Autism and the obstetrician

I first suspected that the diagnosis of childhood autism and related disorders was increasing when I was practicing in New York City. Between 1992 and 2002 I noticed a remarkable increase in reports by my patients that their children, usually boys, had been diagnosed with the condition. I certainly had a high-risk population, including many cases of advanced parental age and frequent twin gestations. I did wonder if this trend resulted from overtesting and overdiagnosis among the children of affluent, high-achieving, anxious older parents concerned that their children were not performing at the 99th percentile or whether I was witnessing an epidemic brought on by some significant environmental exposure.

My office-based observations coincided with a dramatic increase in the reported prevalence of autism spectrum disorders (ASDs), from around 1 in 1000 in the mid-1990s to over 1.1 in 100 (over 1%) in 2007.^1,2 It remains unclear to this day, however, whether this order-of-magnitude increase in the reported prevalence reflects changes in diagnostic criteria, enhanced use of diagnostic services, or a true epidemiological phenomenon. Regardless, obstetricians will increasingly face questions from affected mothers, such as, Did something happen during my pregnancy to cause my child’s condition? and How can I prevent this from happening again?

Genetic causes of autism

ASDs are characterized by lifelong derangements in 3 major neurodevelopmental domains: socialization, communication, and behavior. They range from classic autism-with its severe social isolation, stereotyped repetitive movements, and language delays-to Asperger syndrome, which is associated with significantly higher cognitive function and higher levels of social behavior. Males are significantly more often affected. A recent twin study suggests a strong, but not exclusive, genetic basis for the disorder. A meticulous interrogation of the Danish Twin Registry identified concordance rates for ASD of 95.2% in monozygotic twins compared with 4.3% in dizygotic twins.³

Indeed, a wide variety of genetic abnormalities have now been linked to ASD. About 10% of ASD patients have well-defined Mendelian disorders such as Fragile X syndrome, tuberous sclerosis, and neurofibromatosis that can be detected based on clinical history or with genetic testing or on prenatal ultrasound.⁴ Chromosomal microarrays, increasingly available for prenatal diagnosis, indicate that up to 20% of hitherto unexplained ASD cases are linked to copy number variations-ie, duplications and deletions.⁵ High-throughput sequencing has also begun to identify previously unknown genetic causes. For example, about 12% of ASD patients carry a de novo loss-of-function mutation.⁶

Today, more than 200 autism susceptibility genes have been identified, and the list is likely to grow.⁵ However, despite these recent advances, establishing precise genetic causes of ASD is difficult because the syndrome has highly variable manifestations and, when recurrent, variable expressivity. Nonetheless, periconceptional genetic counseling and selective or high-throughput DNA testing of affected children and their parents seems warranted.

Obstetrical correlates with autism

Antenatal and intrapartum “environmental” factors may also influence the occurrence of ASD. An Australian case-control study involving children born between 1980 and 1995 compared 465 ASD cases with 1313 controls.⁷ Regression analysis suggested that birth order (first births), older maternal age, threatened abortion, fetal distress, and elective cesarean delivery were more likely to be present in ASD cases. A meta-analysis of obstetrical factors associated with autism found correlations with abnormal presentation, umbilical cord complications, fetal distress, birth injury or trauma, multiple birth, maternal hemorrhage, low birth weight (LBW), small for gestational age, congenital malformations, low 5-minute Apgar score, and meconium aspiration.⁸ However, with the exception of maternal hemorrhage, LBW, and meconium aspiration, all these associations were weak (less than 2-fold increased risk) and thus, have little clinical import. But they do suggest that at least some ASD cases may have a multifactorial etiology.

Epigenetic factors

Supporting the role of epigenetic factors in the etiology of ASD is a UK study that identified distinct DNA methylation signatures associated with ASD.⁹ Comparing monozygotic twin pairs discordant for ASD, investigators noted a clearly distinct epigenetic pattern in 50 top-ranked ASD-associated differentially methylated regions (P<0.01). Also consistent with an epigenetic etiology is the finding that polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene are linked to ASD. Meta-analysis of 8 case-control studies involving 1672 patients with ASD and 6760 controls revealed that the C677T MTHFR polymorphism was significantly associated with ASD risk (odds ratio [OR] 1.86; 95% CI, 1.08-3.20 for homozygotes).¹⁰ Interestingly, this meta-analysis showed that the C677T polymorphism was associated with ASD only in children from countries without folate food fortification.

Valproate, which has been strongly linked to neural tube defects (NTDs), has a relatively robust association with ASD. A national registry of more than 650,000 children born alive in Denmark from 1996 to 2006 was used to identify children with in utero valproate exposure and children subsequently diagnosed with ASD.¹¹ The absolute risk of any child developing ASD was 1.53% (95% CI, 1.47-1.58). However, among the 508 children with in utero valproate exposure, the absolute risk of ASD was 4.42% (95% CI, 2.59-7.46), a nearly 3-fold increase in risk (adjusted HR 2.9 [95% CI, 1.7-4.9]). Because folate is prescribed to reduce the risk of fetal NTD in patients with MTHFR mutations and those taking valproate, one may ask whether periconceptional folate supplementation can reduce the risk of ASD.

