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Springerlink Header: Attention-Deficit Disorder (A. Rostain, Section Editor)
This article goes in the January 2017 issue
Topical collection on Attention-Deficit Disorder
Prenatal Risk Factors and the Etiology of ADHD – Review of Existing Evidence
Emma Sciberras
1,2,3,
, Melissa Mulraney
2
, Desiree Silva
4
, David Coghill
2,3,5
Affiliations:
1
Deakin University, Melbourne, VIC Australia;
2
Murdoch Childrens Research Institute, Parkville,
VIC Australia;
3
The Royal Children’s Hospital, Parkville, VIC Australia;
4
School of Paediatrics and Child
Health, University of Western, Perth, Australia;
5
Departments of Paediatrics and Psychiatry, Faculty of
Medicine, Dentistry and Health Sciences, University of Melbourne, Australia
Corresponding Author: Professor David Coghill
Level 2 East, Royal Children’s Hospital, 50 Flemington Road, Parkville, 3052,
Victoria, Australia.
P: +(61) 393456856 E: david.coghill@unimelb.edu.au
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Abstract
While it is well accepted that ADHD is a highly heritable disorder not all of the risk is genetic. It is estimated
that between 10-40% of the variance associated with ADHD is likely to be accounted for by environmental
factors. There is considerable interest in the role that the prenatal environment might play in the development of
ADHD with previous reviews concluding that despite demonstration of associations between prenatal risk
factors (e.g., prematurity, maternal smoking during pregnancy) and ADHD there remains insufficient evidence
to support a definite causal relationship. This article provides an update of research investigating the relationship
between prenatal risk factors and ADHD published over the past 3 years. Recently several epidemiological and
data linkage studies have made substantial contributions to our understanding of this relationship. In particular
these studies have started to account for some of the genetic and familial confounds that, when taken into
account, throw several established findings into doubt. None of the proposed prenatal risk factors can be
confirmed as causal for ADHD, and the stronger the study design the less likely it is to support an association.
We need a new benchmark for studies investigating the etiology of ADHD whereby there is an expectation not
only that data will be collected prospectively but also that the design allows the broad range of genetic and
familial factors to be accounted for.
Keywords: ADHD; Etiology; Prenatal; Environmental; Pregnancy
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Introduction
Although Attention-Deficit/Hyperactivity Disorder (ADHD) is one of the most prevalent and widely
researched developmental conditions affecting young children and adolescents, we still have much to learn
about the underlying etiology of the disorder. While it is well accepted the disorder is highly heritable (>70%)
[1], the search for the genes underlying the phenotypic expression of ADHD has been slow. Early research in
this area focused on candidate gene approaches which have yielded evidence of a small number of potential
genes each having a small effect in predicting ADHD [2, 3] (e.g., DRD4, DRD5, DAT1, HTR1B, SLC6A4,
SNAP25). Genome wide association studies have started to appear and whilst to date no significant genome
wide hits have been published this is probably due to limitations of sample size and it is anticipated that these
will soon be announced. Clearly not all of the risk for ADHD is genetic and it should be noted that in addition to
the pure environmental risk, estimates of heritability also include an element of gene environment interaction. It
is estimated that between 10 to 40% of the variance associated with ADHD is accounted for by environmental
factors [4].
ADHD appears early in life and there is significant interest in the potential role that the prenatal
environment might play in the development of the disorder. Studies have identified numerous prenatal risk
factors, which appear to be associated with ADHD including maternal substance use and stress during
pregnancy, prematurity, low birthweight and a number of other pregnancy, labor, delivery or infancy
complications. Previous reviews have concluded that, despite the demonstration of association, there is as yet
insufficient evidence to support the notion of a truly causal relationship between those prenatal risk factors
identified to date and the later outcome of ADHD [3, 5].
It is particularly difficult to disentangle prenatal risk from postnatal risk factors such as social
adversity, as well as parental mental health and maternally transmitted inherited factors. A recent study of
children born through in vitro fertilization, contrasted the prenatal environment provided by a related versus
unrelated mother enabling comparisons of between those who did and did not smoke during pregnancy on birth
weight and antisocial behavior outcomes, while controlling for genetic risk [6]. Antisocial behavior was higher
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in related but not unrelated offspring of prenatal smokers and nonsmokers. Similarly, Obel and colleagues [7]
used a sibling-matched design to control for genetic confounding when comparing the frequency of ADHD
between children of smoking and non-smoking mothers. In the genetically sensitive analysis, the relationship
between prenatal smoking and ADHD was attenuated. These studies highlight that genetic risk may be the more
likely explanatory factor underpinning the relationship between some prenatal risk factors and later ADHD.
