Gestational age at birth and risk of intellectual disability without a common genetic cause
European Journal of Epidemiology
Gestational age at birth and risk of intellectual disability without a common genetic cause
Hein Heuvelman 0 1 2 3 4 5 6
Kathryn Abel 0 1 2 3 4 5 6
Susanne Wicks 0 1 2 3 4 5 6
Renee Gardner 0 1 2 3 4 5 6
Edward Johnstone 0 1 2 3 4 5 6
Brian Lee 0 1 2 3 4 5 6
Cecilia Magnusson 0 1 2 3 4 5 6
Christina Dalman 0 1 2 3 4 5 6
Dheeraj Rai 0 1 2 3 4 5 6
Stockholm Youth Cohort 0 1 2 3 4 5 6
0 Susanne Wicks
1 Kathryn Abel
2 & Hein Heuvelman
3 Christina Dalman
4 Cecilia Magnusson
5 Edward Johnstone
6 Renee Gardner
Preterm birth is linked to intellectual disability and there is evidence to suggest post-term birth may also incur risk. However, these associations have not yet been investigated in the absence of common genetic causes of intellectual disability, where risk associated with late delivery may be preventable. We therefore aimed to examine risk of intellectual disability without a common genetic cause across the entire range of gestation, using a matched-sibling design to account for unmeasured confounding by shared familial factors. We conducted a population-based retrospective study using data from the Stockholm Youth Cohort (n = 499,621) and examined associations in a nested cohort of matched outcomediscordant siblings (n = 8034). Risk of intellectual disability was greatest among those born extremely early (adjusted OR24 weeks = 14.54 [95% CI 11.46-18.44]), lessening with advancing gestational age toward term (aOR32 weeks = 3.59 [3.22-4.01]; aOR37 weeks = 1.50 [1.38-1.63]); aOR38 weeks = 1.26 [1.16-1.37]; aOR39 weeks = 1.10 [1.04-1.17]) and increasing with advancing gestational age post-term (aOR42 weeks = 1.16 [1.08-1.25]; aOR43 weeks = 1.41 [1.21-1.64]; aOR44 weeks = 1.71 [1.34-2.18]; aOR45 weeks = 2.07 [1.47-2.92]). Associations persisted in a cohort of matched siblings suggesting they were robust against confounding by shared familial traits. Risk of intellectual disability was greatest among children showing evidence of fetal growth restriction, especially when birth occurred before or after term. Birth at nonoptimal gestational duration may be linked causally with greater risk of intellectual disability. The mechanisms underlying these associations need to be elucidated as they are relevant to clinical practice concerning elective delivery around term and mitigation of risk in post-term children.
Intellectual disability; Post-term birth; Gestational age; Siblings
Extended author information available on the last page of the article
Intellectual disability is a group of developmental disorders
evident early in childhood and characterized by cognitive
and functional impairments as a result of delayed or
incomplete development of the mind [
]. Individuals with
intellectual disability have a reduced ability to understand
new or complex information and to learn and apply new
skills, resulting in a reduced ability to cope independently
]. Intellectual disability is thought to affect over 1% of
the population [
] although estimates vary with the
demographic and socioeconomic composition of study
] and with definitions and study design
]. The cost of intellectual disability to individuals and
society is substantial  and people living with these
disabilities often face significant stigma [
encountering substantial health and social inequalities and early
Although there are many risk factors, a specific cause is
identified for less than half of those with mild disabilities
(IQ range 50–69) who make up the majority of cases
]. Mild intellectual disability often clusters within
families  suggesting that genetic or other shared
familial factors may influence risk. When disabilities are
more severe, specific causes are identified in over 75% of
cases, often involving genetic or chromosomal
abnormalities and inborn errors of metabolism [
intellectual disability is present without a specific genetic or
chromosomal cause, it is associated with advanced
maternal age, maternal risk behaviors or medical problems
during pregnancy and fetal growth restriction [
suggesting that these may be risk factors.
While it is known that children born preterm (\ 37
completed weeks) are at greater risk of intellectual
disability than those born at term [
], less is known about the
development of risk along the gestational course, or about
risk among post-term children ([ 41 weeks). An early
smaller study found no difference in intelligence between
children born at term or post-term, although it was limited
in terms of statistical power and length of follow-up [
More recent, larger, studies have suggested post-term birth
may be associated with a range of adverse neurological,
developmental, behavioural and emotional outcomes in
early childhood [
] and there is increasing evidence to
suggest it is associated with cognitive and academic
deficits in later childhood and adolescence [
when the baby is growth-restricted [
The association between the full range of gestational
duration, from very early to very late births, and
intellectual disability has not yet been examined in
populationbased studies. Furthermore, the evidence to date is
insufficient because of incomplete control of confounding from
shared familial factors and insufficient recognition that
genetic causes of intellectual disability may also influence
gestational duration [
Therefore, in a large Swedish population-based cohort,
we aimed to: (1) examine the associations between
gestational age and intellectual disability without a common
genetic cause, taking into account a range of potential
confounders; (2) examine interactions between gestational
duration and fetal growth in relation to risk of intellectual
disability; and (3) explore the causal nature of associations
between gestational duration and risk of intellectual
disability in a nested cohort of matched outcome-discordant
The Stockholm Youth Cohort is a register-based cohort of
all individuals who lived in Stockholm County for at least
1 year between 2001 and 2011 and were aged between 0
and 17 years during that period (n = 736,180) [
unique personal identification numbers, cohort members
and their first-degree relatives were linked with a range of
national and regional registers including information on
pregnancy- and birth related characteristics, socioeconomic
characteristics and medical and psychiatric diagnoses.
