Autism and Prematurity: What We Know
By Hallam Hurt, MD, Education Director and Attending Neonatologist, Neonatal Follow-up Program
In recent years, recognition of autism and autism spectrum disorders (ASD) in the general population has burgeoned. According to the Centers for Disease Control and Prevention (CDC), autism affects an estimated 1 in 36 (2.8%) 8-year-old children in the United States, an increase from 1 in 44 children (2.3%) two years ago, and from to 1 in 54 in 2016. ASD is four times more common in boys than in girls and it occurs in all racial, ethnic and socio-economic groups.
Having certain genetic or chromosomal conditions, older birthing parents, a sibling with autism, various environmental exposures, being of low birth weight, and having exposure to certain medications during pregnancy are risk factors for ASD. But what about preterm babies? Are they at particular risk?
The answer is yes. A spate of articles suggest the risk for ASD in prior preterm infants may be as alarmingly high as 20%, with frequency increasing as gestational age decreases. These numbers are particularly concerning as survival rates for preterm infants are increasing. Thus, in aggregate, the number of individuals with ASD is increasing as well.
Many such reports, however, lack rigor in selection of population for analysis, sample size, as well as requirement for use of diagnostic tests rather than screening tools for diagnosis of ASD. Such issues were addressed in a meta-analysis of prevalence of ASD in preterm infants published in Pediatrics in 2018. In a report of 18 studies rigorously chosen for their description of population evaluated as well as use of a diagnostic rather than screening tool, investigators found an overall ASD prevalence rate of 7%. The report included a total of 3,366 preterm infants with mean gestational age 28.0 weeks and birth weight 1055g (Agrawal et al).
A more recent meta-analysis in 2021 utilized 52 papers classified by assessment method:
- screening tools such as Modified Checklist for Autism in Toddlers, Revised (M-CHAT-R)
- diagnostic assessments such as Autism Diagnostic Observational Schedule (ADOS), Autism Diagnostic Interview - Revised (ADI-R), and Childhood Autism Rating Scale (CARS)
Utilization of a screening assessment resulted in a pooled prevalence estimate of autism of 20% in preterm population in comparison to 6% when using a diagnostic assessment. Overall, authors concluded “odds of an autism diagnosis were 3.3 times higher in individuals born preterm than in the general population.” (Laverty et al)
Other investigations have identified relationships between gestational age at birth and autism. In a large national Swedish cohort, ASD prevalence by gestational age was as follows:
- 6.1% for extremely preterm (22-27 weeks)
- 2.6% for very to moderate preterm (28-33 weeks)
- 1.9% for late preterm (34-36 weeks)
- 1.6% for early term (37-38 weeks)
- 1.4% for term (39-41 weeks)
Thus, these data suggest a dose-response type relationship (Crump et al).
Exploring the relationship between prematurity and ASD
It is intriguing to explore possible linkages between causes of preterm birth and development of ASD. ls whatever triggers preterm birth a causal pathway for ASD?
Perhaps one of the most discussed mechanisms is neuroinflammation, described as present in some preterm births and suggested in autism. A growing literature supports this potential connection, including research in animal models. As is well known, a multiplicity of other factors are associated with preterm birth, although some mothers giving preterm birth exhibit none.
The absence of known risk factors gives rise to exploring genetic underpinnings that may link ASD and prematurity. This potential link is substantiated as some genetic factors are known to be associated with development of ASD.
Take Homes:
- Preterm infants are at higher risk for ASD.
- Prevalence of ASD is ~ 7% in the preterm population, not the more inflated number of ~ 20%.
- A “dose-response” relationship of ASD with gestational age seems likely.
- Mechanisms of linkage between ASD and prematurity remain under investigation.
Final thoughts on this topic
It is critical to remember that the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM V) states that a criteria for ASD is, “disturbances are not explained by intellectual disability or global developmental delay,” two conditions, along with visual, hearing and motor compromise, that may be seen in prior preterm infants. Given these potentially overlapping symptoms, one must be vigilant when evaluating preterm infants for autism as:
- ASD may masquerade as sequelae of prematurity
- Sequelae of prematurity may masquerade as ASD
In the former, one should not assume all findings are related to prematurity, thus delaying further evaluation for ASD. In this regard, early evaluation and diagnosis are important, as appropriate interventions are not covered through Early Intervention alone. In the latter situation, if an infant is compromised by neurodevelopmental findings that mimic ASD, one must not be too hasty to ascribe findings to ASD.
Agrawal S, Shripada RC, Bulsara MK, Patole SK. Prevalence of autism spectrum disorder in preterm infants: a meta-analysis. Pediatrics. 2018;142(3):e20180134.
Crump C, Sundquist J, Sundquist K. Preterm or early term birth and risk of autism. Pediatrics. 2021;148(3):e2020032300.
Bokobza C, Van Steeinwinckel J, Mani S, Mezger V, Fleiss B, Gressens P. Neuroinflammation in preterm babies and autism spectrum disorders. Pediatr Res. 2019;85(2):155-165.
Laverty C, Surtees A, O’Sullivan R, Sutherland D, Jones C, Richards C. The prevalence and profile of autism in individuals born preterm: a systematic review and meta-analysis. J Neurodev Disord. 2021;13(1):41.
