**Abstract**

Preconceptional and prenatal alcohol exposure is a widespread, costly, and preventable influence on neurodevelopment contributing to Autism Spectrum Disorder. Neurodevelopmental Disorder associated with Prenatal Alcohol Exposure is a heterogeneous neurophenotype that underscores the importance of etiology in diagnosis, treatment, and prevention. Expanding upon previously published clinical implications, this perspective elucidates a phenomenology describing neurophenotypic heterogeneity leading to a range of clinical neurophenotypes including Autism Spectrum Disorder as well as neurodevelopmental issues and neuropsychiatric problems. Given that ND-PAE affects up to 1 in 20 people, a pandemic-level public health response is warranted to prevent and treat preconceptional and prenatal alcohol exposure. Given the widespread use of alcohol during reproductive years, governmental enforcement of industry responsibility in consumer protection should include point of sales labeling and risk reduction advertising about the reproductive effects of alcohol products. Widespread dissemination of public health information by physicians and allied health professionals would help improve awareness that use of the solvent (alcohol) can cause reproductive health effects to gametes, zygotes, embryos, and fetuses. Improvements in screening for ND-PAE, nonjudgmental discussions with biological parents about preconceptional alcohol use, pregnancy planning through contraceptive access, and marketing mandates may reduce unintentional exposures prior to pregnancy recognition.

**Keywords:** neurodevelopment, neurophenotype, neuroteratogen, alcohol, fetal alcohol syndrome, neurodevelopmental disorder associated with prenatal alcohol exposure, fetal alcohol Spectrum disorder, preconceptional health, contraception, contracept, FASD, autism Spectrum disorder, prenatal alcohol exposure, epigenetics, methylation

#### **1. Introduction**

Alcohol is a prevalent and potent neuroteratogen affecting as many as 1 in 20 Americans [1], and a worldwide cause of atypical neurodevelopment, particularly due to exposures in unplanned or mistimed pregnancies for "social drinkers" [2, 3]. Clinically, Neurodevelopmental Disorder associated with Prenatal Alcohol Exposure (ND-PAE) and Autism Spectrum Disorder (ASD) have overlapping clinical features [4], in part due to the symptom-based diagnostic paradigm of the Diagnostic and Statistical Manual of Psychiatric Disorders (DSM-5) [5], with few psychiatric symptoms being mutually exclusive to a single psychiatric condition. Since human neurodevelopment is complex and dependent on multifactorial processes, it is no wonder that we have such heterogeneity of expressed neurophenotypes. Alcohol as a solvent perhaps is perhaps the most quintessential neurodevelopmental teratogen known to mankind.

Effects of prenatal alcohol exposure (PAE) exist on a continuum, with milder cases exposed to as few as 7 drinks per week (1 serving per day on average) associated with attention deficits and as few as 4–5 consumed during the late 3rd to early 4th week post conception causing the full Fetal Alcohol Syndrome (FAS) [6]. Alcohol can affect human development at any point from preconceptionally (gametogenesis) to the first few weeks post conceptionally (neurulation and gastrulation through organogenesis) [7] through fetal development to birth. Lactation is also a time when the newborn and infant can be exposed to and affected by a mother's use of alcohol [8]. Neurodevelopmental effects of PAE involve brain functions as well as sensorium (cranial nerves and sensory neurons), motor neurons, autonomic regulation, and neurotransmitter systems. These effects have been described in the DSM-5 as ND-PAE, yet there remains a lack of acknowledgement, understanding, and recognition in the psychiatric community for this diagnosis. Nonetheless, scholars are attempting to highlight the link between PAE and neuropsychiatric illness [9].

