MENTAL RETARDATION AND DEVELOPMENTAL DISABILITIES

RESEARCH REVIEWS 8: 117–134 (2002)

THE EPIDEMIOLOGY OF MENTAL RETARDATION:

CHALLENGES AND OPPORTUNITIES
IN THE NEW MILLENNIUM

Helen Leonard*1,2 and Xingyan Wen3

1
Centre for Child Health Research, The University of Western Australia, Telethon Institute
for Child Health Research, West Perth, Australia
2
Disability Services Commission, Western Australia
3
Australian Institute of Health and Welfare, Canberra, Australia

There are a number of problems and challenges in relating the
science of epidemiology to mental retardation (MR). These relate to how
MR is defined and classified and how these definitions may change over
time. These as well as other differences in ascertainment sources and meth-
ods need to be considered when comparing MR prevalence over time and
place. On the other hand, advances in technology also provide new and
efficient methods of data collection both by data linkage and by use of
web-based methods to study rare diseases.
While prevalence studies have not been individually reviewed, we
have examined the range of data including recent studies relating to how
prevalence differs according to age, gender, social class and ethnicity. Some
problems with available etiological classification systems have been identi-
fied. Recent etiological studies, most of which use different classification
systems, have been reviewed and explanations have been postulated to
account for differences in results. Individual risk factors for MR are consid-
ered whilst the option of considering a population as opposed to a high risk
strategy to MR prevention is raised. This might well involve improving the
social milieu surrounding the occurrence of individual risk factors.
The impact of biotechnological advances such as antenatal and neo-
natal screening and assisted reproduction on MR are discussed. The issue of
how inequalities in access to technology may impact on case identification
and even have the potential to further widen inequalities is raised. The
importance of extending the use of epidemiological tools to study the
social, health and economic burden of MR is also emphasized. However, in
order to apply to MR the “prevention-intervention-research” cycle, which
surely underpins all epidemiology, it is vital to ensure that the methodolog-
ical challenges we raise are adequately addressed. © 2002 Wiley-Liss, Inc.
currently discussion in the United States about changing to a name
that better portrays those affected [Luckasson and Reeve, 2001].
Epidemiology has been defined as “the study of the dis-
tribution and determinants of health-related states or events in
specified populations and the application of the study to the
control of health problems” [Last, 1995]. Applying the conven-
tional principles of epidemiology to the study of MR helps
examine how common MR is in the community; whether
incidence or prevalence has changed over time; and whether
certain population subgroups (according to gender, socio-eco-
nomic status, ethnicity, place of residence) are more or less likely
to be affected. In terms of control of the “health problem,”
epidemiological methods help identify those causal determinants
where prevention is possible and then whether the appropriate
intervention has had an impact on prevalence. Epidemiologists
can evaluate quality of life and access to medical and other
supports for people with MR and their families. Nevertheless,
there are many challenges in applying epidemiological principles
to the study of a field with lack of consensus on “conceptual-
ization, classification and terminology” [Fryers, 1992].
This article focuses on issues relating to definition and

MRDD Research Reviews 2002;8:117–134. methodology but also provides an overview of challenges, op-
portunities and new roles for epidemiology in the study of MR.
The discussion covers material published since the last compre-
Key Words: mental retardation intellectual disability/impairment; etiol- hensive review [Murphy et al., 1998] but earlier literature in-
ogy; Down syndrome; data linkage
cluding the work of Roeleveld et al. [1997] is referenced where
relevant. Examples from the experience in Western Australia
(WA) [Wellesley et al., 1991; 1992; Bower et al., 2000; Leonard
et al., 2002] are used to illustrate some of these issues throughout
INTRODUCTION
the text.

