Pre-autism: What a paediatrician should know about early diagnosis of autism‎

Table 1 Factors that increase the risk for autism

Risk	Details
Preconception risks	Presence of another child previously affected with autism
	Increased maternal and paternal age at birth (3.8% increase)
	Birth order: 61% increase in risk in firstborn
	Maternal Obesity or being overweight before pregnancy increases the risk of autism by 36%
Antenatal risk factors for autism[36]	Maternal asthma, allergies
	Preeclampsia
	Maternal bleeding (81% elevated risk)
	Maternal depression or emotional strain. It is believed that stress hormones can cross the placenta-blood barrier and affect the development of fetal brain
	Gestational diabetes (two-fold increased risk of autism)
	Hypothyroidism
	Phthalates (plasticizers) and pesticide exposure: e.g., chlorpyrifos →, sex-hormone pathways disruption → Autism.
	Folate deficiency
	Vitamin D deficiency
	Maternal Infections, e.g., congenital rubella infection, increase the rate of autism to 1:13
	Hospitalization due to antenatal infection increases the risk of autism by 30%
	Abnormal fetal growth could indicate disrupted fetal brain development. Being small or large for gestational age increases the risk of autism
	Prenatal Hormone Levels: Higher levels of prenatal testosterone may be related to an increased risk of autism
Postnatal risk factors for autism	Urbanization of birthplace
	Prematurity by more than 9 wks → higher odds of autism
	Birth injuries to the cerebellum increase the risk of autism by 3.8-fold
	Neonatal seizure
Potential risk factors for autism in neonates requiring NICU	Family history of neuropsychiatric disorders
	Maternal psychological distress during pregnancy
	Duration of stay ≥ 26 d in the NICU
	Tube feeding tube for ≥ 15 d
	Retinopathy of prematurity
	The need to use three or more antibiotics
	Co-sleeping until two years of age

NICU: Neonatal Intensive Care Unit.

Table 2 Antenatal markers for the risks of autism

Marker	Details
Genetic markers	Single-gene disorders: Fragile X syndrome (FMRI mutations), ‎neurofibromatosis (NF1), tuberous sclerosis complex (TSC1 and TSC2 ‎mutation), Dup15q syndrome, Rett syndrome (MeCP2 mutation), 16p11.2 ‎region deletions, SHANK3, NRXN1, CNTNAP2, and CHD8 genes mutations
	Chromosomal Disorders: Down syndrome, aberrations on the long arm of ‎Chromosome 15, and reciprocal chromosomal translocation between long ‎arms of chromosomes 4 and 14
	Messenger RNA (mRNA) and microRNA (miRNA) expression abnormality
	Abnormal DNA methylation patterns
Cytokines biomarkers	Abnormal profile of interleukin-6, tumor necrosis factor-alpha, interleukin-1 ‎receptor antagonist, TNF- α, Serpin E1, vascular cell adhesion molecule 1, ‎vascular endothelial growth factor D, Epidermal growth factor, Colony ‎Stimulating Factor 1, and 2
Autoantibodies biomarkers	The presence of circulating maternal autoantibodies, especially anti-brain ‎autoantibodies, during pregnancy
	Maternal autoantibody response against Collapsin Response Mediator Protein 1 ‎‎(CRMP1)
	Simultaneous reactivity against bands at 39 kDa and 73 kDa is associated with ‎early-onset autism.
Oxidative stress biomarkers	Maternal urinary levels of free 8-iso-prostaglandin F2α (8-iso-PGF2α)‎
Hormonal biomarkers	High prenatal testosterone levels
	Polycystic ovary syndrome
	Elevated levels of steroidogenic hormones (cortisol, androstenedione, testosterone, 17α-hydroxy-progesterone, and progesterone) in amniotic fluid
	Mid-pregnancy thyroid-stimulating hormone (inverse relationship)
Maternal nutritional biomarkers	Fetal levels of manganese and zinc
	Abnormal zinc-copper cycles (altered rhythmicity, shorter cycle duration, reduced regularity, and diminished complexity)
	Vitamin D deficiency
	Poor folic acid intake
Biophysical markers	Presence of multiple fetal abnormalities (especially cardiac, urinary, cranial, and ‎brain anomalies)‎
	Presence of a narrower head and a relatively broader ocular distance
	Altered prenatal brain growth
	Abnormal Kurjak's antenatal neurodevelopmental scoring test in the last ‎trimester
Radiological profile	Isolated ventriculomegaly
	Altered cortical development
	Enlarged insula ‎lobe
	Increased amygdala volume and fast growth rate

