Development and Autism Part 2

Prenatal Factors in the Development of Autism

Infants do not enter this world as much as they develop into it. The prenatal environment is gaining increasing scientific attention as researchers realize the influential effects it can have on development. Specifically in atypical development, researchers are beginning to turn to prenatal analyses to find evidence for the earliest biomarkers of development going awry. Because autism shows great benefits from the earliest forms of intervention, there is a medical, social and academic interest in examining the earliest form of life as it occurs prenatally (Connors & Zimmerman, 2010; Sheinkopf & Siegel, 1998; Toth, Dawson, Meltzoff, Greenson, & Fein, 2007).

A study comparing children with autism (ASD) and pervasive developmental disorders not otherwise specified (PDD-NOS) to typically developing children analyzed their prenatal, perinatal and neonatal differences, and the demographic differences of their mothers (Juul-Dam, Townsend, & Courchesne, 2001). In their retrospective analysis they found significant differences in instances of maternal uterine bleeding and rhesus incompatibility during pregnancy and of induced, prolonged, or precipitous labor. The infants who were later diagnosed with ASD or PDD-NOS also showed significantly higher incidences of oxygen requirement at birth and presence of hyperbilirubinemia (Juul-Dam et al., 2001).

Uterine bleeding while often caused by benign events can cause maternal stress, which itself can have negative effects on the developing embryo and fetus (K. L. Jones et al., 2010). Uterine bleeding can also be caused by abnormal placental location or premature placental separation, which can affect nutrient uptake, waste elimination and gas exchange (Juul-Dam et al., 2001). Obstruction to these processes can have deleterious effects on the fetus (Ayuk, Hughes, & Sibley, 2000).

Rhesus incompatibility describes maternal antibodies that have developed in response to fetal red blood cells and can lead to fetal hematologic destruction (Juul-Dam et al., 2001). This in turn can cause improper prenatal oxygen flow and neural development, and later seizures (Hollister, Laing, & Mednick, 1996). A study on the effect of these maternal antibodies on pregnant mouse dams showed fetal brain development, and later anxiety, stimulus response and social behavior to be affected in way that resembled autistic symptoms (Singer et al., 2009).

Instances of labor induction can have several reasons from maternal to fetal complications, and can cause both physical and emotional stress to the mother and the neonate (Clark et al., 2009). Induction often involves exogenous oxytocin administration, which is not an adequate substitute for vaginal stimulation that would induce endogenous oxytocin release. During natural human birth, fetal oxytocin functions as an analgesic, whereas exogenous oxytocin levels administered to the mother more quickly transfer to the fetus causing a harmful oxytocin increase in the birthing infant (Khazipov, 2011). Additionally, exogenous oxytocin can cause hyperactive uterine contractions which can lead to abnormal fetal heart rate patterns during birth (Kunz, Loftus, & Nichols, 2012).

Prolonged labor may be caused by misalignments, disproportions between fetus and maternal pelvis, overuse of sedatives, insufficient contractions, or premature damage to the fetal membranes. Cesarean sections resulting from insufficient contractions, for example, have shown to affect infant immune systems, lung capacities and digestive system functions (Neu & Rushing, 2011). Contractions themselves have been suggested to help bond the birthing mother to her baby as they release important neurotransmitters such as oxytocin that facilitate feelings of care and attachment (H.-J. Lee, Macbeth, Pagani, & Young, 2009; Lothian, 2000; Nelson & Panksepp, 1998). The opposite is proposed for cesarean sections and induced labor, which may be required when contractions are inadequate (Lobel & DeLuca, 2007; Mutryn, 1993).

Prolonged labor itself can cause fetal asphyxia, infections or head trauma, which can have negative long-term effects on the developing child (Juul-Dam et al., 2001). Precipitous labor can have negative effects on both the mother and the child, as severe contractions may emerge too quickly not allowing both mother and child to adequately prepare, emotionally and physiologically. This may prevent adequate blood and oxygen flow to the fetus, which can have damaging effects on the brain (Juul-Dam et al., 2001). The need for medical oxygen supply at birth indicates improper lung capacity which can be harmful to brain and organ development and lead to developmental retardation (Juul-Dam et al., 2001). Hyperbilirubinemia, which can be caused by rhesus incompatibility, can also result in brain damage with developmental effects later on in life (Juul-Dam et al., 2001).

Aside from the listed medical issues, the mothers of ASD and PDD-NOS children were more educated (Juul-Dam et al., 2001). The higher rate of education in these mothers is mentioned by L. Kanner as well in the first noted ASD case studies (Kanner, 1943). According to Kanner and D. Kramer, a psychoanalyst, more highly educated parents may permit a more stressful environment due to increased instances of neurosis, anxiety, and the desire to fulfill high expectation (Kramer, 1987).

A review article suggests that advanced parental age, low birth weight and gestational age, and incidences of hypoxia all relate to later diagnoses of autism (Kolevzon, Gross, & Reichenberg, 2007). These factors have shown to affect cognitive and neurological development in that nutritional and oxygen deficiencies can lead to malformations in the system (Hollister et al., 1996). Advanced parental age can carry with it issues of physiological stress, age-related immunocompromises, higher emotional stress, and lower overall energy levels (Croen, Najjar, Fireman, & Grether, 2007).

Another more extensive review also showed advanced parental age during gestation to be a correlating factor in autism (Gardener, Spiegelman, & Buka, 2009). Advanced maternal age can potentially lead to chromosomal abnormalities in the egg, whereas advanced paternal age is linked to copy errors during spermatogenesis. Thus, egg and sperm cellular composition may set the stage for developmental and neurological errors in the gestating child.

