There have been a few explorations, with diverse samples and methodology
, of rubella as a risk factor for autism-spectrum disorders. For all of these, in utero exposure was noted by mothers with recognized rubella during pregnancy. None have investigated “subclinical or inapparent” exposure, although this type of exposure could be harmful. Both rubella vulnerability and subclinical rubella exposure may be increasing. In this study, we evaluated whether rubella-vulnerability was a risk factor for autism spectrum disorders.
In our recent study [6
], we found that 6.38% of women tested as non-immune at the beginning of pregnancy care converted to rubella-exposed when re-tested at delivery. This re-testing at delivery is not a normal part of obstetric care; if subclinical rubella exposure can cause autistic-spectrum disorders, cases of subclinical rubella exposure in utero are being misclassified as non-exposed. This may be a misclassification bias in existing studies; not only would it weaken the ability to detect a true signal, it would bias results toward the opposite finding, since the cases of autism with no recognized maternal rubella would count as contrary
cases. This is problematic since it is widely believed that the cause of autistic spectrum disorders are modest exposures, and are multi-factorial, and are likely cumulative.
In our large outpatient healthcare delivery setting, we were able to draw upon relevant clinical data from several recent years of electronic medical record experience, covering thousands of mother-child pairs, to form a cohort of more than 50 young children with documented autistic-spectrum disorders for whom maternal antepartum rubella immunity data were known. We conducted this exploratory case-control test of whether rubella non-immunity, and rubella low-immunity, might be predictors
of autism in order to evaluate evidence and to share the concept, and a post-hoc power calculation, with others.
We found few cases, overall, of autism, as would be expected. We also found few cases of non-immunity (and low immunity), as would be expected; both are infrequent events. This case-control study failed to detect a statistically significant indication that maternal rubella non-immunity is associated with autism in the young offspring
of these mothers.
Along with low power, autism case ascertainment may be a weakness. The ages of the children involved in this study ranged from 2.5 years to 7.5 years, with fewer cases encountered at younger ages. Not all cases of autism may have been detected, and some detected cases may not have been noted in the electronic medical record. This would be likely if a family has recently had no reason for a pediatric visit while addressing a psychiatric problem. Also, “soft” neurological symptoms caused by subclinical rubella exposure might not have crossed the diagnostic threshold
well enough to lead to pediatric chart documentation. While the controls were age-matched, which should control for the effect of increasing detection with greater child age, this under-detection bias may have been involved. Future studies could limit this bias if they are able to focus on mother-child pairs in which the children are older, as long as immune-status of the mother is available.
Although the finding was negative, we believe that the hypothesis warrants more investigation, including with greater mother-child sample sizes. The idea is plausible, and our result was not well-powered. Such subsequent studies would indicate
whether our finding, an absolute finding that went in the desired direction but was not statistically significant (p=0.85) was a weak signal or was merely noise.
The post-hoc power analysis indicated that a case-control study with a 1:1 match would need 570 cases. If the recently noted incidence of autistic spectrum disorders is one case in 68 children, then a general population sample of 38,760 would be needed to yield 570 cases. Overall, while rubella vulnerability may lead to sub-clinical exposure, and that lead to autism-spectrum disorders or symptoms, epidemiological detection of this phenomenon is challenging. If a relationship does exist, better measures and symptom detection, as well as complementary research designs, would greatly improve the feasibility of detecting this plausible relationship. Future studies could utilize more matching criteria, such as socioeconomic
status or race/ethnicity, in order to minimize statistical noise from other contributors to autism. In the Kelsey-Seybold Clinic system, it has only recently become routine to gather race/ethnicity, and socioeconomic status is not gathered.
Congenital rubella syndrome has been noted in the children of mothers with previously established immunity [12
]. This may be happening because immunity has waned in the mother, the immune response was not strong enough, or their antibodies, though adequately measured, do not neutralize
]. An interesting finding of the study was that about 34% of all the mothers in the study had low-immunity (IgG<20 IU.ml); this is of uncertain significance. Kelsey-Seybold, in Houston, Texas, is comprised largely of a middle class, insured, non-immigrant population; thus the study sample represents this sector of the population. The low-immunity to rubella affecting 34% of all mothers in this study is an opportunity for infection. If the incidence of rubella exposure is increasing, it may become necessary for women of child-bearing age to have a follow-up test, after immunization, to assure immunity. Further, it would be wise to re-immunize women found to have low-immunity.
Using medical record-based ICD codes for inclusions and exclusions could be a source or error, since these records are not always complete or accurate, especially for psychiatric conditions, such as illicit
drug dependence. Stigma, and the administrative gulf between behavioral healthcare and medical healthcare, can interfere with accuracy of substance dependence documentation in the medical record.
This study reports no statistically significant correlation between rubella-susceptibility of mothers in pregnancy and subsequent autism in their children, but it is underpowered. Further studies on the topic of rubella in pregnancy are needed to reveal its impact
on autism and other developmental delays in children.