T
he definition, classification, and measurement of mental
retardation (MR) have involved considerable contro-
versy over time. Some would argue that the lumping
together of so many different underlying disorders and patho-
*Correspondence to: Dr Helen Leonard, TVW Telethon Institute for Child Health
logical processes within a single entity should not even be Research, PO Box 855, West Perth, WA 6872, Australia.
considered. The name assigned to this group of conditions varies E-mail: hleonard@cyllene.uwa.edu.
internationally [Haveman, 1996], and other related terms include Received 21 May 2002; Accepted 23 May 2002
Published online in Wiley InterScience (www.interscience.wiley.com).
“general learning disorder,” “mental handicap,” “learning disabili- DOI: 10.1002/mrdd.10031
ty,” “intellectual handicap,” and “intellectual disability.” There is
© 2002 Wiley-Liss, Inc.
DEFINITIONS AND
CLASSIFICATIONS OF MR
Whilst case definition is funda-
mental to its epidemiology [Haveman,
1996], there has been debate over the
definition and classification of MR for
several decades. This debate has focussed
on both conceptual approaches and key
elements for case identification. Wen
[1997] recently reviewed some interna-
tionally recognized and widely adopted
MR definitions and classifications and
emphasized the need for further im-
provement and standardization. Inconsis-
tency in data collection with great differ-
ences in reported prevalence of MR may
be partially attributable to the revisions and
variations in some major definition and
classification systems.
VARIATIONS IN MAJOR
DEFINITION AND
CLASSIFICATION SYSTEMS
The traditional approach considers
MR as a characteristic of a person and a
condition with the source of difficulty
lying essentially within the individual.
This approach tends to define MR on
the basis of either a medical model or a
statistical model. The medical model fo-
cuses on pathology, which defines MR
by the presence of pathological symp-
toms. The statistical model defines MR
by identifying a certain group of the pop-
ulation as “abnormal,” using comparison
of an individual’s performance and the
performance of a standardized norm
group. The statistical model measures se-
verity of MR by standardized tests, such
as intelligence quotient (IQ) tests. How-
ever, the latest (ninth) revision of the
definition and classification of MR by
the American Association on Mental Re-
tardation (AAMR) has taken significant
steps away from a clinically oriented per-
spective towards a multidimensional ap-
proach in defining MR [Luckasson et al.,
1992]. Although the new revision main-
tains the three key criteria—low general
intellectual functioning as measured by
IQ score, difficulties in adaptive behav-
ior, and the conditions manifesting be-
fore age 18 —it puts more emphasis on
functional and environmental consider-
ations, and less emphasis on an individu-
al’s deficiency. Rather than relying only
on IQ and adaptive behavior measures,
the AAMR definition gives more cre-
dence to the “state” of interaction be-
tween the individual and the social envi-
ronment. Under the new AAMR
definition, the concept of adaptive be-
havior is expanded with the specification
of ten applicable skill areas, relating to
118 MRDD RESEARCH REVIEWS
age-appropriate functioning of the indi-
vidual in the community (Table 1).
Severity of MR had been conven-
tionally based on the statistical distribution
of IQ scores. The new AAMR definition
replaced the previous classification of se-
verity with a new concept of intensity of
support required, assuming that a person’s
level of needed supports parallels the indi-
vidual’s (intellectual) limitations (Table 1).
Such descriptions of severity are considered
to be more functional, relevant, and ori-
ented to service delivery and outcomes
than the labelling classification used previ-
ously [Luckasson et al., 1992]. The AAMR
has also made changes in the upper limit of
IQ score in defining subaverage intellectual
functioning (Table 1). The IQ cut-off
score was set up to 84 (one standard devi-
ation below the mean) in the fifth revision
[Heber, 1961], and was reduced to approx-
imately 70 (two standard deviations) in the
sixth and eighth revisions [Grossman, 1973;
The debate over the key
criteria to define cases
has implications for
epidemiological research
because prevalence
estimates may be
influenced by changes in
these criteria.
1983]. The latest (ninth) revision [Luckas-
son et al., 1992] defines significantly sub-
average as “IQ standard scores of approxi-
mately 70 to 75 or below” (Table 1). The
American Psychiatric Association (APA)
has modified its recent (fourth) versions of
The Diagnostic and Statistical Manual of
Mental Disorders (DSM-IV) by incorpo-
rating the ten adaptive skill areas of the new
AAMR manual into its general definition
of MR. Nevertheless, DSM-IV has re-
tained the conventional severity levels of
intellectual impairment based on IQ scores
and maintained an IQ cut-off point at 70 or
below [American Psychiatric Association,
1994].
In the International Statistical Clas-
sification of Diseases and Related Health
Problems (ICD-10), apart from IQ scores
and functional ability, need for support is
also included as one of the indicators
differentiating mild MR from severe MR
[World Health Organization (WHO),
● EPIDEMIOLOGY OF
1992; 1993]. The ICD-10 manual also
points out that intellectual abilities and
rehabilitation may change over time and
may improve by training and rehabilita-
tion, so diagnosis should be based on the
current levels of functioning. The 1996
ICD–10 Guide to Classification in Men-
tal Retardation suggests the use of stan-
dard scales as measurements of social
functioning [O’Brien, 2001b]. The “in-
tellectual impairments” concept in Inter-
national Classification of Impairment,
Disabilities and Handicap (ICIDH) cov-
ers a wide range of impairments and syn-
dromes, involving impairments in intel-
ligence, memory and thinking. MR is
considered as one of the sub-categories of
intelligence impairments. The ICIDH
definition of intellectual impairments ex-
cludes impairments of language and
learning [World Health Organization
(WHO), 1980]. In the revised version of
ICIDH—International Classification of
Functioning, Disability and Health
(ICF), MR is classified as part of intellec-
tual functions, together with intellectual
growth, intellectual retardation and de-
mentia while memory, thought and
higher level cognitive functions are ex-
cluded [WHO, 2001]. Neither of the
two WHO manuals (ICD-10, ICIDH or
ICF ) has specified an age as a cut-off
point for the developmental period to
define MR, in contrast to the AAMR
definition that requires the diagnosis of
MR before age 18. ICD-10 refers to the
condition as ‘especially characterized by
impairment of skills manifested during
the developmental period,’ while ICIDH
seems to refer to the general population
of all ages.
DIVERSITY IN KEY CRITERIA
FOR CASE IDENTIFICATION
AND CLASSIFICATION
The debate over the key criteria to
define cases has implications for epidemi-
ological research because prevalence es-
timates may be influenced by changes in
these criteria. Zigler and colleagues
[1984] felt that MR should be defined
only on the basis of cognitive skills and
that inclusion of social adaptation, a mea-
sure of interaction between the child and
the environment, would make it difficult
to assess the true prevalence. Barnett
[1986] on the other hand agreed that the
fundamental property of MR was “cog-
nitive inefficiency” but felt that to opera-
tionalise this, the cultural context and
environment had to be taken into ac-
count. In practice, adaptive behavior is
more likely to be ignored in epidemio-
logical research of MR. Many studies use
IQ scores as the sole criterion to estimate
MENTAL RETARDATION ● LEONARD & WEN
 Table 1.
Term Fifth revision [Heber, 1961]
General defini- Subaverage general intellectual
tion functioning which originates
during the developmental pe-
riod and is associated with im-
MRDD RESEARCH REVIEWS
pairment in adaptive behav-
●
iour.
Subaverage Greater than one standard devia-
EPIDEMIOLOGY
tion below the mean.
OF
Assessment General intellectual functioning:
procedure may be assessed by one or
more of the standardised tests
developed for the purpose.
Developmental Approximately 16 years.
period
Adaptive be- Impairment in adaptive behav-
MENTAL RETARDATION
haviour iour: refers to the effectiveness
●
of the individual to adapt to
the natural and social demands
of his environment. May be
reflected in: 1. maturation, 2.
learning, 3. social adjustment.
LEONARD & WEN
Levels of se- Borderline retardation IQ 68–84
verity
Mild retardation IQ 52–67
Moderate retardation IQ 36–51
Severe retardation IQ 20–35
Profound retardation IQ ⬍ 20
*Sources: Grossman 1983; Patton et al., 1990; Luckasson et al., 1992; Wen, 1997.
119
Comparison of Different Versions of AAMR Definitions of Mental Retardation*
Sixth revision [Grossman, 1973]
Significantly subaverage general intellectual functioning ex-
isting concurrently with deficits in adaptive behaviour and
manifested during the developmental period.
Significantly subaverage: two or more standard deviations
below the mean.
Same as Heber.
Upper age limit of 18 years.
Defined as effectiveness or degree with which the individual
meets the standards of personal independence and social
responsibility expected of his age and cultural group. May
be reflected in the following areas: During infancy and early
childhood: 1. sensory-motor skills development, 2. com-
munication skills, 3. self-help skills, 4. socialisation During
childhood and early adolescence: 5. application of basic aca-
demics in daily life activities, 6. application of appropriate
reasoning and judgment in mastery of the environment,
7. social skills During late adolescence and adult life: 8. voca-
tional and social responsibilities and performances.
— —
Mild retardation IQ 52–67
Moderate retardation IQ 36–51
Severe retardation IQ 20–35
Profound retardation IQ ⬍ 20
Eighth revision [Grossman, 1983]
Significantly subaverage general intel-
lectual functioning resulting in or
associated with concurrent impair-
ments in adaptive behaviour and
manifested during the developmen-
tal period.
Significantly subaverage: defined as an
IQ of 70 or below on standardised
measures of intelligence; could be
extended upward through IQ 75 or
more, depending on the reliability
of the intelligence test used.
Same as Heber for intellectual func-
tioning. Adaptive behaviour as-
sessed by clinical assessment and
standardised scales.
Between conception and the 18th
birthday.
Impairments in adaptive behaviour
refers to significant limitations in an
individual’s effectiveness in meeting
the standards of maturation, learn-
ing, personal independence, or so-
cial responsibility that are expected
for his or her age level and cultural
group. May be reflected in the
same areas as 1973.
Mild retardation IQ 50–55 to approx-
imately 70
Moderate retardation IQ 35–40 to
50–55
Severe retardation IQ 20–25 to
35–40
Profound retardation IQ below 20 or
25
Unspecified
Ninth revision [Luckasson et al., 1992]
Substantial limitations in present functioning. It
is characterised by significantly subaverage
intellectual functioning, existing concur-
rently with related limitations in two or
more of the following applicable adaptive
skill areas: communication, self-care, home
living, social skills, community use, self-di-
rection, health and safety functional academ-
ics, leisure, and work. Mental retardation
manifests before age 18.
Significantly subaverage intellectual function-
ing: defined as an IQ standard score of ap-
proximately 70 to 75 or below.
Multidimensional approach including a three-
step procedure for diagnosing, classifying and
determining the needed supports.
Manifesting before age 18.
10 adaptive skill areas: communication, self-
care, home living, social skills, community
use, self-direction, health and safety, func-
tional academics, leisure, and work. The
relevant skills within each adaptive skill area
may vary with chronological age, so that
assessment of functioning must be referenced
to the person’s chronological age.
Intensities of supports:
Intermittent
Limited
Extensive
Pervasive
prevalence of MR. This is partly because
there are no totally objective and stan-
dardized measures of social adaptive be-
havior, particularly in different socioeco-
nomic and cultural environments. For
instance, because of inconsistencies and
lack of standardization of testing, adap-
tive functioning was not included in the
population-based Atlanta study of MR
prevalence [Yeargin-Allsopp et al., 1992].
The authors acknowledged that children
might have been included based on IQ
criteria who would have been excluded by
adaptive functioning criteria.
Replacing the levels of IQ score
with intensities of supports in severity
measures in the new AAMR manual has
been criticized in that it makes it more
difficult to differentiate groups with mild
from those with severe or profound MR,
a division thought by some [MacMillan
et al., 1993] but not by others [Schalock
et al., 1994] to separate organic and non-
organic etiologies. McLaren and Bryson
[1987] claimed that this distinction is not
clear cut and that there is likely to be an
etiological role from the interaction of
