Maternal health around pregnancy and autism risk: a diagnosis-wide, population-based study

Abstract

Background: Many studies have reported an increased risk of autism spectrum disorder (ASD) associated with some maternal diagnoses in pregnancy. However, such associations have not been studied systematically, accounting for comorbidity between maternal disorders. Therefore our aim was to comprehensively test the associations between maternal diagnoses around pregnancy and ASD risk in offspring.

Methods: This exploratory case-cohort study included children born in Israel from 1997 to 2008, and followed up until 2015. We used information on all ICD-9 codes received by their mothers during pregnancy and the preceding year. ASD risk associated with each of those conditions was calculated using Cox proportional hazards regression, adjusted for the confounders (birth year, maternal age, socioeconomic status and number of ICD-9 diagnoses during the exposure period).

Results: The analytic sample consisted of 80 187 individuals (1132 cases, 79 055 controls), with 822 unique ICD-9 codes recorded in their mothers. After extensive quality control, 22 maternal diagnoses were nominally significantly associated with offspring ASD, with 16 of those surviving subsequent filtering steps (permutation testing, multiple testing correction, multiple regression). Among those, we recorded an increased risk of ASD associated with metabolic [e.g. hypertension; HR = 2.74 (1.92-3.90), p = 2.43 × 10-8], genitourinary [e.g. non-inflammatory disorders of cervix; HR = 1.88 (1.38-2.57), p = 7.06 × 10-5] and psychiatric [depressive disorder; HR = 2.11 (1.32-3.35), p = 1.70 × 10-3] diagnoses. Meanwhile, mothers of children with ASD were less likely to attend prenatal care appointment [HR = 0.62 (0.54-0.71), p = 1.80 × 10-11].

Conclusions: Sixteen maternal diagnoses were associated with ASD in the offspring, after rigorous filtering of potential false-positive associations. Replication in other cohorts and further research to understand the mechanisms underlying the observed associations with ASD are warranted.

Keywords: Autism; diagnosis-wide; maternal health; prenatal effects.

Figure 1.

Example of the hierarchical organization of the ICD-9 taxonomy. ICD-9 categories are organized from the most general (level 1, top row), through most specific diagnostic codes (level 4, bottom row). Level 3 diagnoses were used in the current study.

Figure 2.

Diagnoses nominally associated with ASD through the consecutive stages of filtering.

Figure 3.

P-values of the associations between maternal diagnoses and ASD, for diagnoses recorded in at least 10 cases and 10 controls. Each dot represents a −log(p-value) of an association between a distinct maternal diagnosis (level 3 of the ICD-9 codes) and offspring ASD. The results are color-coded by broad ICD-9 categories (level 1), as shown in the legend. Fig. 3A represents p-values for all diagnoses recorded in at least 10 cases and 10 controls; Fig 3B shows the same results, but the diagnoses that were filtered out in permutation testing or subsequent control for multiple testing are shown in grey (N.B. the diagnoses that were non-significant in the multiple regression step are not shown in grey).