Neurodevelopmental complexity of symptoms associated with prenatal alcohol exposure can lead to an ASD-like phenotype, including social communication deficits, neurocognitive issues (e.g., executive functions), sensory integration problems (e.g., interoception, hypo/hypersensitivities), motor deficits, and emotional dysregulation. All of the body systems can be affected by PAE, including immune, endocrine, reproductive, metabolic, cardiovascular, urinary, gastrointestinal, and integumentary. Alcohol affects both the developing sperm up to 3 months preconceptionally (DNA histone modifications) as well as beginning as early as weeks 2–3 post-conception. Research implicates alcohol consumption during adolescence with epigenetic effects on gametes, leading to alterations in the hypothalamic stress response system [10].

Likewise, Autism Spectrum Disorder (ASD) is a broad, umbrella term describing complex atypical neurodevelopment due to a wide array of multifactorial etiologies [11]. Williams and Lewis have developed a useful clinical screening tool for ASD [12]. As a neurophenotype [13], ASD has a wide range of symptoms which can be due to preconceptional epigenetic insults to gametes, *in utero* prenatal exposures to neuroteratogens, genetic (familial) hereditary anomalies, early neurologic birth traumas, and as yet unidentified causes [14]. The heterogeneity of ASD as well as the plethora of etiological factors are beyond the scope of this chapter. Given the range of unknown and otherwise as yet nonpreventable causes of ASD, any reductions in etiology due to a substance so ubiquitous as alcohol would reduce the societal burden of this otherwise complex, difficult to treat condition.

#### *Perspective Chapter: Autism Spectrum Disorder Neurophenotype with Preconceptional… DOI: http://dx.doi.org/10.5772/intechopen.108820*

Since human neurodevelopment is multifactorial, with genetic, epigenetic, and environmental influences, exact etiological associations in each child difficult to elucidate. A proposed paradigm for atypical neurophenotypic development is described in **Figure 1**, which is adapted from Picci and Sherf [15]. The combination of preconceptional issues, genetics, epigenetics, and the prenatal environment are exacerbated by adverse childhood experiences (ACEs) and adolescent use of alcohol, tobacco and other drugs – which are cumulative effects to disrupt healthy neuronal development. This model shows prenatal alcohol exposure in the context of an individual zygote's biological background of epigenetic and/or genetic factors, such as familial autism traits and/or predisposition to effects of prenatal alcohol exposure (e.g., CYP-450 enzyme expression in the mother or fetus). The first preventable hit to neurodevelopment is preconceptional or prenatal use of alcohol, whereas the model assumes that the epigenetic and genetic background of the zygote may not be changed. In order to effectively prevent the first hit, one must contracept if using alcohol and must stop using alcohol up to 3 months preconceptionally in order to prevent epigenetic influences on spermatogenesis. The second hit, ACEs, is currently identified by childhood screening for abuse and neglect, though beyond the scope of this chapter. Further alterations in neurodevelopment happen when adolescent use of substances such as alcohol, tobacco and other drugs, often triggering psychosis, mania, or other severe and persistent mental illness. Hence, the term "*neurodevelopmental*" may be best understood in the context of the *neuro*logical *develop*ment of *mental* disorders.

Because DSM-5 is based on symptomatology, etiological factors of neurodevelopmental conditions are conceptualized by psychiatrists and mental health practitioners as secondary or inconsequential to diagnostic criteria and treatment paradigms. Co-morbidity of ASD and ND-PAE blurs the clinical picture, leaving psychiatrists, pediatricians, mid-level providers, and allied health professionals with a laundry list differential diagnoses and complex formulations. Individuals with prenatal alcohol exposure are at risk for many DSM-5 psychiatric and neurodevelopmental conditions [16]. Co-occurrence may be overlooked for affected children who may have been exposed prior to pregnancy recognition or who have preconceptional alcohol-induced epigenetic factors that would not show up on chromosomal karyotype or genetic

**Figure 1.**

*3-hit model of "neuro-develop-mental" damage.*

microarray analysis [17]. Neurobiology, neuropsychiatry, neuroimaging, and neurogenetics may assist in clarifying clinically overlapping phenotypes (i.e., co-morbid ASD and ND-PAE) when prenatal alcohol exposure is known.