psychosocial and biological factors.
Greenspan [1999] on the other hand felt
that the severity levels previously used
were of little value from an educational
perspective and should be replaced with a
more descriptive term such as “evidence
of inability to benefit from skilled reading
instruction.” The recent AAMR revision
has also been criticized because sub-av-
erage intellectual functioning has been
defined as “an IQ score of approximately
70 to 75 or below.” MacMillan et al.
[1993; 1995] described this range as im-
precise and capable of targeting an addi-
tional 2.8% of the population with IQs
between 71 and 75. They argued that this
definition has been designed as a tool for
advocacy rather than one to meet the
needs of clinicians and researchers.
A binary categorization of severity
of MR by IQ level is often used, with an
IQ ⬍ 50 being considered as severe MR
(SMR) [Kiely, 1987; Decoufle and
Boyle, 1995; Roeleveld et al., 1997].
However, in accordance with the previ-
ous AAMR [Grossman, 1993] and
DSM-IV [American Psychiatric Associa-
tion, 1994] definitions, most Australian
studies, including the Western Australian
study [Wellesley et al., 1992], have used a
definition of severe MR as IQ ⬍ 35 or
IQ ⬍ 40. Thus, the use of different IQ
cut-off points and groupings for severe
MR means that care is required when
comparing severity levels across studies.
Estimates of MR prevalence can
also vary according to whether psycho-
metric or diagnostic criteria or educa-
120 MRDD RESEARCH REVIEWS
tional experience are used to define cases
[Hansen et al., 1980], with minority
groups often disproportionally affected
[Reschly and Jipson, 1976; McMillan et
al., 1993]. Using the prospective River-
side California study [Mercer, 1973],
Hansen et al. [1980] showed that the
estimated MR prevalence could be re-
duced from 2% to 1% by the inclusion of
adaptive behavior as one of the criteria.
The use of assessment of adaptive behav-
ior or nonverbal intellectual measures
helps to reduce false positives [Reschly
and Jipson, 1976; McMillan et al., 1993],
with the reduction more marked in
African-Americans and Hispanics. The
findings in our Australian study [Leonard
The implications for
epidemiological research
of having a stable
definition or classification
system that will allow
comparison over time and
place are critical.
Taxonomy in this field is
particularly difficult
because professionals and
consumers come from a
range of backgrounds and
have different purposes
such as advocacy,
education, medical care
and service provision.
et al., 2002a) of a doubling in the prev-
alence of MR and a marked increase in
the proportion of indigenous children
when educational sources are also in-
cluded are consistent with those from the
Riverside study.
The implications for epidemiolog-
ical research of having a stable definition
or classification system that will allow
comparison over time and place are crit-
ical. Taxonomy in this field is particularly
difficult because professionals and con-
sumers come from a range of back-
grounds and have different purposes such
as advocacy, education, medical care and
service provision. Fryers [1987; 1992]
stressed the importance of epidemiolog-
● EPIDEMIOLOGY OF
ical taxonomy with universally accepted
classification systems, categorizations and
standardized ways of measuring. He
stated that there is a need for a conceptual
framework that would relate the different
definition and classification systems in a
way amenable to scientific investigation
and that the tool for this was the then
ICIDH, which puts more weight on the
relationship between the individual and
the environment. ICD-10 provides an
etiological framework and diagnostic
classifications of diseases, disorders and
other health conditions, and this is now
complemented by the additional infor-
mation provided by International Classi-
fication of Functioning, Disability and
Health (ICF) (ICIDH-2) [World Health
Organization (WHO), 2001] on func-
tioning and person-environmental inter-
action. Information about diagnosis plus
functioning provides a broader and more
meaningful picture of MR in the popu-
lation.
FURTHER METHODOLOGICAL
ISSUES AFFECTING
PREVALENCE
Differences in definition and ascer-
tainment methods including type of data
sources and purpose behind data collec-
tion [Hansen et al., 1980] are also critical
considerations in the epidemiology of
MR. They certainly account for some of
the variation in prevalence [Roeleveld, et
al., 1997; Larson et al., 2001]. Both Kiely
[1987] and Roeleveld et al. [1997] have
used various criteria including method of
case ascertainment and classification to
evaluate the validity of previously pub-
lished prevalence studies. Cases should be
ascertained from entire populations, and
not limited only to individuals receiving
selected specialty services (e.g., hospital-
based services) or living in institutions.
Such individuals may not be representa-
tive of the larger population of affected
individuals. On the other hand registers
set up for the purpose of population-
based ascertainment [Fryers and Mackay,
1979] can also be at risk of overascertain-
ment if cases who are deceased or whose
status is otherwise changed (e.g., by
moving out of the study area) are not
removed [Larson et al., 2001]. Roeleveld
et al. [1997] differentiated between “true
prevalence,” i.e., “the total number of
mentally retarded people in a popula-
tion,” and “ascertained prevalence,” i.e.,
“the number of cases recorded by the
authorities.” However, Yeargin-Allsopp
et al. [1992] found that when quality and
quantity of services are high and multiple
administration data sources are used, ad-
ministrative prevalence closely approxi-
MENTAL RETARDATION ● LEONARD & WEN
 Fig. 1. Prevalence of SMR in children of school age 1960 –2002.
mates “true prevalence.” Yeargin-Allsopp
et al. [1992] have described a “multiple
source” approach to ascertainment of MR.
They carried out a comprehensive epide-
miological study of children with develop-
mental disabilities using several different
data sources including school hospital and
other service records. Most children were
ascertained from education data sources.
They did not identify through the hospital
system any cases that were not ascertained
elsewhere.
Technological advances have now
made linkage of multiple data sources a
powerful tool in epidemiological studies
and provide significant opportunities for
the etiological investigation of MR
[Boussy and Scott, 1993; Bower et al.,
2000]. Using record linkage involving
the birth notifications register, a contin-
uous census system known as the Central
Population Register, the Cause-of Death
Register, the Statistical Database for
Child Care Support and regional MR
registers Gissler et al. [1998; 1999] found
the cumulative incidence of MR to be
6.1 per 1000 in children aged 0 –7 years.
By linking service agency records with a
population cohort of 4,590,333 Califor-
nian births Croen et al. [2001] found a
prevalence of 5.2 per 1000. They used
these data to investigate the contribution
MRDD RESEARCH REVIEWS ● EPIDEMIOLOGY
of various maternal and infant character-
istics to the etiology of MR of unknown
cause. Records of Western Australian
children with MR identified from a reg-
ister were linked with three educational
data sources and with the 240,358 births
between 1983 and 1992 [Leonard et al.,
2002a]. The prevalence of MR was
14.2/1000 for children aged 6 –16 years.
PREVALENCE
As discussed in early sections, the
considerable variations in the estimates of
prevalence across countries and regions
from 2 to 85/1000 [Roeleveld et al.,
1997] may be attributable to the varia-
tions in major classification systems and
the diversity in study operational defini-
tions and methodologies. Nevertheless,
many reviews of international epidemio-
logical studies suggested that the preva-
lence of severe MR (SMR) is approxi-
mately 3 to 4 per 1000 in children
[Starza-Smith, 1989; Roeleveld et al.,
1997] and in adults [Reschly, 1992] in
both developed and developing countries
[Kiely, 1987]. Figures 1 and 2, showing
the prevalence of SMR and MMR, have
been adapted from Roeleveld et al.
[1997] and modified by the inclusion of
recent studies F, G, S, C and L [Fernell et
al., 1996; Fernell et al., 1998; Stromme
OF MENTAL RETARDATION ● LEONARD & WEN
and Valvatne, 1998; Gissler et al., 1999;
Cans et al., 1999; Leonard et al., 2002a].
The addition of the new studies does not
alter the pattern for mild MR (MMR)
(IQ 50 –70) which was already very vari-
able. Roeleveld et al. [1997] had previ-
ously commented that it was not known
whether this variability represented true
differences or differences in methodol-
ogy. However some of the more recent
population-based studies suggest a lower
prevalence of SMR than the 3.8/1000
average previously found [Roeleveld et
al., 1997]. As already discussed for a bi-
nary categorisation of severity the nature
of the recent Western Australian data
[Leonard et al., 2002a] made it necessary
to use a lower IQ cut-off point (IQ ⬍ 35
or 40 according to psychological test) to
define SMR. Therefore one might ac-
cordingly expect the Western Australian
estimate to be lower for SMR and higher
for MMR in comparison to other stud-
ies. In defining SMR previously from
Western Australian data [Wellesley et al.,
1992], Roeleveld et al. [1997] included
as severe children who had been classified
in the original study as moderate (IQ
35–54)—a categorisation not available
from the present data. However, the pre-
vious estimate of SMR (IQ ⬍ 35) for
children born in Western Australia be-
121
 Fig. 2. Prevalence of MMR in children of school age 1960 –2002.
tween 1967 and 1976 of 1.6/1000
[Wellesley et al., 1992] is extremely close
to our current estimate of 1.4/1000. What
is different is the prevalence of what we
have defined as MMR which has almost
doubled from 5.4 to 10.6 per 1000 by the
inclusion of education department data
using record linkage. These examples un-
derscore the importance of attention to
definitions and ascertainment methods in
the interpretation of results particularly in
data relating to different time periods.
AGE
The selection of population age
groups at risk (children, adults, the el-
derly or total population) will result in
different estimates of prevalence. Opin-
ion concerning the value of examining
age-specific MR prevalence rates varies
[Kiely, 1987; Roeleveld et al., 1997].
Data from the Australian Bureau of Sta-
tistics disability survey (1993) showed
that the age-specific prevalence rate in-
creased with age. It peaked at age 10 –14
years, declined slightly among adoles-
cents, and then fell markedly among
adults [Wen, 1997]. This pattern is con-
sistent with the findings from other in-
ternational studies [Kiely 1987; McLaren
and Bryson, 1987]. The dramatic in-
122 MRDD RESEARCH REVIEWS
crease and marked fall of the reported
age-specific prevalence rates across age
groups may not necessarily mirror varia-
tions in the actual prevalence among the
population. Rather, it probably reflects
differences in case ascertainment. The
high prevalence of MR among children
at school age demonstrates the great im-
pact of the education system on case
identification. The Metropolitan Atlanta
Developmental Disabilities Study se-
lected the age of ten years for case ascer-
tainment, as the investigators felt that
some disabilities might not become ap-
parent until this age.
The age variation may also be due
to the ability of adults with MMR to
adapt to the demands of society with the
passage of time. The adaptive behavior
criterion was originally added to the IQ
assessment in the fifth revision of the
AAMR manual [Heber, 1961] to remove
the false positives which were specific to
MMR and only identifiable through the
school system. As also noted by Murphy
et al. [1995], it is important to recognize
that IQ scores can change over time both
in individuals and groups. An IQ test is a
measure not of innate intellectual func-
tioning but of performance on a set of
skills defined by test instruments. Hence,
● EPIDEMIOLOGY OF
any accumulated experience or improve-
ment in performance a person brings to
the test situation will be reflected in the
IQ score. This phenomenon could ac-
count for the fact that in the Western
Australian study, although there was little
difference in the eligibility criteria for the
two ascertainment sources, a proportion
of children identified though the state
education services had been previously
evaluated by the state disability services
but did not meet the case definition for
the study [Leonard et al., 2002a]. The
differentials in mortality between people
with MR and the general population
may also account, to some extent, for the
lower prevalence of MR among the adult
population.
GENDER
A higher prevalence of MR among
male children has been noted [Richard-
son et al., 1986]. Drews et al. [1995]
found that males were between 1.6 to 1.7
times more likely to experience MMR,
SMR, isolated MR or MR accompanied
by other neurological disorders than fe-
males (Table 2). Croen et al. [2001]
found that the relative risk for males for
MMR (1.9) was greater than for SMR
(1.4) (Table 2) for MR of unknown eti-
MENTAL RETARDATION ● LEONARD & WEN
 ology. Analysis of data from the Austra-
lian population disability survey revealed

