Prevalence of Prenatal and Perinatal Birth Complications in Individuals with and without ASD-Associated Copy Number Variants

Background: Although the etiology of ASD is unknown, both genetic and environmental factors have been implicated in autism spectrum disorder (ASD) risk. Recent advances in identifying ASD associated genetic events, such as copy number variation (CNV), underscore the role of genetics in the etiology of ASD (Sanders et al., 2015). Studies have also found that prenatal and perinatal birth complications are associated with increased risk for ASD (Gardener et al., 2009, 2011). However, the relationship between pre- and perinatal birth complications and genetic events associated with ASD is not well understood.

Objectives: The objectives are: 1) To examine the prevalence rates of birth complications in individuals diagnosed with ASD with an ASD associated CNV and those with idiopathic ASD. 2) To examine whether rates of birth complications differ between individuals with deletion versus duplication CNVs. 3) To assess the prevalence of prenatal and perinatal birth complications separately within these groups.

Methods: Participants included 285 individuals with at least one CNV (178 duplications, 107 deletions) and 2083 individuals without CNVs from the Simons Simplex Collection (SSC), none of whom had likely gene disrupting mutations (Iossifov et al., 2014). ASD associated CNVs were identified by Girirajan et al., 2013. We obtained prenatal and perinatal data from the Medical History Interview completed with parents. As defined by Froehlick-Santino et al., 2013, prenatal complications included vaginal bleeding, low gestational age, and maternal medication usage and perinatal complications included low birth weight (<2500g), jaundice, and “markers of hypoxia”. We performed chi-square analyses to assess prevalence rates of birth complications for individuals with ASD associated duplications, deletions or no-CNVs.

Results: 70 (65.4%) of cases with a deletion had reported pre- or perinatal complications, while 104 (58.4%) of cases with a duplication and 1252 (60.1%) of the no-CNV group had birth complications. Non-parametric analyses examining the relationship between genetic status (presence of a deletion CNV, duplication CNV or no CNV) and presence of birth complications revealed no differences in rates of birth complications: X² (2, N = 2368) = 1.458 p= 0.482. When pre- and perinatal complications were examined separately, rates of perinatal complications were higher (50.5% of the total sample) than prenatal complications (20.4% of the total sample) but no significant differences between groups were observed.

Conclusions: Our results show that children with ASD associated deletions and duplications have similar rates of birth complications compared to children without any CNVs. The rate of perinatal complications was higher than the rate of prenatal complications, but no significant differences between groups were found. These findings provide strong evidence that there is no relationship between ASD associated CNVs and birth complications; however, an alternative explanation is that this may be due to study exclusion criteria, which eliminated individuals with serious birth complications and restricted sample variability. Previous work has identified the presence of specific phenotypic patterns (e.g. head circumference) related to duplications and deletions at the same locus (Jacquemont et al., 2011). Therefore, future work to investigate the interactions of environmental factors and CNVs on birth complications is needed.