Elsevier

Annals of Epidemiology

Volume 24, Issue 9, September 2014, Pages 629-634.e1
Annals of Epidemiology

Original article
Mediators of the association between parental severe mental illness and offspring neurodevelopmental problems

https://doi.org/10.1016/j.annepidem.2014.05.010Get rights and content

Abstract

Purpose

Parental severe mental illness (SMI) is associated with an increased risk of offspring autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD). We conducted a study to examine the extent to which risk of preterm birth, low birth weight, and small for gestational age mediated this association.

Methods

We obtained data on offspring born 1992–2001 in Sweden (n = 870,017) through the linkage of multiple population-based registers. We used logistic and Cox regression to assess the associations between parental SMI, adverse pregnancy outcomes, and offspring ASD and ADHD, as well as tested whether adverse pregnancy outcomes served as mediators.

Results

After controlling for measured covariates, maternal and paternal SMI were associated with an increased risk for preterm birth, low birth weight, and gestational age, and for offspring ASD and ADHD. These pregnancy outcomes were also associated with an increased risk of ASD and ADHD. We found that pregnancy outcomes did not mediate the association between parental SMI and offspring ASD and ADHD, as there was no substantial change in magnitude of the risk estimates after controlling for pregnancy outcomes.

Conclusions

Parental SMI and adverse pregnancy outcomes appear to be independent risk factors for offspring ASD and ADHD.

Introduction

Autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) are neurodevelopmental problems whose symptoms often persist into and throughout adulthood, resulting in high societal costs and stress on families [1], [2], [3], [4], [5]. ASD encompasses three developmental disorders (i.e., autism, Asperger, and pervasive developmental disorder-not otherwise specified) characterized by difficulties in communication and abnormalities in social interaction and behavior, whereas ADHD is described by inattention and hyperactivity [6], [7]. According to recent reports by the Centers for Disease Control and Prevention, the prevalence of ASD and ADHD are rising [6], [7]. Thus, research is needed to understand the etiology of both disorders.

One possible key to understanding the causal mechanisms of ASD and ADHD lies in the association between parental severe mental illness (SMI) and offspring neurodevelopmental problems [8], [9], [10], [11]. Individuals with ADHD are at increased risk of having a first degree relative with schizophrenia or bipolar disorder [11]. These associations may be the result of shared genetic factors, as each disorder has been demonstrated to be highly heritable [12], [13]. Studies have also found that genetic factors are shared by numerous forms of severe psychopathology, suggesting that genetic factors typically influence multiple traits pleiotropically [12], [13], [14]. However, the current literature does not provide evidence for the causal mechanisms that underlie the association between parental SMI and offspring neurodevelopmental problems [8], [9], [10], [11].

Adverse pregnancy outcomes such as preterm birth (PTB), low birth weight (LBW), and small for gestational age (SGA) are linked to both SMI and childhood neurodevelopmental problems [15], [16], [17], [18]. This mutual association with adverse pregnancy outcomes may shed light on the mechanism linking parental SMI with offspring ASD and ADHD. Prescription drug use, alcohol use, and smoking during pregnancy have been cited as potential mechanisms that may explain the link between adult SMI and adverse birth outcomes in their offspring [15], [19]. It is hypothesized that the associations between PTB, LBW, and SGA and offspring ASD and ADHD arise from abnormalities in the developmental of nervous and endocrine systems resultant of restrictions to fetal growth in utero [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30]. Adverse pregnancy outcomes, thus, may serve as mediators in the association between parental SMI and offspring ASD and ADHD [31].

Few studies have examined adverse pregnancy outcomes as mediators in the relation between parental SMI and offspring neurodevelopmental problems, however. One previous study concluded that perinatal factors and parental psychiatric diagnoses were independent risk factors for ASD [10]. This study was limited by the researchers' inability to analyze the independent association between maternal and paternal mental illness and offspring ASD. The results of such an analysis could provide further insights into whether the association between parental SMI and offspring neurodevelopmental problems may result from causal intrauterine effects [32]. And, the previous study only predicted ASD, whereas much can be gleaned of additionally predicting ADHD, a condition highly related to ASD [33], [34].

We used prospectively-collected population-based Swedish registers and logistic and Cox regression models to examine the extent to which adverse pregnancy outcomes act as mediators of the association between parental SMI and offspring ASD and ADHD. We hypothesized that adverse pregnancy outcomes would mediate, at least in part, the association between parental SMI and offspring ASD and ADHD.

Section snippets

Study population

The study sample was obtained by linking information available in multiple Swedish population-based registers. Specifically, the Multi-Generation Register provides information on familial relationships in Sweden since 1933 [35]; the Medical Birth Registry contains data on more than 99% of births since 1973 [36]; the National Patient Register provides information on inpatient psychiatric diagnoses since 1973 and outpatient diagnoses since 2001; the Education Register provides information on the

Demographics

Table 1 provides descriptive statistics for all eligible offspring born between 1992 and 2001 in Sweden. Of these offspring, 7236 (0.8%) have received a diagnosis of ASD; 15,254 (1.8%) have received a diagnosis of ADHD; 19,288 (2.2%) were born SGA; 25,748 (3.0%) were born LBW; and 37,451 (4.3%) were PTB. A total of 9134 mothers (1.5%) and 8285 fathers (1.4%) were diagnosed with an SMI.

Parental SMI and adverse pregnancy outcomes

Table 2 provides the results of logistic regression analyses for maternal and paternal SMI predicting PTB, LBW,

Discussion

The present study used a large Swedish population-based sample to examine the associations between parental SMI, adverse pregnancy outcomes, and offspring neurodevelopmental problems. The results suggest that adverse pregnancy outcomes do not mediate the association between maternal and paternal SMI and offspring ASD and ADHD. More specifically, in agreement with previous research [15], [16], [17], [18], we found that the risk of offspring PTB, LBW, and SGA are elevated if the mother and/or

Conclusions

Adverse pregnancy outcomes and maternal and paternal SMI are independent risk factors for ASD and ADHD. The similarity in moderate association magnitude between maternal and paternal SMI and offspring ASD and ADHD indicates that the associations are likely not due to causal intrauterine effects [32]. Our results provide evidence consistent with the theory that genetic factors may explain much of the association between parental SMI and offspring ASD and ADHD [14]. Future research should

Acknowledgment

The study was supported by grants from the National Institute of Child Health and Human Development (HD061817), National Institute of Mental Health (MH094011), the Swedish council for working life and social research, the Swedish Research Council (Medicine), and the Swedish Society of Medicine.

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    Competing interests: None.

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