This population-based study examined the association between three birth characteristics (birth weight, gestational age and SGA/AGA/LGA status) and each of the three most common subtypes of ASD, childhood autism, Asperger syndrome and PDD. Childhood autism and PDD were associated with all three factors. No associations were found between Asperger syndrome and birth weight, gestational age or SGA/AGA/LGA-status after controlling for potential confounders. Our findings indicate that risk factors might be different for ASD subtypes. The autism spectrum is usually defined based on similarities in symptoms. Given the likely multifactorial etiology of ASD, it is conceivable that different etiologic factors (in this case birth characteristics) can be related to different syndromes within the spectrum.
These findings indicate that both intrauterine growth restriction and very preterm birth are related to risk of childhood autism and PDD. Based on this study, prematurity was an independent risk factor for childhood autism and PDD even after adjustment for impaired fetal growth. There appeared to be dose-response effects between prematurity and both childhood autism and PDD as the risk ratios increased with decreasing gestational age. Our findings confirm the results of previous studies showing an association between childhood autism and low birth weight1,3–5
Furthermore, VLBW and prematurity are associated with neurodevelopmental and intellectual disabilities, such as learning disabilities, attention problems and poor executive function24–27
that are often present in children diagnosed with ASD.28
Premature infants with very low birth weight often need long hospitalizations in the neonatal intensive care unit (NICU). The infants in the NICU are treated with highly advanced medical technology and the number of survivors has increased, but neurodevelopmental consequences still exist.29
The NICU infants may experience postnatal complications such as intraventricular hemorrhages and white matter injuries, which may mediate the effects of intrauterine growth restriction and prematurity on the risks of autism and PDD. It has been suggested that the proportion of NICU infants that are later classified with ASD has increased.30
It is also possible that the environment of the NICU adversely affecting physiological, emotional and social maturation may result in negative effects on child neurodevelopment.29,31–33
Another possibility is that prematurity/VLBW and ASD may share similar neurodevelopmental antecedents, including exposure to adverse prenatal factors such as infection, nutritional deficits, hypoxia, and other obstetric insults, as well as genetic susceptibilities.
Both childhood autism and PDD were associated with SGA. The association between childhood autism and SGA is consistent with findings from previous population-based studies from the Nordic countries1,4,5
, and there is a lack of previous studies of the association between SGA and PDD. The finding that SGA incurs over a two-fold increased risk specifically for PDD has not been demonstrated in previous research. Consistent with our results, the magnitude of the association between SGA and childhood autism in previous studies was rather low; odds ratios have varied between one and two. Additionally, in the study by Buchmayer et al11
a similar association was found between SGA and the broader group of ASD.
There are several possible explanations for the findings related to SGA. First, there may be shared genetic mechanisms for SGA and ASD.2
Recently, a polymorphism in the gene for insulin-like growth factor-I (IGF-I) was found to be associated with lower birth weight (weight reduction of 215 g compared with subjects without the polymorphism).34
Conceivably, this or other genes that predispose to low birth weight may also account for part of the association between this exposure and childhood autism and PDD. Second, parallel to VLBW, SGA is a marker of several prenatal risk factors that may be associated with autism such as fetal hypoxia, placental pathology, pre-eclampsia or infections during pregnancy.1,2,22,35,36
Third, maternal risk behaviours, such as smoking, alcohol or other substance use, have been associated with low birth weight, prematurity37
and neuropsychiatric morbidity.38,39
Asperger syndrome was not associated with birth weight, gestational age or SGA status when adjusted for confounding factors. Our results are similar to a recent Swedish study12
which found no associations between obstetric risk factors (prematurity, low Apgar scores, growth restriction, or macrosomia) and Asperger syndrome. Most previous studies of risk factors for Asperger syndrome, however, have been either clinic-based or limited to rather small sample sizes.40,41
These findings suggest that susceptibility genes and/or prenatal risk factors for retarded fetal growth or prematurity may have a lower prevalence in Asperger syndrome than other ASD.
The main strengths of this study include: (1) a large, population-based sample of 1.1 million births, yielding high statistical power to demonstrate associations; (2) inclusion of cases treated in both inpatient and outpatient settings, which increases the generalizability of the findings and may reduce bias; (3) high quality and completeness (eg, <0.1% missing of birth weight and gestational age information, limiting the potential for diagnostic misclassification).42,43
In Finland, most hospitals follow the VLBW infants up to 2 years of age and thereafter according to clinical judgment. This follow-up, unfortunately, is not sufficient to diagnose all ASD. However, all children are also followed by child welfare clinics that are responsible for screening developmental problems, such as symptoms of ASD. As noted before, child welfare clinics are an important part of primary health care settings, referring children with ASD symptoms to more specialized services. However, this study has limitations that need to be considered. First, cases were classified based on discharge diagnoses from the FHDR. Consequently, some diagnostic misclassification is likely to exist. However, as reported previously,44
77 of 80 subjects with register-based diagnoses of childhood autism fulfilled the diagnostic criteria according to the Autism Diagnostic Interview – Revised (ADI-R), indicating high validity of register-based diagnoses of childhood autism. At present, validation studies for the other diagnoses (Asperger syndrome or PDD) have not been conducted. Thus, results regarding these diagnoses may be viewed with somewhat less confidence than those regarding the associations with childhood autism. However, because in Finland the clinical assessment of any ASD is done in specialized services mostly by specialists in child psychiatry or pediatric neurology, we believe that the validity of the diagnoses of Asperger syndrome and PDD is at least satisfactory. Second, because the FHDR includes children who have been referred from the child health clinics to specialized services; it is probable that many cases with mild symptoms are missing. However, we expect the coverage of moderate and severe ASD cases to be good, for three reasons. First all children in Finland under school age (7 years) visit child health clinics at least once a year. Second, similar to other Nordic countries such as Sweden and Denmark, Finland has a public health system which covers for all treatments for ASD. Third, all inpatient treatment for ASD and all outpatient treatment for these disorders since 1998 are coded in the FHDR. Therefore, a child with moderate or severe symptoms of ASD will most likely be referred to specialized services for diagnostic assessment and possible treatment, and subsequently become registered in the FHDR. Since the inclusion of outpatient diagnoses in the FHDR began in 1998, we were not able to include cases that were diagnosed and treated only in outpatient units prior to that year. However, since the most recent diagnosis was used for case identification, and ASD is generally a chronic condition, we expect that this would have captured many cases treated exclusively as outpatients with onset prior to 1998 in our study sample. Finally, the issue of emigration from the cohort needs to be considered. Although emigration can be viewed as a potential cause of selection bias, if it is related to birth complications and ASD, it should be noted that the emigration rate is very low in Finland; during the study period the annual rate has varied between 0.2–0.4%.58
Hence, emigration is expected to have played a very small role, if at all, in influencing the findings.
We have demonstrated that low birth weight, very low gestational age and SGA are related to increased risks of childhood autism and PDD. The findings may have important implications for understanding prenatal risk factors and susceptibility genes for ASD that may impair fetal growth and/or lead to premature birth. The fact that different risk factors were found for childhood autism and PDD on the one hand, and Asperger syndrome on the other, suggests that different vulnerability factors and their interactions may be responsible. These findings stimulate search for specific environmental factors and genes that act during the prenatal period to increase the susceptibility for ASD.