When SES dichotomised RR for MMR compared with

that the gender difference increased with

*SMR 0.4 for post-graduate education reference ⬍high

age up to 15 years, after which the dif-

SMR 2.6 for children of low SES parents 0.2 for

*MMR 0.3 for post-graduate education reference

ference then decreased substantially
[Wen, 1997]. Among people aged 40 and

16⫹ years (isolated MR) reference 12 years

Maternal Education or Socioeconomic status
over, there was no consistent pattern of
gender difference across age groups. It is
also reported that the marked gender dif-
ferences in prevalence among Canadian
children, apparent prior to 12 years, be-

⬍high school (adjusted)

come insignificant after that age [McLaren
and Bryson 1987].

school (adjusted)
In terms of biological factors, the
gender difference in prevalence is often
Prevalence of MR in Selected Studies Undertaken in the Past Decade

attributed to X linked conditions [Tari-

verdian and Vogel, 2000; Chelly and
Mandel, 2001], including both Fragile X
as well as unidentified X linked condi-
tions [Partington et al., 2000]. A male
Race Comparison group:

disadvantage is also seen in relation to

African-American or In-

*MMR 1.5 (adjusted)

*SMR 1.6 (adjusted) neonatal mortality. Among infants with

digenous Australian

very low birthweight, mortality for boys

was 22% compared with 15% for girls
1.5 (1.2–1.8)

[Stevenson et al., 2000]. Moreover, Za-

MMR 1.8

MMR 2.6
SMR 1.4

SMR 1.7

ren et al. [2000] found that maternal

smoking had a proportionally greater
detrimental effect on male than female
fetal growth. More recently Matte et al.
(adjusted)

(adjusted)
*MMR 1.9
female ratio

*SMR 1.4
MMR 1.6

MMR 1.6

[2001] also found that the association be-

SMR 1.7

SMR 1.5
Male to

tween birthweight and IQ was stronger

1.5
1.4

1.4
1.3

1.4
1.4

in males than females, once again sup-

porting this male disadvantage. The same
male excess is seen in attention deficit
SMR (IQ ⬍ 50)

12.0 (11.3–12.7)

14.2 (13.8–14.7)

3.04 (IQ ⬍ 50)

Prevalence per

hyperactivity disorder, the commonest of

7.61 (7.2–8.0)
3.5 (3.3–3.7)

2.8 (2.8–2.9)
6.2 (5.3–7.0)

5.2 (5.2–5.3)

6.1 (5.5–6.7)

the conditions contributing to the appar-

ent epidemic in diagnosed psychosocial
1000

disorders over the past two decades

[Kelleher et al., 2000]. Using the term
percentage of expected birth weight for
population

gestational age as a measure of appropri-

4590333
210,789
325,347

423,000

172,914
240358
Source

30,037

60,254
89534

ateness of fetal growth, Zubrick et al.

[2000] have demonstrated the association
between low birth weight, also a risk
Number

factor for MR, and an increase in child

of cases

11 892

23,956
1602
1150

1074

3426

mental health problems with boys again

185

367
527

much (38%) more likely to have a prob-

Table 2.

lem. It seems plausible that shared causal

New South Wales,
Akershus County,
Western Australia

Western Australia

pathways will contribute to a continuum

France-3 regions

California, USA

of neurodevelopmental and psychologi-

Atlanta, USA

Australia
Norway

cal outcomes which include MR and in

Location

Taiwan

Finland

which there is an increased male suscep-

tibility.
Since no gender differences were
found for MMR in the testing situation
Stromme and Hagberg [1998]

Yeargin-Allsopp et al. [1995]

in a study of 950 nonreferred Arizona

Decoufle and Boyle [1995]

children [Reschly and Jipson, 1976] it is

Partington et al. [2000]
Wellesley et al. [1992]

Murphy et al. [1995]

Leonard et al. [2001]

also possible that there are factors that

Gissler et al. [1999]
Drews et al. [1995]

Croen et al. [2001]

*MR of unknown etiology

Cans et al. [1999]

Hou et al. [1998]

