Advanced Parental Age Predicts Risk for Autism Spectrum Disorder in Children

Advanced Parental Age Predicts Risk for Autism Spectrum Disorder in Children CME/CE
News Author: Laurie Barclay, MD
CME Author: Hien T. Nghiem, MD
Disclosures

Release Date: April 5, 2007; Valid for credit through April 4, 2009 Credits Available

Physicians - maximum of 0.25 AMA PRA Category 1 Credit(s)™ for physicians;
Family Physicians - up to 0.25 AAFP Prescribed credit(s) for physicians;
Nurses - 0.25 nursing contact hours (None of these credits is in the area of pharmacology)

To participate in this internet activity: (1) review the target audience, learning objectives, and author disclosures; (2) study the education content; (3) take the post-test and/or complete the evaluation; (4) view/print certificate View details.



Learning Objectives
Upon completion of this activity, participants will be able to:

Report the outcomes associated with advanced paternal age.
Evaluate the association between maternal and paternal ages and risk for ASDs.
Authors and Disclosures
Laurie Barclay, MD
Disclosure: Laurie Barclay, MD, has disclosed no relevant financial relationships.



Hien T. Nghiem, MD
Disclosure: Hien T. Nghiem, MD, has disclosed no relevant financial relationships.


April 5, 2007 — Advanced maternal and paternal ages are independently linked with risk for autism spectrum disorder (ASD) in children, according to the results of a historical birth cohort study reported in the April issue of the Archives of Pediatrics & Adolescent Medicine.

Lisa A. Croen, PhD, from the Kaiser Permanente Medical Care Program in Oakland, California, and colleagues studied all singleton children born at Kaiser Permanente in Northern California from January 1, 1995, to December 31, 1999, and they identified 593 children who had ASD diagnoses (International Classification of Diseases, Ninth Revision, Clinical Modification, code 299.0 or 299.8) recorded twice or more in Kaiser Permanente outpatient databases before May 2005. These 593 children were compared with the remaining 132,251 singleton Kaiser Permanente births.

Primary endpoints were relative risks (RRs) for ASD, estimated from proportional hazards regression models evaluating maternal and paternal ages, adjusted for each other and for the sex, birth date, and birth order of the child; maternal and paternal educational levels; and maternal and paternal races/ethnicities.

The risk for ASDs increased significantly with each 10-year increase in maternal age (adjusted RR, 1.31; 95% confidence interval [CI], 1.07 - 1.62) and paternal age (RR, 1.28; 95% CI, 1.09 - 1.51). Children with autistic disorder had increased adjusted RRs for both maternal and paternal ages (maternal age: RR, 1.18; 95% CI, 0.87 - 1.60; paternal age: RR, 1.34; 95% CI, 1.06 - 1.69), as did children with Asperger disorder or pervasive developmental disorder not otherwise specified (maternal age: RR, 1.45; 95% CI, 1.09 - 0.93; paternal age: RR, 1.24; 95% CI, 0.99 - 0.55). Although sex differences were not statistically significant, associations with parental age were somewhat stronger for girls than for boys.

"We found that risk of ASD was independently associated with advanced maternal and paternal age in a contemporary cohort of California-born children," the authors write. "Major strengths of this study include a large population-based sample and prospective collection of autism diagnoses and covariates, thus avoiding biases due to differential reporting and recall by parents of affected and unaffected children."

Study limitations include possible underascertainment of ASDs, failure to control for pregnancy complications, and possible confounding by healthcare-seeking behavior measured in the first few years of life.

"If the relationship between parental age and ASD is causal, the fraction of autism in this sample attributable to having a mother or father older than 35 years is 4% to 13%," the authors conclude. "Future investigations focused on the identification of both genetic and environmental factors that correlate with advanced parental age are warranted."

The Centers for Disease Control and Prevention and the Kaiser Foundation Research Institute funded this study in part. The authors have disclosed no relevant financial relationships.

Arch Pediatr Adolesc Med. 2007;161:334-340.

Clinical Context
In the past few decades, the prevalence of ASDs has increased significantly. The cause of ASDs is unknown; however, there is evidence for a strong genetic contribution. Advanced maternal age has been associated with risk for autism in several studies, but the role of paternal age in autism has been examined less frequently. Currently, advanced paternal age has been associated with adverse reproductive outcomes, such as miscarriage, fetal death, childhood cancers, autoimmune disorders, schizophrenia, and other neuropsychiatric disorders. These outcomes may be explained by the age-associated increase in de novo mutations in male germ cells.

The aim of the current study was to explore the association between maternal and paternal ages and risk for ASDs in offspring.

Study Highlights
In this historical birth cohort study, all singleton children born at Kaiser Permanente in Northern California from January 1, 1995, to December 31, 1999, were included in the study.
593 children diagnosed with ASD (International Classification of Diseases, Ninth Revision, Clinical Modification, code 299.0 or 299.8) were identified. 277 (47%) were classified as cases of autistic disorder and 316 (53%) as cases of pervasive developmental disorder not otherwise specified or Asperger disorder.
These children were compared with all 132,251 remaining singleton Kaiser Permanente births.
The main outcomes measured included RRs estimated from proportional hazards regression models. In addition, the risk for ASDs was evaluated in relation to maternal and paternal ages, adjusted for each other, and for the sex, birth date, and birth order of the child; maternal and paternal educational levels; and maternal and paternal races/ethnicities.
The results of this study demonstrated that adjusted RRs for both maternal and paternal ages were elevated for children with autistic disorder (maternal age: RR, 1.18; 95% CI, 0.87 - 1.60; paternal age: RR, 1.34; 95% CI, 1.06 - 1.69) and children with Asperger disorder or pervasive developmental disorder not otherwise specified (maternal age: RR, 1.45; 95% CI, 1.09 - 1.93; paternal age: RR, 1.24; 95% CI, 0.99 - 1.55).
Specifically, the risk for ASDs increased significantly with each 10-year increase in maternal age (adjusted RR, 1.31; 95% CI, 1.07 - 1.62) and paternal age (RR, 1.28; 95% CI, 1.09 - 1.51).
Associations with parental age were stronger for girls than for boys; however, sex differences were not statistically significant.
The cumulative incidence of ASD by the age of 10 years increased nearly 2-fold from the youngest (< 20 years, 1 in 251) to the oldest mothers (≥ 40 years, 1 in 123) and more than 3-fold from the youngest (< 20 years, 1 in 387) to the oldest fathers (≥ 40 years, 1 in 116).
Compared with controls, children with ASDs were more likely to be boys and to have older, more highly educated, and white non-Hispanic parents.
Independent of parental age and all other covariates, the risk for ASDs was inversely correlated with birth order, positively correlated with birth date, and significantly elevated for boys and children whose mothers had a college or postgraduate education.
Pearls for Practice
The role of paternal age in autism has been studied less frequently than that of maternal age, but advanced paternal age has been associated with adverse reproductive outcomes, such as miscarriage, fetal death, childhood cancers, autoimmune disorders, schizophrenia, and other neuropsychiatric disorders.
Advanced maternal and paternal ages are independently associated with ASD risk.
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