CHD8: Chromodomain helicase DNA binding protein 8; CNTNAP2‎: Contactin Associated Protein 2; Dup15q syndrome: Duplications of the portion of 15q11.2-13.1 chromosome; kDa: Kilodalton; MeCP2 mutation: Mutations of the methyl-CpG binding protein 2; NRXN1‎: Neurexin 1 RNA: Ribonucleic acid; SHANK3: SH3 and multiple ankyrin repeat domains 3; TNF-α: Tumor Necrosis Factor Alpha; TSC1: Tuberous sclerosis complex 1; TSC2: Tuberous sclerosis complex 2.

Table 3 Neonatal and early infancy markers for the risks of autism

Marker	Details
Physical markers	Large or abnormal head sizes at birth and throughout early childhood
	Smaller head sizes in girls
	Long body lengths at birth
	Hypertelorism, anteriorly rotated ears, long back of the nose, abnormal shape of ‎the mouth, and facial asymmetries
	Abnormal motor development during the first year of life e.g., hypotonia, ‎hyperreflexia, poor movement quality, ‎head lag, delayed or missing major ‎motor development, and delayed milestones, such as sitting or crawling, or ‎‎prefer using one hand over the other
	Asymmetric visual tracking
	Reduced heart rate variability
	Enhanced pupillary light reflex during infancy‎
	More liable for sleep disturbances and gastrointestinal symptoms, such as ‎constipation, diarrhea, or gastroesophageal ‎‎reflux
Social & behavioural markers	Deficits in social behavior, specifically in joint attention, eye contact, orienting ‎to names, facial expressions, social smiles, attention, and tolerance of social ‎touch
	Atypical sensory processing, with hypersensitivity or hyposensitivity to touch, ‎sounds, or visual stimuli
	Dislike being touched and cuddled
	Lie in the bassinet constantly and cry when being held up
	Avoid eye contact or have difficulty following a person's gaze when directing ‎the infant's attention to something
	Reduced visual attention to social stimulation
	Impaired orienting to novel stimuli at the age of two months‎
	Reduced interest in social interaction or decreased responsiveness to social cues
	Lie on one of the extremes of being very low or very high needs
Immunological profile	Neonatal cord blood anti-brain antibodies, especially against both 39kDa and ‎‎73kDa proteins
	Abnormalities in the concentrations of total IgG and IgG 4
	Presence of anti-dopamine D2L receptors and anti-tubulin autoantibodies and ‎the ratio of the anti-dopamine D2L to D1 receptor antibodies
	Folate receptor-alpha autoantibodies
	High immunoglobulin A in the stool
Inflammatory profile	High neonatal C-reactive protein levels
	Decreased levels of α-2-macroglobulin, ferritin, and serum amyloid P
	High IL-1B, IL-4, IL-6, IL-8, interferon-gamma, eotaxin, and monocyte ‎chemotactic protein-1 levels
	Low transforming growth factor-β1 levels
Biochemical & metabolic profile	Low blood levels of Brain-derived neurotrophic factor
	Neonatal hyperbilirubinemia
Hormonal profile‎	Reduced neonatal CSF or plasma vasopressin concentration
	Low plasma or salivary oxytocin levels
	Reduced oxytocin receptor number
Brainstem function‎	Abnormal neonatal auditory brainstem responses

CSF: Cerebrospinal fluid; IgG: Immunoglobulin G; IL: Interleukin; kDa: Kilodalton.

Table 4 Challenges to early detection of autism

Challenges	Details
Cultural & educational	Lack of adequate awareness
	Cultural and linguistic barriers
	Stigma and fear
Disease-related	Continuous variability in symptoms and signs
	Diagnosis is largely subjective
	Frequent co-morbidities and overlapping with other disorders
	Lack of specific biological markers and ‎diagnostic criteria and tests
Resources-related	Limited funding, access to screening, and healthcare facilities