make boys more likely to be referred for

services and hence identified as having
Publication

MR. The Western Australian study also

found that boys with Down syndrome
(DS) had significantly lower WeeFIM
scores than girls, though it is not clear
whether this is biologically or socially
MRDD RESEARCH REVIEWS ● EPIDEMIOLOGY OF MENTAL RETARDATION ● LEONARD & WEN 123
determined [Leonard et al., 2001]. Gissler
et al. [1999] studied gender differences in
a range of childhood morbidities and dis-
abilities including MR (Table 2). In ad-
dition to the clearly increased risk for
MR, males were over twice as likely to
have delayed development and to require
special education. These differences per-
sisted after adjustment for health related
variables. This raises the issue of the pos-
sible social determinants of gender differ-
ences and the potential for intervention
in the educational system.
SOCIAL CLASS
In addition to the demographics of
age and sex, MR prevalence can also be
influenced by social, economic, cultural,
racial/ethnic and other environmental
factors. Many studies have consistently
found that the prevalence of MMR was
strongly associated with low socioeco-
nomic status [Drews et al., 1995], and
some suggested that MMR was rarely
found in the highest socioeconomic
groups, unless accompanied by evidence
of organic damage. In a Norwegian study
representing 30,037 births, children of
parents with lower socioeconomic status
were found to have a significantly in-
creased risk of MMR but not of SMR
[Stromme and Magnus, 2000] (Table 2).
The Metropolitan Atlanta study
(Table 2) results support the idea of two
distinct types of MR: isolated MR,
which is mainly influenced by social and
demographic factors; and MR with other
neurological conditions, which is largely
affected by biological or pathological fac-
tors [Drews et al., 1995]. In a further
analysis of the same Atlanta data, Dec-
oufle and Boyle [1995] confirmed the
strong inverse relationship between ma-
ternal education and isolated MR (Table
2). These findings were in keeping with
the previous hypothesis of Zigler et al.
[1984] that there are two distribution
curves, one following the Gaussian curve
with a mean of 100 and a second repre-
senting “organic” damage, with a much
lower IQ distribution. Yet, in a very large
population-based study of 4,590,333 births
that focused on MR of unknown etiology,
Croen et al. [2001] found a relationship
between low maternal education and both
MMR and SMR (Table 2). However, de-
spite this finding, 59% of MR of unknown
etiology occurred in children of women
with college and postgraduate education.
This was in contrast to the findings of
Drews et al. [1995], who found that iso-
lated MMR was rare in children of moth-
ers with the highest median income and
more than 12 years of education.
124 MRDD RESEARCH REVIEWS
International comparisons indicate
that, in general, lower prevalence esti-
mates of MMR have been reported from
Scandinavia [Hagberg et al., 1981;
Stromme and Valvatne, 1998]. When the
Organization for Economic and Cooper-
ative Development graphed the relation-
ship between parental level of education,
a proxy for socioeconomic status, and
youth literacy scores, Sweden was found
to score highest with the most shallow
gradient [Willms, 1997]. This is another
example of the correlation between the
level of social inequality or equitable in-
come distribution and a range of health
and other outcomes [Kawachi and
Kennedy, 1997]. In contrast to the de-
veloped world, the impact of MR in
developing countries has been less well
studied, although it is likely to be much
more important and the opportunities for
prevention much greater. Worldwide io-
It seems plausible that
shared causal pathways
will contribute to a
continuum of
neurodevelopmental and
psychological outcomes
which include MR and
in which there is an
increased male
susceptibility.
dine deficiency is the leading cause of
preventable MR and its elimination is
within reach with enormous benefits
[Delange et al., 2001]. Moreover Chi-
nese studies show that genetic factors
may also underly the susceptibility to io-
dine deficiency [Wang et al., 2000]. In
the meantime, epidemiological data re-
lating to MR in China with its 1.3 billion
population are limited [Sonnander and
Claesson, 1997]. However, in Bangla-
desh it has been shown that the associa-
tion with socioeconomic status was
much more marked for MMR than for
SMR [Islam et al., 1993].
ETHNICITY
In parallel with their greater use of
special education services, there is a gen-
erally higher prevalence of MR among
African-American children as compared
with children of other racial groups
● EPIDEMIOLOGY OF
[Yeargin-Allsopp et al., 1995; Murphy et
al., 1995]. MMR was more common in
African-American children in Atlanta, af-
ter controlling for selected socioeco-
nomic and demographic factors such as
sex, maternal age, birth order, maternal
education and economic status (Table 2)
[Yeargin-Allsopp et al., 1995]. More re-
cent California data [Croen et al., 2001]
also showed an increase of about 50% in
African-American children having MR
of unknown etiology as compared to
other racial groups (Table 2). Findings
with respect to the Australian indigenous
population are similar to the African-
American population in Atlanta [Leonard
et al. 2002] (Table 2).
In assessing the reasons for racial
differences in prevalence it is important
to consider both methodological issues
and potential confounders including case
definitions, study design, demographic
composition of the study population,
maternal factors, early intervention ef-
forts and other social, economical and
cultural factors. Researchers have specu-
lated that unmeasured confounders such
as maternal intelligence and housing den-
sity may have contributed to their find-
ings. Indeed, although controlling for all
confounders is difficult many of the mea-
surable ones have been examined in in-
dividual studies [Yeargin-Allsopp et al.,
1995; Croen et al., 2001]. However, in a
recent comparative analysis of changes in
children’s IQ scores in two socioeco-
nomically disparate communities, it was
found that growing up in a racially seg-
regated and disadvantaged community,
more than individual and familial factors,
may contribute to a decline in children’s
IQ scores in early school years [Breslau et
al., 2001].
As noted by Yeargin-Allsopp et al.
[1995], children from minority cultures
are also more likely to be labelled as
having MR as a result of cultural differ-
ences including socially different behav-
ior and culturally inappropriate IQ tests
[Zigler, 1987]. Reschly and Jipson [1976]
showed that by the application of non-
verbal intellectual measures the racial dif-
ference in MR (IQ ⬍ 70) was much
reduced. Kearins [2000] has provided
guidelines on how Australian indigenous
children could be more appropriately as-
sessed. The rate of MR for Australian
indigenous children was nearly three
times greater in children identified
through the educational system than in
children attending the state disability ser-
vice [Leonard et al., 2002]. This could
either indicate inappropriate labelling of
indigenous children in the educational
system or it could mean that a higher
MENTAL RETARDATION ● LEONARD & WEN
proportion of eligible indigenous than
Caucasian children were not accessing
disability services. We were unable to
compare the prevalence of MR by eth-
nicity in children diagnosed before and
after school entry. However, we did find
that there was an increasing trend with
age and that only 10% of seven-year-old
as compared with 14.7% of twelve-year-
old children in our cohort were indige-
nous (unpublished data).
Yeargin-Allsopp et al. [1995] con-
sidered possible prenatal or postnatal fac-
tors which may be increasing the risk of
MR in African-American children.
These included the increased prevalence
of maternal conditions such as diabetes,
hypertension and chronic renal disease, a
pattern also mirrored in the Australian
indigenous population [McLennan and
Madden, 1999]. Possible postnatal child
factors included elevated lead levels and
anemia. A more recent study [Hurtado et
al., 1999] reviewed by Pollitt [1999] used
record linkage to show that for each dec-
rement in haemoglobin the risk of mild
to moderate MR increased by 1.28-fold
after controlling for birthweight, mater-
nal education, sex, maternal age, race and
child’s entry age into the program. Other
etiological pathways for the racial differ-
ences may involve intergenerational fac-
tors as has been postulated in the African
American population [Chapman and
Scott, 2001]. It is likely that these issues
will need to be addressed by changes in
social policy rather than by implementa-
tion of individual interventions.
ETIOLOGY
Issues Relating to Some Etiological
Classification Systems
The fifth revision of the AAMR
classification system [Heber, 1961] placed
emphasis on the presumed cause of MR
and combined etiologies such as DS
(which could be considered a sufficient
cause of MR) with component causes,
such as intrauterine growth retardation.
It did not clearly provide a map to de-
termine which diagnoses should be con-
sidered “genetic” and which “multifac-
torial.” Nor was it clear how diagnostic
categories can be translated into prenatal,
perinatal, postnatal and unknown group-
ings. The ninth revision of the AAMR
classification manual [Luckasson et al.,
1992] updates the etiologic categories,
but under prenatal causes still includes
teratogens and maternal diseases that may
only be a contributing factor to the causal
pathway. It also indicates as postnatal
Rett syndrome and a range of neurode-
generative disorders whose etiology is
MRDD RESEARCH REVIEWS ● EPIDEMIOLOGY
clearly genetic. Although manifesting
postnatally, these conditions should be
classified as prenatal in origin. Therefore,
the most recent revision of the AAMR
classification system is still not ideal and
does not adequately reflect our present
understanding of biological mechanisms.
Wilska and Kaski [1999] have
adapted the methods and systems used to
assist with the work up of individuals with
MR in Finland over the last two decades to
develop an etiological classification system
based predominantly on timing. They feel
that their model is as equally appropriate for
etiological investigation as it is for clinical
evaluation, and that it is applicable both to
service providers and society. Their classi-
fication system can be depicted as a multi-
dimensional etiological tree. It has five ma-
jor divisions: 1) genetic, CNS multiple and
malformation syndromes of unknown ori-
A universally accepted,
consistent, and reliable
etiological classification
system for MR and one
flexible enough to include
recently elucidated
disorders would be
helpful both from a
clinical and
epidemiological
perspective.
gin; 2) external prenatal disorders 3)
paranatal disorders; 4) postnatal disorders;
and 5) unknown etiology. These can be
then be divided into further groups, sub-
groups and individual diagnoses. This sys-
tem has the flexibility to allow extra
branches to be added when new genetic
disorders are identified. A universally ac-
cepted, consistent, and reliable etiological
classification system for MR and one flex-
ible enough to include recently elucidated
disorders would be helpful both from a
clinical and epidemiological perspective. It
would assist with the investigation of the
still sizeable proportion of undefined MR,
some of which is likely to be genetic.
Recent Etiological Studies of MR
Using the system of Heber et al.
[1961], Wellesley et al. [1991] designated
72% of cases ascertained in their popula-
OF MENTAL RETARDATION ● LEONARD & WEN
tion-based study as having a prenatal,
perinatal or postnatal etiology (Tables 2
and 3). Hou et al. [1998] used the clas-
sification system reported by Crocker
[1989] that, like the AAMR system
[Luckasson et al., 1992], is also based on
the timing of the insult (i.e., prenatal,
perinatal, postnatal and unknown) in a
large etiological population-based study
in Taiwan (Tables 1 and 2). A genetic
etiology was identified in 54.7 % of the
cases, including 16.2% with multifactorial
inheritance. DS accounted for 82.4% and
Fragile X 12.3% of the chromosomal ab-
normalities. Contiguous gene syndromes,
particularly Angelman and Prader Willi,
were the next most common.
Using medical information from
the department of special education,
Cans et al. [1999] investigated children
aged 7–16 years with SMR (IQ ⬍ 50)
with and without cerebral palsy (CP)
from a population base of 325,347 chil-
dren (Tables 2 and 3). They assigned
cases to etiological groupings: definite
(25%, e.g., trisomy 21, metabolic disor-
ders); suspected (25.8%, e.g., fetopathy or
fetal asphyxia); and unknown (49.3%)
and also classified whether or not CP was
present. The results suggested differences
in the underlying pathogenic factors be-
tween those with and without CP.
Fernell [1998] studied the cause of
SMR (defined as an IQ below 50 to 55)
in a population of 14138 Swedish chil-
dren (Table 3). The etiology of two
thirds of cases was identified as arising
prenatally, 4/64 from the perinatal period
and 3/64 postnatally while in the remain-
der it was unclassified. Stromme and
Hagberg [2000] recently investigated
MR etiology from a larger population
base of 30,037 Norwegian children (Ta-
bles 2 and 3). Using multiple sources,
they identified 185 children who were
clinically investigated using a rigorous di-
agnostic work-up. Cases were subdi-
vided into “biopathological” and “un-
specified” and classified according to
timing of the event as in the study of
Hou et al. [1998]. Compared with the
50.3% that Cans et al. [1999] assigned to
a known or suspected etiology, they
identified a “determined” biopathologi-
cal etiology in 62/79 (78.5%) cases with
SMR. However this group included an
unknown category relating to unspeci-
fied syndromes and brain anomalies. As
did Hou et al. [1998], Cans et al. [1999]
and Fernell [1998], they found DS to be
the most common single entity whilst
other specific genetic MR syndromes
and fetal alcohol syndrome were less
common with a prevalence in the region
of 1:10,000 –15,000 children but with
125
126
Table 3. Recent Etiological Studies of MR
Case pop- Etiological classifi- Common clinical Proportion with
Location ulation Source of cases cation entities diagnosis Work-up

Wellesley et al. [1992] Western Australia 1602 Authority for Intellec- Heber Down syndrome 72% (prenatal, Used available diag-
tually Handicapped (13.9%), specific perinatal and noses
Persons IQ ⬍ 70 aetiologies not postnatal)
otherwise de-
fined.
Cans et al. [1999] France-3 regions 1150 Departmental Commis- Known, suspected Down syndrome 25% (known) 26% Used diagnostic &
sion for Special Edu- or unknown (16%) (suspected) medical information
cation from health practi-
tioners
Hou et al. [1998] Taiwan 11892 Special schools & insti- Prenatal, perinatal, Down syndrome 68% (prenatal, Panel of clinicians re-
tutions postnatal or (13%), Fragile X perinatal and viewed family his-
unknown (1.9%), Prader postnatal) tory & medical
[Crocker, 1989] Willi (0.5%) An- records. Cytogenetic
gelmans, Noon- & molecular studies.
ans (0.29%) Neuroimaging for

MRDD RESEARCH REVIEWS

structural defects

●
Stromme and Hegberg Akershus County, 185 Multiple sources Biopathological or Down syndrome 66% (prenatal, Karyotyping, metabolic
[1998] Norway unspecified (9.5%), fetal alco- perinatal and screening, neuroim-
hol syndrome postnatal) 14% aging, FISH
(1.7%), Fragile X undetermined
(A or E) (1.7%)
William syn-
drome (1.7%)

EPIDEMIOLOGY
Yeargin-Alsopp et al. [1995] Atlanta 715 Metropolitan Atlanta Prenatal, perinatal, Down syndrome 22% Review of medical

OF
Development Dis- postnatal or (4.7%), Fetal al- conditions
abilities Study-multi- unknown cohol syndrome
ple sources (2%)
Fernell [1998] Stockholm, Sweden 64 Hospital paediatric Prenatal, perinatal, Down syndrome 77% (including Examination of medi-
clinic and local cen- postnatal or (20.3%) perinatal and cal records
tre for MR unknown postnatal
causes)
Partington et al. [2002] New South Wales, 429 Australian Child and Known, descrip- Down syndrome 45% (causal diag- Accepted diagnosis,
Australia-5 re- Adolescent Develop- tive or un- (14.6%), Prader- nosis) 28% (de- clinical genetics re-
gions ment longitudinal known Willi (0.7%), An- scriptive diag- view or further in-
study gelman (0.7%) nosis) vestigations

