Perinatal risk factors and pregnancy complication associated with autism

Pregnancy complications identify children who could benefit from early screening and intervention for autism

Children who are exposed to perinatal complications, especially birth asphyxia and preeclampsia, are much more likely to be diagnosed with autism

A study based on the health records of nearly 600,000 children born in Kaiser Permanente hospitals in Southern California between 1991 and 2009 found strong links between autism and complications before and during birth. This research confirms the findings of earlier studies showing that early-life physical health issues can be used to differentiate babies and toddlers who are at high risk of developing autism.

Children who are exposed to certain perinatal complications, especially birth asphyxia and preeclampsia, are much more likely to be diagnosed with autism. Other perinatal complications that were associated with autism in this latest study included premature separation of the placenta from the uterus, breech/transverse fetal presentation, fetal dystocia/abnormal size or position, and a prolapsed/exposed umbilical cord.

Compared to children not exposed to any perinatal complications, those babies who were exposed to complications only during birth had a 10 percent higher chance of developing autism. That number rose to a 22 percent increased risk of developing autism for children exposed to complications before labour began, and to a staggering 44 percent increased risk for those who were exposed to complications both before AND during birth.

Babies exposed to meconium-stained amniotic fluid are at increased risk of autism

Another retrospective birth cohort analysis of nearly 10 million children born in California found that babies who are exposed to meconium-stained amniotic fluid before birth have a significantly increased risk of autism, even after adjusting for factors associated with either premature meconium release or autism such as maternal obesity, preeclampsia, late delivery and prenatal asphyxia.

The authors concluded that “resuscitation of neonates with respiratory compromise from in utero meconium exposure may mitigate long-term neurodevelopmental damage” and highlighted the need to elucidate “the molecular mechanisms underlying specific clinical stressors that prompt in utero meconium passage”.

Investigations of underlying mechanisms point to gestational vitamin D, perinatal inflammation and immune activation

Several recent investigations attempting to illuminate some of the underlying molecular mechanisms behind prenatal autism risk focus on gestational vitamin D deficiency as well as perinatal inflammation and immune activation.

In a recently published study Krakowiak and colleagues looked at over 200 neonatal blood samples of children with a confirmed diagnosis of autism, compared to neonatal blood sample of typical developing children, in order to explore whether immunological signs at birth are predictive of autism. Their study found that specific markers of inflammations are associated with autism later in childhood, and that specific cytokine profiles vary depending on severity of autism.

The increased levels of interleukin IL-1 beta, which plays a central role in the regulation of immune and inflammatory responses to infections, were associated with a threefold increased likelihood of mild to moderate autism, whereas elevated levels of cytokine IL-4 levels, which plays a role in differentiations of immune cells and targeting of immune responses, was associated with a 1.4-fold increase in the likelihood of severe autism.

Maternal infection, autoimmune and metabolic conditions increase risk of autism

The risk for autism is known to be increased both by maternal immune activation via infection during pregnancy, and the presence of autoimmune diseases in the mother. Possible mechanisms may include direct effects of pathogens and, more indirectly, the effects of mothers (auto)immune responses on the developing brain.

Recent studies such as the one by Jones et al. show that mothers of children with more severe forms of autism – autism with intellectual disability – have significantly raised levels of numerous pro-inflammatory molecules mid-gestation. The meta-analysis by Jiang et al. observed that the risk is particularly high among those mothers requiring hospitalisation for infection during pregnancy. Risk may also be modulated by the type of infectious agent, time of infectious exposure and site of infection.

Several recent investigations have added to the growing body of evidence of the association between maternal metabolic disorders and autism. Children of mothers with metabolic disorders such as pre-pregnancy obesity, pre-existing and gestational diabetes, are almost twice as likely to develop autism.

Low-grade inflammation and activation of the innate immune system in these mothers have been suggested as possible mechanisms leading to increased risk of autism in their offspring.

Findings by Krakowiak et al. demonstrated an association between maternal metabolic conditions, particularly gestational diabetes, and having autism-specific maternal autoantibodies to the fetal brain. This association was particularly strong in mothers of children with severe form of autism.

References:

Chen SW, Zhong XS, Jiang LN, et al. (2016) Maternal autoimmune diseases and the risk of autism spectrum disorders in offspring: A systematic review and meta-analysis. Behav Brain Res. Jan 1;296:61-9. doi: 10.1016/j.bbr.2015.08.035.

Connolly N, Anixt J, Manning P, et al. (2016) Maternal metabolic risk factors for autism spectrum disorder-An analysis of electronic medical records and linked birth data. Autism Research; doi: 10.1002/aur.1586.

Estes ML, McAllister AK. (2016) Maternal immune activation: Implications for neuropsychiatric disorders. Science. Aug 19;353(6301):772-7. doi: 10.1126/science.aag3194.

Getahun D., Fassett M.J., Peltier M.R., et al. (2017) Association of Perinatal Risk Factors with Autism Spectrum Disorder. Am J Perinatol. Feb;34(3):295-304. doi: 10.1055/s-0036-1597624.

Jiang HY, Xu LL, Shao L, et al. (2016) Maternal infection during pregnancy and risk of autism spectrum disorders: A systematic review and meta-analysis. Brain Behav Immun. Nov;58:165-172. doi: 10.1016/j.bbi.2016.06.005.

Jones KL, Croen LA, Yoshida CK, et al. (2016) Autism with intellectual disability is associated with increased levels of maternal cytokines and chemokines during gestation. Mol Psychiatry. May 24. doi: 10.1038/mp.2016.77.

Krakowiak P., Goines P.E., Tancredi D.J., et al. (2017) Neonatal Cytokine Profiles Associated With Autism Spectrum Disorder. Biol Psychiatry. Mar 1;81(5):442-451. doi: 10.1016/j.biopsych.2015.08.007.

Krakowiak P, Walker CK, Tancredi D, et al. (2016) Autism-specific maternal anti-fetal brain autoantibodies are associated with metabolic conditions. Autism Research; doi: 10.1002/aur.1657.

Lombardo V, Mi Moon H, Su J, et al. (2016) Maternal immune activation dysregulation of the fetal brain transcriptome and relevance to the pathophysiology of autism spectrum disorder. Preprint article doi: 10.1101/064683.

Miller K.M., Xing G., & Walker C.K. (2017) Meconium exposure and autism risk. J Perinatol.  Feb;37(2):203-207. doi: 10.1038/jp.2016.200.

Nahum Sacks K, Friger M, et al. (2016) Prenatal exposure to gestational diabetes mellitus as an independent risk factor for long-term neuropsychiatric morbidity of the offspring. Am J Obstet Gynecol. Sep;215(3):380.e1-7. doi: 10.1016/j.ajog.2016.03.030.

Vinkhuyzen A.A., Eyles D.W., Burne T.H., et al. (2016) Gestational vitamin D deficiency and autism-related traits: the Generation R Study. Mol Psychiatry. Nov 29. doi: 10.1038/mp.2016.213.