Prevention: folate supplementation

Maternal folate consumption does, indeed, appear to reduce the risk of ASD in offspring. A study of pregnancies resulting in ASD-affected offspring examined maternal folate consumption from all sources and concluded that a mean daily folate intake of ≥600 μg (vs <600 μg) was associated with a reduced ASD risk (adjusted OR 0.62; 95% CI, 0.42, 0.92; P=0.02), and risk estimates decreased with increasing folic acid intake (P-trend = 0.001).¹² Not surprisingly, the association between folic acid and reduced ASD risk was strongest for mothers and children with the MTHFR C677T variant. Optimal prevention required increased folate consumption starting 3 months before pregnancy.

The population-based, prospective Norwegian Mother and Child Cohort Study (MoBa) surveyed 85,176 children born between 2002 and 2008 and identified 270 with ASDs.¹³ Among mothers who took folic acid, the percent with an affected child was 0.10% (64/61,042) versus 0.21% (50/24,134) among those not exposed to folic acid. The adjusted OR for ASD among children of folic acid users was 0.61 (95% CI, 0.41-0.90). Of note, prenatal fish oil supplements showed no benefit, even though such use was associated with the same maternal characteristics as folic acid use. This suggests that selection bias is unlikely to account for the apparent beneficial effect of folate supplementation.

Folate may exert its beneficial effects in a variety of ways. For example, it may reduce homocysteine levels in mothers or fetuses homozygous for the MTHFR C677T variant. However, recent evidence that ASD is linked to defects in epigenetic regulator genes and gene regions (eg, MeCP2, 15q11-13 duplications, PTEN, CHD8) may also explain folate’s potential efficacy.¹⁴

Take-home message

Obstetricians are ideally positioned to ensure that expert counseling and appropriate DNA studies are conducted in families affected by childhood ASD to identify possible genetic causes. In addition, 4 mg per day of folate, which has multiple other prenatal health benefits, should be prescribed at least 3 months before another conception is attempted by women whose prior child or children have ASD that is either unexplained or likely to be responsive to folate (eg, maternal MTHFR C677T variants).

References

1.    Williams JG, Higgins JP, Brayne CE. Systematic review of prevalence studies of autism spectrum disorders. Arch Dis Child. 2006;91(1):8-15.

2.    Kogan MD, Blumberg SJ, Schieve LA, et al. Prevalence of parent-reported diagnosis of autism spectrum disorder among children in the US, 2007. Pediatrics. 2009;124(5):1395-1403.

3.    Nordenbæk C, Jørgensen M, Kyvik KO, Bilenberg N. A Danish population-based twin study on autism spectrum disorders. Eur Child Adolesc Psychiatry. 2013 May 10. [Epub ahead of print].

4.    Devlin B, Scherer SW. Genetic architecture in autism spectrum disorder. Curr Opin Genet Dev. 2012;22(3):229-237.

5.    Heil KM, Schaaf CP. The genetics of Autism Spectrum Disorders--a guide for clinicians. Curr Psychiatry Rep. 2013;15(1):334.

6.    Buxbaum JD, Daly MJ, Devlin B, Lehner T, Roeder K, State MW; Autism Sequencing Consortium. The autism sequencing consortium: large-scale, high-throughput sequencing in autism spectrum disorders. Neuron. 2012;76(6):1052-1056.

7.    Glasson EJ, Bower C, Petterson B, de Klerk N, Chaney G, Hallmayer JF. Perinatal factors and the development of autism: a population study. Arch Gen Psychiatry. 2004;61(6):618-627.

8.    Gardener H, Spiegelman D, Buka SL. Perinatal and neonatal risk factors for autism: a comprehensive meta-analysis. Pediatrics. 2011;128(2):344-355.

9.    Wong CC, Meaburn EL, Ronald A, et al. Methylomic analysis of monozygotic twins discordant for autism spectrum disorder and related behavioural traits. Mol Psychiatry. 2013 Apr 23. doi: 10.1038/mp.2013.41. [Epub ahead of print].

10. Pu D, Shen Y, Wu J. Association between MTHFR gene polymorphisms and the risk of autism spectrum disorders: a meta-analysis. Autism Res. 2013 May 7. doi: 10.1002/aur.1300. [Epub ahead of print].

11. Christensen J, Grønborg TK, Sørensen MJ, et al. Prenatal valproate exposure and risk of autism spectrum disorders and childhood autism. JAMA. 2013;309(16):1696-1703.

12. Schmidt RJ, Tancredi DJ, Ozonoff S, et al. Maternal periconceptional folic acid intake and risk of autism spectrum disorders and developmental delay in the CHARGE (CHildhood Autism Risks from Genetics and Environment) case-control study. Am J Clin Nutr. 2012;96(1):80-89.

13. Surén P, Roth C, Bresnahan M, et al. Association between maternal use of folic acid supplements and risk of autism spectrum disorders in children. JAMA. 2013;309(6):570-577.

14. Berry RJ, Crider KS, Yeargin-Allsopp M. Periconceptional folic acid and risk of autism spectrum disorders. JAMA. 2013;309(6):611-613.