MENTAL RETARDATION
●
LEONARD & WEN
wide confidence intervals. Prevalence of
Fragile X (A or E) (2% of children with
MR) was consistent with the findings of
the much larger Taiwan study [Hou et
al., 1998]. The three cases of fetal alcohol
syndrome gave an estimated prevalence
of 1 per 10,000 births, significantly lower
than the 28 – 46 per 10,000 live births
reported in the United States [Sampson
et al., 1997; Bagheri et al., 1998]. This
study, like others, identified the presence
of neurological impairments such as epi-
lepsy and CP in 20% and 14% of the
population respectively. They also
showed that microcephaly (head circum-
ference less than 2.5th percentile) was
eight times more common than in the
general childhood population.
Partington et al. [2000] reviewed
the clinical diagnosis in 429 cases of MR,
aged 4 –18 years, whose parents were liv-
ing in 1990 –1991 in five different areas
in New South Wales (the most populated
Australian state) [Einfeld and Tonge,
1996]. Cases were classified according to
whether they had a firm causal, a descrip-
tive, or an unknown diagnosis (Tables 2
and 3). As in the study of Stromme and
Hagberg [2000], clinical and laboratory
investigations were instituted (although
the extent of these is not documented).
The prevalence of discrete diagnostic en-
tities was consistent between the two
studies with four cases each of tuberous
sclerosis and Fragile X syndrome and
three of Prader Willi, Angelman and
Rett syndrome. The authors note, how-
ever, that their population is biased to-
wards individuals with an IQ ⬍ 50
where one would expect a higher prev-
alence of identifiable syndromes.
Yeargin-Allsopp et al. [1997] pre-
viously reviewed biomedical causes of
MR in their Atlanta population-based
study (Tables 2 and 3). Unlike Stromme
and Hagberg [2000] and Partington et al.
[2000], but like Cans et al. [1999], they
relied completely on available records
from multiple sources to designate the
probable cause. They used a hierarchial
system based on timing of the event sim-
ilar to Stromme and Hagberg [2000] and
Hou et al. [1998] but with more struc-
ture and detail. They were able to iden-
tify a defined biomedical cause in 22% of
all cases (13.4% of MMR and 33.2% of
SMR). This proportion is much lower
than that of Hou et al. [1998] and
Stromme and Hagberg [2000], but more
consistent with the recent Californian
record linkage study [Croen et al., 2001].
For the cohort of 1,560 Western
Australian children identified from the
state disability service and born between
1983 and 1992 the syndromes, other than
MRDD RESEARCH REVIEWS ● EPIDEMIOLOGY
frank chromosomal abnormalities, in
which three or more live cases were
identified were tuberous sclerosis, Prader
Willi, Williams, Fragile X, Noonan,
Rett, Angelman, Sanfilippo, Aarskog,
Cornelia de Lange, neurofibromatosis
and Coffin Lowry [Leonard, unpublished
data]. With a denominator of just under a
quarter of a million births and ten the
maximum number of cases for any disor-
der, the prevalence would not exceed
1:25,000 for any of these conditions.
Thus, apart from DS, the proportion of
MR cases affected by individual biomed-
ical entities is very small. Most of these
would be genetic syndromes with over
one thousand entries for MR on Online
Mendelian Inheritance in Man in 2001
[OMIM, 2001].
For many genetic syndromes, diag-
nosis in the past was made on clinical
grounds often with the assistance of spe-
cific criteria [Trevathan and Moser,
1988; Williams, 1995]. Diagnostic tests
are now available, at least in the devel-
oped world, for most of these disorders
either by fluorescent in situ hybridiza-
tion, DNA testing including methylation
studies or gene sequencing. Moreover
submicroscopic deletions in the subtelo-
meric chromosomal regions, now being
found to be associated with MR [de
Vries et al., 2001] may occur in 3.6% of
previously undiagnosed cases [Baker et
al., 2002]. X linked genes have also now
been identified, many within the last five
years, in fifteen syndromes causing SMR,
and in a further eight MMR may or may
not be present [Chelly and Mandel,
2001]. The commonest of these would
be Fragile X and Rett syndrome affecting
1:4,000 males [Turner et al., 1996] and
1:10,000 females [Leonard et al., 1997],
respectively. As well as the Methyl CPG
binding protein 2 in the latter [Amir et
al., 1999], other recently identified genes
include the doublecortin gene in X
–linked lissencephaly [Gleeson et al.,
1998] and the Ring box/B-box protein
gene in the Opitz G/BBB syndrome
[Quaderi et al., 1997]. It is also worthy to
note that MECP2 mutations are now
being found in males with neurodevel-
opmental disorders [Clayton-Smith et al.,
2000; Couvert et al., 2001] and in new-
born or nonprogressive encephalopathy
[Wan et al., 1999; Villard et al., 2000;
Imessaoudene et al., 2001], as well as in
X linked mental retardation [Orrico et
al., 2000; Meloni et al., 2000; Couvert
et al., 2001]. This has led Couvert et al.
[2001] to suggest that MECP2 muta-
tions could be as common a cause of
MR as Fragile X syndrome and for
OF MENTAL RETARDATION ● LEONARD & WEN
Dotti et al. [2002] to characterise a new
type of X linked MR.
Variation in Prevalence of Known
Etiologies
Variation between studies in the
prevalence of cases with a known etiol-
ogy is likely to be influenced both by
how a “known etiology” is defined, by
the extent of the clinical investigations
undertaken and possibly by the specialty
of the diagnostician. Although Yeargin-
Allsopp et al. [1997] acknowledge that
factors such as intrauterine growth retar-
dation (IUGR) (also included as causal in
the system used by Hou et al. [1998]) and
low birth weight are risk factors for MR,
they do not consider that they meet the
criteria for a biomedical cause. Neverthe-
less, their proportion of unequivocal ge-
netic causes would still seem lower than
in the studies of Hou et al. [1998] and
Stromme [2000]. Despite the fact that the
Atlanta study had a larger base population
than the Norwegian study no cases of
Williams, Angelman, Rubenstein Taybi
or even Rett syndrome were identified,
suggesting perhaps some under diagnosis.
On the other hand fetal alcohol syn-
drome, although still only representing
2% of MMR, was the second common-
est cause after DS. This was in approxi-
mate agreement with the findings of
Stromme and Hagberg [2000] of 3 cases
out of 178 children with mild and severe
MR but much lower than the rates
quoted by Sampson et al. [1997]. There
could be a number of other reasons for
the variation in the prevalence and dis-
tribution of known etiological entities in
different populations. It could be that
differences in the prevalence of genetic
conditions are real and related both to the
genetic characteristics and rates of con-
sanguinity in the underlying population
[Hutchesson et al., 1998]. On the other
hand it may be that “idiopathic or unde-
termined” MR is commoner in some
communities because of underlying psy-
chosocial or unidentified environmental
determinants. Consequently discrete bio-
medical causes would represent a smaller
proportion of all cases. Alternatively, be-
cause cases with unknown etiology are
more likely to be identified through the
educational than the medical system,
they may have been better ascertained in
studies using multiple sources.
INDIVIDUAL RISK FACTORS
FOR MR
Atlanta cases were also categorized
according to the presence of associated
conditions, disabilities and non-CNS de-
fects as well as risk factors such as low
127
birthweight, intra-uterine growth retar-
dation (IUGR) and maternal conditions
[Yeargin-Allsopp et al., 1997]. Potential
and confirmed risk factors for MR now
include low birthweight, preterm birth
[Mervis et al., 1995], multiple births
[Croen et al., 2001], as well as maternal
exposures and conditions such as smok-
ing [Drews et al., 1996], alcohol [Amer-
ican Academy of Pediatrics, 2000], thy-
roid disease [Haddow et al., 1999], and
urinary tract infection [Camp et al.,
1998; McDermott et al., 2001].
Low birthweight has been the most
studied risk factor. Mervis et al. [1995]
found that low birthweight children over
all had nearly three times the risk of MR.
However the risk was higher for very
low birthweight (⬍ 1,500 g) children
than for moderately low birthweight
(1,500 –2,499 g) children, and higher for
SMR than MMR. Children with normal
birth weight who were born pre-term
were also at increased risk of MR. Sim-
ilarly, Camp et al. [1998] found that up
to 16.5% of infants with a birthweight
of ⬍ 2,000g had MR at age 7 years. At
the age of five years Californian children
who had been low birthweight had a
more than threefold risk of MMR [Mc-
Dermott et al., 1993]. Kok et al. [1998]
followed very preterm SGA infants for
nine years and found that they were
more likely to require special education
than appropriate for gestational age in-
fants. Paz et al. [2001] on the other hand
found that 17-year-olds who were born
at term with growth restriction had
slightly lower IQ levels than normally
grown infants after adjusting for a range
of confounders. These included maternal
and paternal education, maternal age, pa-
rental smoking, ethnic origin, socioeco-
nomic status, birth order, pregnancy and
delivery factors. In the very large popu-
lation based study of Croen et al. [2001]
low birthweight was the strongest pre-
dictive factor for both MMR and SMR
of unknown cause, but in the study of
Cans et al. [1999] it was only associated
with SMR accompanied by CP.
Meta-analysis has shown a two fold
increase in the risk of low birth weight
infants to smoking mothers [English et
al., 1995]. Therefore, this may have con-
siderable implications for MR preven-
tion. Drews et al. [1996] however suggest
that maternal smoking may increase the
occurrence of MR by mechanisms other
than low birthweight. A recent report
using data from the National Collabora-
tive Perinatal Project [McDermott et al.,
2001] also found an increased relative risk
of 1.4 (CI ⫽ 1.01–1.95) of MR or de-
velopmental delay in the children of
128 MRDD RESEARCH REVIEWS
mothers who had a urinary tract infection
in the third trimester.
In keeping with the population-
based approach to prevention discussed
by Rose [2001], Matte et al. [2001] have
recently shown that a small shift in the
distribution of birthweight will have a
much greater impact on population dis-
tribution of intellectual functioning than
a specific focus on the prevention of low
birth weight per se. Similarly it is likely
that social policy aimed at reducing pov-
erty levels in the community may have a
much greater impact than focus on indi-
vidual risk [Chapman and Scott, 2001].
The detrimental influence on IQ of