Risk Factors for Autism Spectrum Disorders:
- Certain genetic or chromosomal conditions
- Older birth parents
- Sibling with autism
- Various environmental exposures
- Low birth weight
- Exposure to certain medications during pregnancy
- Prematurity
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Autism and Prematurity: What We Know
By Hallam Hurt, MD, Education Director and Attending Neonatologist, Neonatal Follow-up Program
In recent years, recognition of autism and autism spectrum disorders (ASD) in the general population has burgeoned. According to the Centers for Disease Control and Prevention (CDC), autism affects an estimated 1 in 36 (2.8%) 8-year-old children in the United States, an increase from 1 in 44 children (2.3%) two years ago, and from to 1 in 54 in 2016. ASD is four times more common in boys than in girls and it occurs in all racial, ethnic and socio-economic groups.
Having certain genetic or chromosomal conditions, older birthing parents, a sibling with autism, various environmental exposures, being of low birth weight, and having exposure to certain medications during pregnancy are risk factors for ASD. But what about preterm babies? Are they at particular risk?
The answer is yes. A spate of articles suggest the risk for ASD in prior preterm infants may be as alarmingly high as 20%, with frequency increasing as gestational age decreases. These numbers are particularly concerning as survival rates for preterm infants are increasing. Thus, in aggregate, the number of individuals with ASD is increasing as well.
Many such reports, however, lack rigor in selection of population for analysis, sample size, as well as requirement for use of diagnostic tests rather than screening tools for diagnosis of ASD. Such issues were addressed in a meta-analysis of prevalence of ASD in preterm infants published in Pediatrics in 2018. In a report of 18 studies rigorously chosen for their description of population evaluated as well as use of a diagnostic rather than screening tool, investigators found an overall ASD prevalence rate of 7%. The report included a total of 3,366 preterm infants with mean gestational age 28.0 weeks and birth weight 1055g (Agrawal et al).
A more recent meta-analysis in 2021 utilized 52 papers classified by assessment method:
- screening tools such as Modified Checklist for Autism in Toddlers, Revised (M-CHAT-R)
- diagnostic assessments such as Autism Diagnostic Observational Schedule (ADOS), Autism Diagnostic Interview - Revised (ADI-R), and Childhood Autism Rating Scale (CARS)
Utilization of a screening assessment resulted in a pooled prevalence estimate of autism of 20% in preterm population in comparison to 6% when using a diagnostic assessment. Overall, authors concluded “odds of an autism diagnosis were 3.3 times higher in individuals born preterm than in the general population.” (Laverty et al)
Other investigations have identified relationships between gestational age at birth and autism. In a large national Swedish cohort, ASD prevalence by gestational age was as follows:
- 6.1% for extremely preterm (22-27 weeks)
- 2.6% for very to moderate preterm (28-33 weeks)
- 1.9% for late preterm (34-36 weeks)
- 1.6% for early term (37-38 weeks)
- 1.4% for term (39-41 weeks)
Thus, these data suggest a dose-response type relationship (Crump et al).
Exploring the relationship between prematurity and ASD
It is intriguing to explore possible linkages between causes of preterm birth and development of ASD. ls whatever triggers preterm birth a causal pathway for ASD?
Perhaps one of the most discussed mechanisms is neuroinflammation, described as present in some preterm births and suggested in autism. A growing literature supports this potential connection, including research in animal models. As is well known, a multiplicity of other factors are associated with preterm birth, although some mothers giving preterm birth exhibit none.
The absence of known risk factors gives rise to exploring genetic underpinnings that may link ASD and prematurity. This potential link is substantiated as some genetic factors are known to be associated with development of ASD.
Take Homes:
- Preterm infants are at higher risk for ASD.
- Prevalence of ASD is ~ 7% in the preterm population, not the more inflated number of ~ 20%.
- A “dose-response” relationship of ASD with gestational age seems likely.
- Mechanisms of linkage between ASD and prematurity remain under investigation.
Final thoughts on this topic
It is critical to remember that the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM V) states that a criteria for ASD is, “disturbances are not explained by intellectual disability or global developmental delay,” two conditions, along with visual, hearing and motor compromise, that may be seen in prior preterm infants. Given these potentially overlapping symptoms, one must be vigilant when evaluating preterm infants for autism as:
- ASD may masquerade as sequelae of prematurity
- Sequelae of prematurity may masquerade as ASD
In the former, one should not assume all findings are related to prematurity, thus delaying further evaluation for ASD. In this regard, early evaluation and diagnosis are important, as appropriate interventions are not covered through Early Intervention alone. In the latter situation, if an infant is compromised by neurodevelopmental findings that mimic ASD, one must not be too hasty to ascribe findings to ASD.
Agrawal S, Shripada RC, Bulsara MK, Patole SK. Prevalence of autism spectrum disorder in preterm infants: a meta-analysis. Pediatrics. 2018;142(3):e20180134.
Crump C, Sundquist J, Sundquist K. Preterm or early term birth and risk of autism. Pediatrics. 2021;148(3):e2020032300.
Bokobza C, Van Steeinwinckel J, Mani S, Mezger V, Fleiss B, Gressens P. Neuroinflammation in preterm babies and autism spectrum disorders. Pediatr Res. 2019;85(2):155-165.
Laverty C, Surtees A, O’Sullivan R, Sutherland D, Jones C, Richards C. The prevalence and profile of autism in individuals born preterm: a systematic review and meta-analysis. J Neurodev Disord. 2021;13(1):41.
Risk Factors for Autism Spectrum Disorders:
- Certain genetic or chromosomal conditions
- Older birth parents
- Sibling with autism
- Various environmental exposures
- Low birth weight
- Exposure to certain medications during pregnancy
- Prematurity
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