ADVANCING PATERNAL AGE IS FOUND TO BE A RISK FACTOR FOR AUTISM IN ALL THE STUDIES THAT LOOK FOR PATERNAL AGE IN AUTISM
PRENATAL AND PERINATAL RISK FACTORS FOR AUTISM
A REVIEW and INTEGRATION OF FINDINGS
Alexander Kolevzon, MD; Raz Gross, MD, MPH; Abraham Reichenberg, PhD
Arch Pediatr Adolesc Med. 2007;161:326-333.
Objective To review the evidence for the presence of prenatal and perinatal factors that affect the risk of autism and autism spectrum disorders.
Data Sources Relevant articles were identified by searching MEDLINE, screening reference lists of original studies, and searching major journals likely to publish epidemiological studies on the topic.
Main Exposures Parental characteristics and obstetric complications.
Main Outcome Measures Rates of autism and autism spectrum disorders.
Results Seven epidemiological studies were identified that fulfilled inclusion criteria. The parental characteristics associated with an increased risk of autism and autism spectrum disorders included advanced maternal age, advanced paternal age, and maternal place of birth outside Europe or North America. The obstetric conditions that emerged as significant fell into 2 categories: (1) birth weight and duration of gestation and (2) intrapartum hypoxia.
Conclusions Evidence to suggest that parental age and obstetric conditions are associated with an increased risk of autism and autism spectrum disorders is accumulating. Although not proven as independent risk factors for autism, these variables should be examined in future studies that use large, population-based birth cohorts with precise assessments of exposures and potential confounders.
The results of this review show that 3 of the 4 population-based studies28-29,32 to examine paternal age reported a significant association with risk of autism and ASDs. The fourth study31 also found that paternal age was older in fathers of case patients with autism compared with fathers of controls, although this relationship was statistically weaker in the adjusted analysis. Thus, advancing paternal age is consistently associated with increased risk of autism and ASDs.
Advanced paternal age has been associated with several congenital disorders, including Apert syndrome,40 craniosynostosis,41 situs inversus,42 syndactyly,43 cleft lip and/or palate,44-45 hydrocephalus,44 neural tube defects,46 and Down syndrome.47 In addition, advanced paternal age has been associated with schizophrenia15 and decreased intellectual capacities in the offspring.48 The most widely proposed mechanism underlying these congenital anomalies is known as the "copy error" hypothesis, first proposed by Penrose.49 After puberty, spermatocytes divide every 16 days, and by the age of 35 years, approximately 540 cell divisions have occurred. As a result, de novo genetic mutations that result from replication errors and defective DNA repair mechanisms are believed to propagate in successive clones of spermatocytes. These mutations accumulate with advancing paternal age and thus help explain how this disorder, which has a large genetic component, can be maintained in the population despite reduced reproduction in affected individuals.
This study does not differeniate between familial and non-familial autism.
Low Birthweight and advancing paternal age have been found to go together.