growing up in a disadvantaged and ra-
cially segregated environment under-
scores the importance of social policy in
the prevention of MR.
FURTHER AREAS TO EXPLORE
Biotechnological Advances
Affecting Prevalence of MR
The prevalence of MR can be re-
duced by primary or secondary preven-
tion. In primary prevention the interven-
tion results in a reduction in the
occurrence of new cases, e.g., immuni-
zation to prevent congenital rubella syn-
drome [Stanley et al., 1986]. Both ante-
natal and neonatal screening are forms of
secondary prevention. Antenatal screen-
ing using a variety of different methods
[Wald et al., 1999] can identify pregnan-
cies with increased risk of DS. Neonatal
screening allows conditions to be de-
tected at a stage when treatment can be
instituted and MR prevented. In con-
trast, tertiary prevention which aims at
reducing disability associated with MR
could actually improve survival and
hence increase prevalence.
Because DS is the commonest
known cause representing 14 –15% of
MR [Bower et al., 2000], changes in its
incidence or prevalence may have the
greatest impact on overall prevalence of
MR. Parallel with the temporal increase
in median age at childbirth in recent de-
cades in developed nations has been an
increase in the proportion of trisomy 21
conceptions [Alberman et al., 1995]. This
will be offset by the increased use of
maternal serum screening, prenatal diag-
nosis and termination [O’Leary et al.,
1996]. However, while the birth preva-
lence of DS is likely to fall, overall prev-
alence may not because of improved sur-
vival [Leonard et al., 2000b]. Surgical
treatment of congenital heart disease has
had a major impact on infant survival
whilst better health management and
● EPIDEMIOLOGY OF
care are likely to affect survival into
adulthood.
The use of artificial reproductive
technology, which is increasing over
time, is another factor with possible im-
plications for MR [Society for Assisted
Reproductive Technology and Ameri-
can Society for Reproductive Medicine,
2000; Menezo et al., 2000]. At the
present time, research results in relation
to the finding of developmental problems
in children born by assisted conception
are contradictory [Bowen et al., 1998;
Bonduelle et al., 1998; Sutcliffe et al.,
2001; Strömberg et al., 2002] with two
of these four studies finding an associa-
tion between delayed development and
conception by intracytoplasmic sperm in-
jection or in vitro fertilisation. Moreover,
using record linkage, an increase in birth
defects has recently been identified in
Western Australian children conceived by
assisted reproductive technology [Hansen
et al., 2002].
On the other hand, implementa-
tion of newborn screening programs, a
technological advance practiced for over
thirty years, have virtually eliminated
MR due to phenylketonuria [Abadie et
al., 2001] and congenital hypothyroidism
[Kurinczuk et al., 2002] in developed
countries. Similar to preventing congen-
ital rubella syndrome, immunization pro-
grams are likely to have a major impact
on MR due to post natal infections such
as Haemophilus influenzae b [Bower et
al., 1994; 1998].
However, these biotechnological
advances are very much confined to the
Western world. Although some preven-
tion activities may have been established
in many developing countries, there are
often no overall systematic intervention
programs and service activities are often
fragmented and less than adequate [Son-
nander and Claesson, 1997; Durkin et al.,
2000]. Moreover, the vaccination [Shann
and Steinhoff, 1999] and neonatal screen-
ing programs [Gu and Chen, 1999] prac-
ticed in developed nations are less likely to
be available.
Inequality in Access to Diagnosis
and its Impact on Case
Identification
As is likely with assisted concep-
tion, access to technological interven-
tions, advanced medical care and exten-
sive diagnostic work-ups may not be
uniform across groups in society. The
effect is to create a potential bias which
may increase or decrease the likelihood
of identifying cases for epidemiologic re-
search. For instance, Brett et al. [1994]
noted that amniocentesis use was more
MENTAL RETARDATION ● LEONARD & WEN
common in white than black women.
The sequelae to this possible discrimina-
tion in the availability of prenatal diag-
nosis could be a relative increase in the
birth prevalence of DS in those groups in
society with least resources to care for
such children. In the same way that ac-
cess to prenatal diagnosis [Brett et al.,
1994] and neonatal intensive care [Allen
et al., 2000] may not be uniform, access
to diagnostic investigations may also
vary. Syndromes causing MR tend to be
individually rare and some may only be
diagnosed as a process of exclusion after
multiple investigations. The cost of these
can be considerable and in some coun-
tries could be prohibitive without med-
ical insurance. For example, in Norway,
Stromme and Hagberg [2000] com-
mented that limited resources curtailed
the full extent of their planned telomeric
probe investigation. An apparently lower
prevalence of certain birth defects has
been reported in Aboriginal children
[Bower et al., 1989]. Thus a lower prev-
alence of the diagnosis of specific entities
in some populations could be influenced
by a reduced access to investigations or
the diagnostic process. Epidemiological
data on single disorders and, in fact, as we
have noted earlier, on all MR depend
heavily on the diagnosis having been
made. This may be more or less likely in
certain sociodemographic groups and it is
important to be aware of this potential
bias which may either increase or de-
crease the likelihood of identifying cases.
Whilst Slone et al. [1998] found that
hospital referrals for MMR were under-
represented in low socioeconomic areas,
disadvantaged children may be more
likely to be labelled as MR [Zigler et al.,
1984].
FURTHER APPLICATIONS OF
EPIDEMIOLOGY TO MR
Using as a model some specific
conditions associated with MR including
DS and X linked MR, Alberman et al.
[1992] have illustrated how trends in MR
might be projected. In doing so, their
primary purpose was to provide informa-
tion for UK local authorities for the plan-
ning of health, education and social ser-
vices for this population. To predict
trends for each condition, it is necessary
to take into account known risk factors
(and the sociodemographic trends which
affect them), possible prenatal interven-
tions, current prevalence, future esti-
mated prevalence, survival, associated
health problems and facilities required for
accommodation, education and place-
ment. Unfortunately, other than for DS,
much of these data are incomplete both
MRDD RESEARCH REVIEWS ● EPIDEMIOLOGY
for individual and for groups of disorders.
This is partly because for such rare con-
ditions insufficient cases will be gener-
ated from individual centers and possibly
because clinicians may be reluctant to
engage in population-based research.
The epidemiology of MR involves more
than just the study of incidence and prev-
alence and needs to start examining the
social and economic burden of MR.
It is now evident that over and
above state funded resources, the extra
care required to be provided by the fam-
ilies of disabled children is substantial
[Roberts and Lawton, 2001]. Time costs
involved for parents in the care of chil-
dren with and without disabilities were
recently compared [Curran et al., 2001].
It was found that the care needs of se-
verely disabled children far surpass non-
disabled children, making it impossible
for the majority of mothers to return to
paid employment. Thus it is important to
note that factors other than birth preva-
lence contribute to the social and eco-
nomic burden associated with specific
MR disorders. These factors include
functional dependence, morbidity and
life expectancy, areas about which par-
ents may often have many questions
[O’Brien, 2001a]. For instance whilst
one would expect only one affected girl
with Rett syndrome to be born for every
ten with Down syndrome (DS), in terms
of functioning and need for health and
support services, Rett syndrome is gen-
erally much more severe. We have al-
ready shown that in Rett syndrome the
WeeFIM score, a measure of functional
ability, is less than one third of the value
attained by children with DS [Leonard et
al., 2001; 2002b]. Dykens and Hodapp
[2001] have also illustrated how func-
tioning in different domains may vary in
specific genetic MR syndromes and pos-
tulate that this may lead us to a further
understanding of the development of
these processes in people without MR.
Examples given are Down, Williams and
Fragile X syndromes. Specific differences
in behavioral phenotypes are now being
recognized [Moldavsky et al., 2001] and
may also have implications for the dy-
namics of families affected by specific dis-
orders and for types of services required
[Fidler and Hodapp, 1999]. About two
out of five children with MR have co-
morbid psychopathology according to
Stromme and Diseth [2000] and Einfeld
and Tonge [1996]. Using a random sam-
ple from a population-based register and
recognized diagnostic schedules, the
prevalence in adults seems to be even
greater with one in two affected and “be-
havior disorder” cited as the commonest
OF MENTAL RETARDATION ● LEONARD & WEN
entity [Cooper and Bailey, 2001]. MR
epidemiology might benefit from the de-
velopment of new measures which do
not just reflect numbers of cases but
which incorporate the presence or ab-
sence of psychopathology and the degree
of functional ability. These two domains
can impact substantially on the burden
associated with MR. Indeed the study of
how both specific and generic services
impact the lives of people with MR and
the rationale, if any, behind the changes
occurring in service provision are impor-
tant areas for epidemiological research.
Clinical epidemiology is also the
science used to evaluate both antenatal
(e.g. DS [Gilbert et al., 2001]) and neo-
natal (e.g., phenylketonuria [Abadie et
al., 2001]) screening programs including
their economic analyses. Toledano-Al-
hadef et al. [2001] have recently exam-
ined the effectiveness, including an eco-
nomic evaluation, of a fragile X carrier
screening program. Using a prevalence of
1:113 for premutation or full mutation
carriers the program was deemed cost-
effective. Tandem mass spectrometry
[Pollitt, 1999] now allows for the testing
at birth of multiple conditions simulta-
neously. Although, like phenylketonuria,
all conditions being tested are very rare,
some do not fit the traditional criterion
for screening which states that early iden-
tification will allow treatment to proceed
so that further damage can be prevented
