Short and Long Inter-Pregnancy Interval Increases Risk of Autism Spectrum Disorders

Background:  Short and long inter-pregnancy intervals have been associated with increased risk of preterm birth, small for gestational age and adverse neurodevelopmental outcomes including schizophrenia. However, the association between IPI and autism spectrum disorder (ASD) has not been fully investigated.

Objectives:  To evaluate the association between inter-pregnancy interval and risk of ASD in a large, multiracial birth cohort from the US.

Methods:  We assessed the association between inter-pregnancy interval and risk of ASD in the cohort of children born at Kaiser Permanente Northern California (KPNC) between 2000 and 2009. This birth cohort was matched to the California birth certificate files to identify their siblings born between 1990 and 2009. Children with ASD were identified primarily from ICD-9 diagnostic codes 299.0, 299.8 and 299.9 recorded in KPNC electronic medical records. To identify additional children with ASD who were born at KPNC but left the health plan before being diagnosed with an ASD, we linked the study cohort to the California Department of Developmental Services client databases. Inter-pregnancy interval was defined as the time from the birth of the first child to the conception of the second in a sibship. We used survival analysis and logistic regression models to evaluate the association between inter-pregnancy interval and risk of ASD in second-born children who had a first-born full sibling born at KPNC with no diagnosis of ASD.

Results:  Of the 44,413 second-born children who had a first-born full sibling without an ASD, 547 (1.2%) were diagnosed with an ASD by the end of the study period. There were no differences between second-born children with ASD and those without ASD with respect to parental age, maternal education, place of birth, race/ethnicity, and child birth year. After adjustment for child sex, birth year, parental age, and maternal race/ethnicity and education children born after an inter-pregnancy interval less than 12 months or greater than 72 months (5 years) had a 2-3 fold increased risk of ASD compared to children born following an interval of 36-47 months. Respective adjusted hazard ratios with confidence intervals were: <6 months: 2.8 (1.8 - 4.5); 6-8 months: 2.5 (1.6 - 3.8); 9-11 months: 1.9 (1.2 - 2.8); 12-23 months: 1.6 (1.1 - 2.2); ≥ 72 months: 2.3 (1.5 - 3.6). The pattern of association between ASD and IPI was substantially unchanged after additional adjustment for maternal second trimester BMI or change in maternal BMI between the first and second pregnancies.

Conclusions: Inter-pregnancy intervals shorter than 2 years or longer than 5 years are associated with increased risk of ASD, with the shortest (<6 months) and longest intervals associated with the highest risk. The mechanism explaining this association is unknown and requires further research.