This review found suboptimal obstetrics to play a role in later autistic diagnoses. As mentioned before, prolonged and precipitous labor seem to correlate with incidences of autism, probably due to the potential dangers both to the fetus and to the mother during these conditions. Additionally, gestational diabetes is shown to often precede autism. Gardener et al. (2009) point out that the relationship between gestational bleeding and later autism may have to do with the incidences of hypoxia, which not only leads to poor oxygen flow but also to a heightened dopaminergic activity evident in autistic individuals later in life (Gardener et al., 2009; Previc, 2007).

The review mentions the relationship between maternal psychoactive drug-use during pregnancy as linked to autistic development. While other drugs show no such link, psychiatric medication seems to relate to autism. One of the components in mood-stabilizing drugs is valporic acid, which has been shown to create autistic like social behaviors in rats prenatally exposed (Bambini-Junior et al., 2011). It is important to note, however, that the relationship between these medications and autistic outcomes could have to do with either the drug components themselves, the conditions they are meant to treat, or potential genetic factors inherited by the fetus (Gardener et al., 2009).

To test the idea of genetic susceptibility influencing the aforementioned factors, pregnancy conditions were compared in those families with affected siblings or mothers with psychiatric or neurological conditions to those families without (Dodds et al., 2010). Pregnancies with assumed genetic susceptibility seemed to be less affected by other maternal factors and obstetric suboptimalities than those without these genetic susceptibilities.

A factor that seemed to play a role regardless was maternal obesity or intense weight gain during pregnancy. The researchers speculate a link to leptin which typically increases slightly during pregnancy, but is generally heightened both in obese individuals, but also in autistic individuals without weight issues (Dodds et al., 2010).

Leptin is a hormone involved in thermoregulation, appetitive behaviors and metabolism, regulates energy output and intake, and is commonly studied as derived from brown adipose tissue (Rezai-Zadeh & Münzberg, 2013). The increased leptin levels in autistic individuals may link to their common issues with sufficient nutrient intake, their physiological and motor abnormalities but also their social attachment. Brown-fat-derived leptin is thought to play an important role in early thermoregulation of infant mammals (Alberts & Harshaw, 2014). If leptin is transferred to the developing fetus via the placenta, this may have consequences on brown adipose tissue thermogenesis (Gong, 1997; Lea et al., 2000). Brown fat is an important factor in thermoregulation, and its levels drive infant mammals to huddle or seek social warmth with others (Alberts & Harshaw, 2014). If an autistic child stores more brown fat it may not need the same amount of closeness or warmth provided by the mother, giving off an estranging anti-social, non-attached impression (Hoppes & Harris, 1990).

Another study investigated whether the timing of prenatal stressors correlated with autistic diagnoses later on. Beversdorf et al. (2005) found that overall there were more incidences of stressful events during pregnancy for those children later diagnosed with autism than for those with Down syndrome or typical development. More importantly, they found that the stressors in the cases of autism occurred within the first 21 to 32 weeks of gestation (Beversdorf et al., 2005). This time period is especially important for the formation of the cerebellum, a structure of the brain that is most susceptible to pathological modifications during the first 32 weeks of gestation and has been related to autistic neuroanatomical atypicalities (Beversdorf et al., 2005). Additionally, cerebellar damage has been shown in rats to occur more during prenatal stress responses involving glucocorticoids (Beversdorf et al., 2005). Cerebellum malformations can have effects on sensory integration and processing, emotion regulation, and balance – areas in which individuals with autism display difficulties (Zwaigenbaum et al., 2005).

In order to examine the possible effects of viral infections on brain development and its to link to neurological characteristics found in autism, pregnant mouse dams were exposed to human influenza (Fatemi et al., 2002). The exposure affected neuronal cell proliferation in newborn mice with long-lasting effects into adulthood (Fatemi et al., 2002). Specifically, researchers found pyramidal cell density to be increased at birth with a reduction in nonpyramidal cell density that increased rapidly in adulthood in an atypical manner. The increased pyramidal density was paired with an on-going pyramidal atrophy, a neuronal atypicality suggested in adult autistic brains (Buxhoeveden et al., 2006). Despite the atrophy throughout life, brain sizes in infected mice seemed to be significantly bigger overlapping with the macrocephaly often found in autistic adults (Kanner, 1943; Miles, Hadden, Takahashi, & Hillman, 2000).

In the comparative study, cell atrophy throughout development lead to deficient prepulse inhibition of startle responses and social anxiety in the mice, which parallels the deficient prepulse inhibition often found in autistic patients (Perry, Minassian, Lopez, Maron, & Lincoln, 2007). Additionally, the increased pyramidal cell production paired with somal atrophy and atypical late-onset increased density of nonpyramidal cells or interneurons may lead to excess inhibition and reduction in somatosensory prepulse inhibitions (Fatemi et al., 2002). Overall, this dysregulation in the proliferation and growth of neurons in mice prenatally exposed to viruses may be comparable to one of the many mechanisms that may cause neural and behavioral abnormalities in autism.

Finally, researchers have tried to trace the gender-specific prevalence of ASD to sexual dimorphic oxytocin profiles. Generally, males more commonly develop the disorder than do females. The sexually dimorphic endocrine system differentiates early during prenatal development creating sex-dependent sensitivities to both hormones and neurotransmitters (Behringer, Finegold, & Cate, 1994). Early developing fetuses thus show different levels of sensitivity to both androgens and neurotransmitters, such as oxytocin. Because oxytocin is both more abundant in females and less abundant in individuals with ASD, alongside the aforementioned developmental effects of oxytocin, this neurotransmitter may provide insight into what makes a system more prone to developing the disorder (Carter, 2007; Nelson & Panksepp, 1998).

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