Studies on maternal medical factors predicting child's autism tend to focus on few factors within the same analysis. This can be problematic as some of these factors are etiologically or phenomenologically dependent, which makes it harder to determine which factors can have the largest contribution to predicting child’s diagnosis. In Study 1, a case-control approach revealed 15 predictors of autism for the first-born, and eight of those were replicated in the second-born along with 12 additional predictors. In Study 2, we compared a subset of predictors, relating to pregnancy course and perinatal factors for siblings discordant for diagnosis. In this analysis two factors were significant, replicating those found in Study 1. Our analyses broadly showed that obstetric factors and maternal medical conditions were most predictive of child's autism. Below we will discuss the main findings.
Gestational bleeding during the second or third trimesters was associated with child’s autism in all analyses (yet the effect is small in the first-born), replicating previous studies (6). Gestational bleeding is a non-specific condition, and can indicate a host of other pregnancy complications, such as placental insufficiency and preeclampsia, which have also been associated with autism (26) (but were of low prevalence in the current study and should be studied further). Interestingly, a cumulative factor of pregnancy complications was significant only for the first, but not second-born, which may reflect an indirect association through maternal age, as pregnancy complications are associated with older maternal age (29).
The current findings suggest that infertility, rather than infertility treatments and other obstetric conditions, is related to autism, as we find this effect after controlling for infertility treatments and multiple obstetric complications, some of which are independently related to autism. Previous findings regarding the association between autism and infertility and fertility treatments were mixed. One study (27) found a higher incidence of autism among children born after infertility treatments, as compared to natural conception. The association remained statistically significant even after adjusting for parity, infant gender, and parental age, all factors that are independently associated with both infertility treatments and autism. In contrast, Hvidtjørn and colleagues (2010) found no association between autism in children and infertility treatments, in a large cohort study. Other studies (22, 35) also didn’t find any association between infertility treatments and autism diagnosis, in two separate studies conducted in California, USA. One hypothesis to explain the mixed findings is that infertility treatments are indirectly related to autism through an association with obstetric complications, pre-term labor, and low birth-weight, which are all factors that have been independently associated with an child's autism (6, 7, 24), and with older parental age (21, 36, 37). Parner and colleagues (2012) analyzed a cohort of all singleton births between 1980 to 2003 in Denmark and found that older parental age is associated with child's autism(38). Similarly, a cohort study of singleton births between 1989 to 2002 conducted in California, USA, also found that advanced parental age was associated with child's autism (39). Older maternal age may be associated with autism not only because of the increased risk of chromosomal abnormalities in the ova (6), but also due to the relationship between mature age and increased risk for pregnancy complications (29).
The current findings suggest that gestational diabetes and type II diabetes are both related to autism, but not BMI prior to pregnancy or weight gain during pregnancy. Previous studies found a relationship between various metabolic conditions such as maternal obesity prior to pregnancy, increased weight gain during pregnancy and gestational diabetes (defined as glucose intolerance with onset or first recognition during pregnancy) with autism and with general poor neurodevelopmental outcomes (40, 41). Krakowiak and colleagues found that mothers of children diagnosed with autism had a higher rate of gestational diabetes and obesity (defined as BMI > 30), compared to mothers of TD children (28). In addition, Xiang and colleagues found higher rates of child's autism among mothers diagnosed with type II diabetes before pregnancy, and among women diagnosed with gestational diabetes by 26 weeks of pregnancy (42). The current findings emphasize the importance of these metabolic conditions in autism.
The non-significant findings also shed light on the relative importance of various factors. Here we found no evidence for an association between child’s gestational age and autism. Pre-term labor and low birth-weight were previously found to be non-specific risk-factors for neurodevelopmental and intellectual disabilities such as learning disabilities, attention problems, and poor executive function (25). According to one study, low birth-weight infants (< 2500 g) have a 60% increased likelihood of autism, and pre-term infants (< 32 weeks) had twice the chance of developing autism, for both sexes (31). In addition, Burstyn and colleagues (2010) found that low birth-weight (< 2500 g) increased the likelihood for autism diagnosis by 33%. However, pre-term labor and low birth-weight often can be the consequents of obstetric complications (26), and the current findings emphasize the importance of obstetric complications over gestational age in predicting child’s autism.
Immune system activation during pregnancy is another suspected environmental mechanism for child’s autism. Animal studies show that immune activation during pregnancy is associated with abnormal brain development (16, 43). Specifically, Shi and colleagues found a reduction in social behavior and elevated anxiety behaviors among mice born to mothers infected by a virus during pregnancy (44). Studies in humans find similar associations. Lee and colleagues (2015) found that maternal infection (viral or bacterial) which leads to hospitalization, increased the likelihood for autism by 37%, in a cohort study of all live births born 1984–2007, in Sweden (17). However, another study found an association only for hospitalization due to bacterial infections(16, 45), and another found no association between infection and autism in a Danish population (46). We also do not find evidence for this effect in the current study. Only autoimmune disorders and only for the firstborn were related to child’s autism, similar to other findings in the field (e.g., (9, 47, 48), but see (49, 50)).
Importantly, some maternal medical conditions which were found in previous research as associated with autism, were not found to be significant or did not replicate across the analyses. For example, maternal PCOS was found to be related to child's autism in multiple large-scale analyses (8, 13), but in our study was not significant.
The main limitation of the study is the use of self-report, recollection data, as opposed to the use of medical records. It is possible that some conditions and diagnoses were misremembered or missed entirely. Therefore, the findings of the current study should be replicated using medical records in order to validate the findings. Another limitation of the study is the sample size, which did not allow to examine the relationship between child’s autism and relatively rare disorders and conditions. A larger sample, or a sample biased to include reports of mothers who suffered specific serious health and obstetric complications would allow to focus on these effects.