or the burden of the disease reduced.
Thus it is extremely important to con-
sider the cost, yield and outcome, includ-
ing negative effects, of both antenatal and
neonatal screening programs [Peckham
and Dezateux, 1998; Nelson et al.,
2001b; Gilbert et al., 2001]. Evaluations
such as this, which can be the province of
the clinical epidemiologist, should not be
restricted to screening programs but can
also be applied to clinical investigations.
Whilst no definite etiology is found in
between 32% and 75% of children with
MR, the number of laboratory and ra-
diological investigations becoming avail-
able is increasing exponentially. Thus
there is the need for clinical epidemiol-
ogists to develop evidence-based proto-
cols that will provide the optimum diag-
nostic yield most efficiently.
For many genetic syndromes the
next stage in research after the identifica-
tion of the gene involves describing the
phenotypic diversity produced by differ-
ent mutations in the same gene. In some
X linked syndromes such as Rett [Amir
and Zoghbi, 2000] and ATRX [Gibbons
and Higgs, 2000] syndromes the modu-
lating effect of X inactivation status on
the female phenotype also has to be taken
129
into account [Van den Veyver, 2001].
Studying the relationship between geno-
type and phenotype is a new role for the
clinical epidemiologist. In such studies it
will be important to take into account
the confounding effects of age and other
nongenetic influences on the phenotype.
Population-based registers such as that in
Australia for Rett syndrome provide an
excellent source of cases for such studies
[Leonard et al., 2000a] but unfortunately
such registers rarely exist for other syn-
dromes. Cases tend to be selected for
study based only on clinic referral pat-
terns and may not be representative of
the underlying population of affected
subjects.
A recent breakthrough in the eti-
ological investigation of MR is the find-
ing of raised levels of specific neuropep-
tides and neurotrophins in neonatal
blood spots of children with MR and
autism [Nelson et al., 2001a]. The pat-
tern of elevation was similar for childen
with MR and autism and different from
controls and children with CP. Vasoac-
tive intestinal peptide was the analyte
which most clearly discriminated chil-
dren with MR or autism from controls.
This innovative research took advantage
of available stored Guthrie blood spots
whilst reports of placental pathology can
also provide useful information for etio-
logical research [Viscardi and Sun, 2001].
Thus it is also important for epidemiol-
ogists to branch out and explore fresh
data sources in the new millennium.
ADDITIONAL
METHODOLOGICAL
CHALLENGES AND THE USE
OF RECORD LINKAGE
The source of data used by Alber-
man et al. [1992] for DS in their study of
future trends in severe learning disabiity
was a national register [Mutton et al.,
1991]. Through a similar mechanism we
have studied survival [Leonard et al.,
2000b], functioning [Leonard et al.,
2001], morbidity and use of health ser-
vices for the Western Australian DS
childhood population [Leonard and
Fletcher, 1999]. When such registers ex-
ist, longitudinal data on these individual
disorders can be collected, providing the
necessary information to predict trends
and allowing good epidemiological stud-
ies to be performed. One of the few
other syndromes in which the epidemi-
ology has been well studied is Rett syn-
drome [Kozinetz et al., 1993; Leonard et
al., 1997; Hagberg and Hagberg, 1997].
The Australian register allows us to col-
lect an equivalent range of data for Rett
syndrome as we have in DS. It was as-
130 MRDD RESEARCH REVIEWS
sisted by the establishment in Australia of
a unit [Gazarian et al., 1999], based on
the British Paediatric Surveillance Unit
[Hall and Roberts, 1993] and designed to
facilitate research into rare childhood dis-
orders. In addition to Rett syndrome,
several other pediatric disorders causing
or with the potential to cause MR, such
as Prader Willi syndrome, fetal alcohol
syndrome, congenital CMV, congenital
rubella, neonatal herpes simplex virus in-
fection, invasive haemophilus influenzae
infection, HIV infection and AIDS, are
or have been studied using this mecha-
nism [Australian Paediatric Surveillance
Unit, 2001]. Systems such as these have a
vital role in the epidemiology of disor-
ders causing MR. Equally important,
however, is an ethic amongst clinicians
that values the importance of supporting
the collection of population-based data
for rare disorders. As the use of informa-
tion technology has exploded over the
last decade, bioinformatics has developed
as a new discipline. It provides significant
opportunities for the study of conditions
which are individually rare and may re-
quire the pooling of international data to
provide adequate sample size. Harnessing
web-based technology both in the col-
lection and appropriate dissemination of
information relating to MR is an exciting
opportunity. Plans are underway to col-
lect both molecular and clinical data on
Rett syndrome on an international basis
by modelling the system already being
used for phenylketonuria [Phenylalanine
Hydroxylase Locus Knowledgebase].
However, such advances will not be
without their challenges especially as
identifiers are required when linking in-
formation from different sources [Kruse
et al., 2001].
Boussy and Scott [1993] have pro-
vided a detailed overview of the applica-
tion of record linkage to the investigation
of MR. In a recent study using record
linkage by Croen et al. [2001] the infant
and maternal characteristics available
were limited to birth weight, plurality
and birth order. In Western Australia
there is a unique system of linked data-
bases relating to births, deaths, hospital
morbidity and childhood disability [Stan-
ley et al., 1997]. These data relating to
births since 1980 are stored as the Mater-
nal and Child Health Research Database.
The specific linkage of these data to a
comprehensive database of medical and
demographic information on children
and adults with MR [Bower et al., 2000]
provides a unique mechanism for etio-
logical investigation of MR. It is note-
worthy however that Gissler et al. [1998]
stressed the need for researchers to be
● EPIDEMIOLOGY OF
proactive in communicating the impor-
tance of health registers and linked data
projects to epidemiological research. In
particular it is imperative to ensure that
the public is educated about the benefits
of epidemiological research and the issue
of the impracticablility of gaining consent
for large record linkage studies [Holman
2001].
As acknowledged by Louhiala
[1995], whose study attempted to exam-
ine changes in risk factors over time,
there are as many methodological prob-
lems associated with the etiological in-
vestigation of MR as there are with its
definition. Use of multiple sources, as
others and we have done, helps to opti-
mize ascertainment. As raised by Drews
et al. [1995] the likely dependence on
prevalence rather than incidence data as a
source of cases is a particular difficulty for
etiological investigation. There may be
differential loss due to migration and to
mortality. In an earlier Finnish study in-
volving a cohort of 12,000 children fol-
lowed till the age of 14 years [Rantakallio
and von Wendt, 1985] this was over-
come by comparing risk factors for MR,
CP, epilepsy and death with those of
healthy children. As a clear overlap be-
tween the etiological determinants of
MR and neonatal and childhood death is
biologically plausible, this issue certainly
needs to be taken into consideration. A
further issue is that MR tends to be stud-
ied as a dichotomous variable whilst in
reality children with IQs in the range
70 –75 are likely to share similar risk fac-
tors to those with an IQ of 65– 69. And
only the latter would be regarded as
cases. In etiological investigations it
might be preferable, where feasible, as
done recently by Matte et al. [2001] to
treat IQ as a continuous variable.
CONCLUSION
In summary, there is established
evidence that the prevalence of MR does
differ by gender, maternal race, socioeco-
nomic and educational status and is in-
fluenced by birthweight, although the
size of the effect has varied among stud-
ies. On the other hand, the positive re-
lationships between MR and both ma-
ternal smoking and maternal urinary tract
infection have only been reported in a
small number of studies [Drews et al.,
1996; Camp et al., 1998; McDermott et
al., 2001]. These are nevertheless areas
where specific interventions could be
feasible. However a better preventive
strategy may be the improvement of the
social milieu surrounding the occurrence
of such risk factors. The determination of
attributable risks for individual factors can
MENTAL RETARDATION ● LEONARD & WEN
help project the number of children
likely to be affected by MR in given
populations and hence allow the appro-
priate planning of support, accommoda-
tion, educational and medical services. In
tandem with the ability to project future
needs, it is very important to aim to
establish mechanisms by which temporal
trends can be measured. Keeping case
definitions, ascertainment sources and
methods constant will allow prevalence
to be measured over time so that the
effects of changing and competing influ-
ences can be monitored. Only if we are
able to do this can the complete cycle of
a “prevention—intervention—research”
sequence actually occur.
To implement this important “pre-
vention—intervention—research” cycle,
which surely underpins the role of epi-
demiology in MR, it will be necessary to
address all the important methodological
issues we have raised. It is clear that use of
multiple sources and record linkage are
efficient strategies in this process. How-
ever, the next step may be to establish
systems which allow linkages across gen-
erations and jurisdictions [Chapman and
Scott, 2001]. Such research processes will
have the capacity to identify the inter-
generational risk factors, which impact
on child disadvantage and indicate how
we can use social policy to intervene.
This sort of intersectoral collaboration is
essential both in understanding the deter-
minants of MR as well as in the provision
of the most appropriate and cost effective
services to these children and their fam-
ilies. Thus many of the research questions
needing to be answered in relation to
MR fit well within the scope of the new
disciplines of both social and genetic ep-
idemiology. There are exciting opportu-
nities ahead to make major inroads into
this field-opportunities that must not be
missed whilst grappling with the meth-
odological challenges we have raised. f
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