This study examined low birth weight as a potential environmental risk factor associated with ASD in a large cohort of Swedish twins. Analyses of discordant twin-pairs using the cotwin-control design, in which the affected twin serves as the case and unaffected twin the control, indicated that lighter twins in birth weight discordant pairs (> 400 gram or 15% difference) were more than twice as likely to meet criteria for ASD (i.e., score ≥ 4.5 on the ASD module of the A-TAC measure) than the heavier twin in the pair (odds ratio for all twins = 3.25, MZ twins = 2.50, DZ twins = 2.80). Analyses of birth weight as a continuous risk factor indicated a 13% reduction in risk of ASD per 100 gram increase in birth weight. Birth weight was also associated with individual ASD-like traits, with stronger effects detected for social and language features than ritualistic/repetitive behaviors. Examining the effect of birth weight on A-TAC scores in the entire sample population (where the majority of twins did not have meet A-TAC criteria for ASD) revealed a modest but consistent association, with a 2% reduction in A-TAC scores per every increase of 100 grams.
As a whole, these findings add to prior reports of an association between birth weight and ASD (Bryson et al., 1988
; Burd et al., 1999
; Maimburg & Vaeth, 2006
; Kolevzon et al., 2007
). They further indicate that birth weight is associated with ASD-like traits, and the social and language impairments associated with ASD in particular, supporting a prior report that differences in MZ twins’ social ASD-like traits were associated with differences in birth weight, whereas ritualistic/repetitive behaviors were not (Ronald et al., 2010
). The large population based twin sample employed minimized ascertainment bias. And, by virtue of the cotwin-control design, the present results preclude many additional environmental or genetic (including maternal genetic) factors that could influence birth weight, and which are not fully accounted for in studies of singletons. Similar effects observed in MZ and DZ pairs suggest that the association between birth weight and ASD does not appear to be attributable to confounding environmental and/or genetic factors affecting both features.
In the case of MZ twins, who share gestational age, differences in birth weight can provide an index of differences in fetal growth that may be relevant to clinical outcome in twin-pairs discordant for disease. Findings could therefore support a role of restricted fetal growth in adverse neurodevelopment leading to ASD, although it should be noted that this study examined only birth weight and not any direct measures of fetal growth. It is unclear how fetal growth restriction might influence brain development in ways specific to autism. Additional studies are clearly needed to clarify the pathophysiological mechanisms underlying the association between birth weight and ASD, and the potential role of fetal growth restriction in particular.
Further work is also needed to help clarify the clinical significance of several of the findings reported here. Whereas associations between birth weight and ASD appeared robust in twin-pairs discordant for both ASD and birth weight, this subgroup of twins was relatively small, and confidence intervals were large. Additionally, analysis of the full sample (where the majority of twins were reported to exhibit no symptoms of ASD and thus received a zero on the ASD A-TAC module) indicated only a slight increase in ASD symptoms with incremental decreases in birth weight. Small effect sizes in mean A-TAC scores in the entire sample may nevertheless contain significant effects in individual twin-pairs. We also found no association between birth weight and ASD severity (indexed by total A-TAC scores on the ASD module) in the limited sample of 16 ASD concordant twin-pairs, suggesting that the effects of birth weight on ASD risk criteria in more severely affected concordant pairs are not as apparent as those observed in discordant pairs.
The lack of direct clinical assessment of ASD and reliance on the A-TAC for assigning ASD status is a potential limitation of the study. As with other large-scale twin studies (Constantino & Todd, 2003
; Hoekstra et al., 2009
; Ronald et al., 2010
), direct assessment of the large population based sample assessed in CATSS was not feasible, and assessment of ASD therefore involved informant based proxies for clinical diagnosis of ASD and ASD-like traits using the A-TAC. Two validation studies (Hansson et al., 2005
; Larson et al., 2010
) have now demostrated that the A-TAC has high sensitivity and specificity to provide research proxies for clinical diagnosis of autism and other targeted disroders. This instrument has also been successfully used as a dimensional measure of ASD-like traits in recent work (Lundstrom et al., 2011
), supporting its use in the present investigation. Nevertheless, direct clinical assessment, including evaluation of intellectual disability, would provide important verification of findings, and allow for more thorough investigation of their clinical significance and potential differential relationships with intellectual disability. Additionally, assessment of family members who may exhibit ASD or subclinical ASD-like traits would enrich these data by affording analysis of familial loading related to the relationship between birth weight and ASD.
Finally, it is important to note that findings from twin samples may not be generalizable to singleton samples, further warranting cautious interpretation of results. Twins on average have lower birth weights than singletons (Spellacy et al., 1990
), and there has been some suggestion of increased rates of ASD in twin samples (Bailey et al., 1995
). The associations detected in this study may therefore not extend to singleton births. With these caveats in mind, results from this study appear to support existing literature implicating low birth weight as a risk factor for ASD. The twin design employed allowed for control of several confounding factors not fully addressed in prior work. Results also highlight several areas for further study, which, together with continued large-scale efforts to identify causal genetic variants, may help to illuminate the complex etiology of ASD.