Other Contributing Factors in Neuropsychiatric Disorders 253virus, it is well established that there are significantly fewer congenital
anomalies in fetuses infected after the first trimester [42].
Mahic et al. [38] have recently evaluated possible associations between
maternal infection with Toxoplasma gondii, rubella virus, cytomegalovirus
(CMV), herpes simplex virus 1 (HSV‐1), and HSV‐2. They analyzed the serum
samples collected during mid‐pregnancy from 442 mothers of children with
ASD and compared them with 464 frequency‐matched control IgG antibodies
to the infectious agents mentioned above (from Norway). They uncovered
that high levels of HSV‐2 IgG antibodies in maternal mid‐pregnancy plasma
were associated with increased risk of ASD in male offspring when adjusted
for parity and child’s birth year. No association was found between ASD and
the presence of IgG antibodies to Toxoplasma gondii, rubella virus, CMV, or
HSV‐1. Their study has created controversy and awaits replication from other
scientists.
More recently, epidemiological studies have reported increased risk of ASD
associated with maternal infection during pregnancy. However, as we stated
above, that high risk may only be associated during the first trimester of the
maternal infection, since we believe that the fetal BBB is much firmer after the
first trimester. Generally, the results are negative with regards to maternal
infection and having offspring that develop ASD. For example, a population
based study of all children born in Denmark from 1980 to 2005 found no
overall association between maternal infection diagnosis and ASD over the
course of the entire pregnancy, but did report a nearly threefold increased risk
for ASD following hospitalization for viral infection in the first trimester as
well as an increased risk following hospitalization for bacterial infections in
the second trimester [44]. Similarly, in another Danish population based study
there was no association between common cold during pregnancy and an
increased risk of ASD [45]. The only caveat was influenza infection that was
associated with a nearly twofold risk of ASD and fever for >1 week was associ
ated with a nearly threefold increase. The fever appears to be an issue during
early pregnancy and a study from California (Kaiser Permanente) found that
fever during pregnancy, particularly fever experienced without taking anti‐
fever medication, was associated with an increased risk of ASD, though over
all experiences of maternal influenza were not associated with an increased
risk in this study [46]. A subsequent study found that severe maternal infec
tions that required hospitalization were associated with an increased risk of
ASD, whereas diagnosed infections that did not need hospitalization were not
associated with ASD. Here, we would like to point out that the potential
conundrum of influenza infection and the potential ability of influenza anti
bodies to react with neuroantigens needs further investigation, as pointed out
by many investigators.
We hypothesize that the leakage of the fetal antigens into the maternal blood
may be the result of certain environmental factors that are cytopathic to