Several recent large scale population-based studies have advanced our understanding of the prenatal
risk factors of ADHD [e.g., 8, 9-11]. These population-based study designs have the advantage of having
sufficient statistical power to allow adjustment of and for multiple potentially confounding variables and the
detection of small effects. A widespread limitation in the literature is the reliance on retrospective recall of
events during pregnancy. Population data linkage studies can access prospectively collected patient medical
records thus minimising recall bias and reducing socially desirable responding.
This article aims to provide a recent update of the research examining the relationship between ADHD
and prenatal factors from 2013 to 2015. We start each section with a summary of what was known about the
relationship between prenatal risk factors and ADHD (where applicable) using updated findings from a
systematic review, which was originally submitted to the England and Wales Department of Health in 2011
[5].This review was updated but not published in 2013.
Prematurity
Summary from previous review: Sufficient evidence of a temporally ordered association, with a Risk Ratio (RR)
of 2.64 (range: 1.7 to 3.3) [5].
Recent findings: Three population-based data linkage studies have examined the risk of ADHD related to a
range of pregnancy/labour factors. Halmøy et al. [10] conducted one such study using data from Norwegian
national registries. The sample comprised all adults born between 1967 and 1987 who survived until 18 years of
age (n = ~1.17 million) including 2,323 cases of adult ADHD who were approved for stimulant treatment
between 1997 and 2005. Similarly, Silva et al. [9] conducted a population-based record linkage case-control
study of children prescribed stimulant medication for ADHD in Western Australia (N=12,991) compared to
30,071 children not taking stimulant medication. Lastly, Henriksen et al. [8] conducted a nationwide cohort
study of all live singleton births in Denmark between 2000 and 2008 after spontaneous onset of labour (N =
546,146) of which, 4,617 had a diagnosis of ADHD. All three of these studies found an association between
prematurity and risk of ADHD whereby the risk increases as gestational age decreases. For example, in children
born late pre-term (33 to <37 weeks gestation) risk estimates range from Hazard Ratio (HR) = 0.96 to RR = 1.3,
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while in children born extremely pre-term (< 29 weeks) risk estimates range from Odds Ratio (OR) = 1.2 to RR
= 5.0 [10, 9, 8]. These relationships held in adjusted models (controlling for maternal age, maternal education,
and marital status, year of child birth, gender, and all pregnancy/labour/newborn factors of interest), indicating
that prematurity may independently increase risk.
A study in the US failed to replicate this association between gestational age and risk of ADHD [12]. This study
only compared children born late preterm (34 to <37 weeks gestation) with those born at term, providing further
support for a possible inverse linear association between gestational age and risk of ADHD. Similarly, a case-
control study from the US reported that children with ADHD (N = 2,243) were no more likely than controls (N
= 5,631) to have been born prematurely [13]. It seems biologically plausible that prematurity would be
associated with ADHD, as there is less time for neural development, but it is likely that the association operates
through a number of mechanisms such as increased incidence of obstetric complications that may lead to neural
insult [14] or to genetic factors which may confer risk for both ADHD and premature birth. There is little
evidence to suggest that post-term birth is associated with ADHD.
Low Birth Weight
Summary from previous review: Some suggestive evidence of an association with adjusted OR/RR 1.5 to 9.6
across 19 studies (n=129,858) but inconsistency across studies [5]. Many studies did not report the proportion of
low birth weight children that were also premature.
Recent findings: Consistent with the findings regarding prematurity, Clements et al. [13] found no association
between low birth weight and ADHD. In contrast the large population-based studies by Halmøy et al. [10],
Henriksen et al. [8], and Silva et al. [9] all reported that low birth weight conferred risk for ADHD in unadjusted
analyses. Two of these studies [9, 10] reported that children who are born small for gestational age (SGA) were
at increased risk for ADHD (OR males = 1.13, OR females = 1.16 [9]; RR = 1.3 [10]). However Silva et al. [9]
found the relationships between ADHD and both low birth weight and SGA attenuated in their fully adjusted
model (accounting for maternal smoking, preterm labor, oxytocin use). Neither Halmøy et al. [10] or Henriksen
et al. [8] were able to adjust for maternal smoking. The inconsistencies in the literature may therefore relate to
methodological issues with the observed association between low birth weight and ADHD being driven by
other, unmeasured, factors such as maternal smoking during pregnancy.
Other pregnancy, labour/delivery and neonatal/infancy complications