292
6. Center for Disease Control and Prevention. "U.S. Obesity Trends: National Obesity Trends." Retrieved April 12, 2012. http://www.cdc.gov.gate.lib.buffalo.edu/obesity/data/trends.html#National
Conflict of Interest:
None declared
Re: Thank you for your P3R to Pediatrics Monday, April 9, 2012 5:45 PM From: "Charles R. Fred" <cfredc1@yahoo.com> View contact details To: "Pediatrics P3Rs" <pediatrics-p3r@highwire.stanford.edu>
My letter contains an error:
This sentence is incorrect (Beta cells do not secrete glucagon):
Usually, when beta cells sense these low glucose levels, they secrete glucagon.
The sentence should read:
Usually, when the pancreas senses these low glucose levels, its alpha cells secrete glucagon.
Thanks, Charles R. Fred
Conflict of Interest:
None declared
Conflict of Interest:
None declared
(Excerpted from my paper in progress: "Unified Physiology of the Metabolic Syndrome.")
Loss of oxygen is universally recognized as causing CNS damage in foetuses, neonatals and infants. No physician would be surprised if a foetus, neonatal or infant who was transiently deprived of oxygen suffered irreparably impaired CNS development. However it's not the lack of oxygen but the lack of ATP that is the immediate cause of CNS cell damage.
For CNS cells to produce ATP, constant blood borne supplies of both oxygen and glucose are required. Since we have far greater internal reserves of glucose than of oxygen, oxygen-deprivation brain damage usually takes center stage as a medical problem.
But, given certain occasional physiological states, quite normal people suffer bouts of reactive hypoglycemia - low glucose in the brain's blood supply. These occasions manifest themselves as anxiety attacks, or if more severe, as panic attacks. The fight-or-flight axis is triggered. I myself have observed an oral surgery nurse disabled by dizziness and shaking forty-five minutes after eating a bagel containing finely milled wheat. It had never happened to her before.
Reactive hypoglycemia is often regarded as a pathological condition. However, it usually occurs in healthy people in response to ingestion of modern high glycemic index carbohydrates which differ from those "expected" by the pancreas. Sudden, transient rises in blood glucose (glucose peaks) are misinterpreted as large glucose loads because during evolution, before cooking, few dietary sources of such transient peaks could be chewed and digested by hominoids.
The amount of insulin released is excessive for the glucose load, removing too much glucose from the plasma.
Usually, when beta cells sense these low glucose levels, they secrete glucagon. This glucagon stimulates release of glucose from liver glycogen reserves. This sounds fine, but exceptional conditions can lead to CNS glucose deprivation.
First, the blood glucose drop might be too large and too fast - so the brain is deprived of glucose before the glucagon mechanism can compensate.
Second, the pathologically high insulin levels might inhibit glucose release from the liver.
Third, the liver's glucose fuel tank might be empty.
Fourth, the muscles may be so low in intracellular glucose that they remove too much glucose from the plasma.
We don't know if foetuses, neonatals and infants are more susceptible to reactive hypoglycemia - in themselves or in their pregnant mothers. But we do know that developing brains are far more sensitive to ATP deprivation than older brains.
Infants can't tell their mothers that they feel shaky and anxious 45 minutes after small amounts of high glycemic index baby food or fruit juice. Thus it is entirely reasonable to suspect that many infants sustain repeated, even chronic instances of CNS ATP deprivation - scary stuff indeed.
Consistent with Krakowiak, et al's fine epidemiological paper, obese and diabetic (at a young age) mothers probably consume a higher amount of high glycemic index beverages and foods. Similarly, the autism epidemic temporally parallels the obesity and diabetes epidemics.
This simple causal chain fits both physiologically and epidemiologically, but seems not to appear in the autism literature.
Conflict of Interest:
None declared
As a practicing Family Physician doing obstetric and pediatric care for the past 29 years, I have personally seen the incidence of autism climb in my patient population. I have also seen the numbers of routine prenatal ultrasounds skyrocket. When I think of distinguishing environmental exposures of pregnant women with metabolic conditions, the first thing that comes to my mind is their management with additional surveillance ultrasounds. Epidemiologically, the rise in ultrasound and autism match. What do data from the CHARGE study have to say about that?
Conflict of Interest:
None declared