We excluded individuals with genetic and inborn
metabolic syndromes who had been diagnosed with
intellectual disability (13.6% of cases in our study population),
children born outside Sweden, multiple births, adoptees,
children \ 4 years of age by the end of follow up on the
31st of December 2011, with a missing link to biological
parents, or with missing data on gestational age or other
covariates (Fig. 1). To account for potential recording
errors, we excluded individuals with improbable birth
weights (\ 350 g or [ 6000 g) and those with improbable
combinations of birth weight and gestational age by
deleting observations with values smaller than the 25th
percentile minus 3 interquartile ranges, or larger than the
75th percentile plus 3 interquartile ranges, from sex- and
week-specific birth weight distributions (Table S8) [
This left a cohort of 499,621 individuals to examine
population-level associations between gestational age and
intellectual disability. To examine associations among
matched siblings, we excluded individuals without full
siblings in the cohort and families with
outcome-concordant offspring (n = 491,587) leaving a cohort of 8034
matched outcome-discordant full siblings.
Born alive between January 1st 1984 and December 31st 2011 (n=736,180) 1
Those with gene c or inborn metabolic errors who also had
intellectual disability (n=1,054 [13.6% of ID cases])
Child with missing data on gesta onal age due to being born
outside Sweden (n=72,463)
Mul ple births, adoptees and children aged <4 years on
December 31st 2011 (n=130,715)
Missing link to biological parents (n=7,171)
Missing on gesta onal age (n=21,779)
Missing data on covariates (n=3,117)
Population-level analysis n=499,621 (nID=5,069)
Improbable weight (n=17) or weight-for-gesta onal age (n=243)
Matched outcome-discordant sibling comparison of
n=8,034 children born to n=3,199 mothers
Individuals without full siblings in the cohort and families with
outcome-concordant offspring (n=491,587)
We obtained information on gestational age at birth from
the Medical Birth Register (MBR), constructing a
categorical variable to define extremely to very preterm births
(21–31 completed weeks), moderately to late preterm
births (32–36 weeks), term births (37–41 weeks),
postterm births (42 weeks) and very post-term births
(43–45 weeks) for use in descriptive statistics and as an
exposure variable in regression analyses. We also used a
continuous definition of gestational age (in days) for
We used a multisource ascertainment approach to identify
cohort members with intellectual disability, similar to the
case identification for autism described elsewhere [
used the national patient register, the Stockholm county
child and adolescent mental health register, the Stockholm
County healthcare database (VAL) and the Stockholm
adult psychiatric register to identify all inpatient or
outpatient diagnoses of intellectual disability recorded using
ICD-10 (F70-79) and DSM-IV (317-318) codes and
supplemented these diagnoses with a record of care at
specialist habilitation services for individuals with intellectual
disability in Stockholm County. We identified individuals
with genetic defects and inborn errors of metabolism
commonly associated with intellectual disability to identify
cases where a known genetic or metabolic cause was
present (Table S1).
To control for secular change in obstetric and diagnostic
practice, we obtained year of birth from the Medical Birth
Register (MBR). We then identified additional covariates
which in the literature have been associated with pregnancy
duration and risk of intellectual disability in offspring.
From the MBR, we extracted data for offspring sex [
parity (1/2/3/4 ?) [
], maternal age (\ 20/20–24/
25–29/30–34/35–39/40–44/45 ?) [
] and gestational hypertension or
]. We obtained birth weights  from
the MBR to construct a measure of weight-for-gestational
age by examining week- and sex-specific birth weight
distributions, and identifying those in the lower and upper
deciles of these distributions as born small or large for
gestational age respectively. Weight-for-gestational age is
therefore conceptualized as the distance between the birth
weight of an individual and the average birth weight of all
who were born in the same gestational week as that
individual. As weight-for-gestational age is orthogonal to
gestational age itself, this avoids the issue of collinearity
when the measure is included as a covariate in the
analytical model. To examine potential interactions between
gestational age and weight-for-gestational age, we
constructed a categorical measure to identify those born
preterm (\ 37 weeks) and small for gestational age,
appropriate for gestational age (11th centile to 90th centile)
or large for gestational age; those born at term
(37–41 weeks) and small, appropriate or large for
gestational age; and those born post-term (C 42) and small,
appropriate or large for gestational age. We also extracted
information for maternal and paternal country of birth
(Sweden/other Nordic/other European/Russia or Baltic
States/Africa/Middle East/Asia or Oceania/North America/
South America) [
], maternal and paternal history of
psychiatric treatment [
], quintiles of disposable
family income adjusted for inflation and family size
], and parental educational attainment (B 9 years/
10–12 years/C 13 years) [
] at (or as close as possible
Analyses were conducted in Stata/MP version 14.2. We
examined the characteristics of the study cohort by
gestational duration at birth. To examine population-level
associations between gestational duration and risk of
intellectual disability, we used generalized estimating
equation (GEE) multivariable regression models with a
logit link function, exchangeable correlation structure and
robust variance estimators to ensure that the standard errors
of our estimates were robust against clustering of
intellectual disability within families [
]. We calculated
restricted cubic regression splines based on five knot
locations (5th, 27th, 50th, 73rd and 95th percentiles of the
gestational age distribution) to allow for non-linear
associations between continuously varying gestational duration
and later risk of intellectual disability [
]. We statistically
adjusted our estimates for covariates and calculated odds
ratios by continuously varying gestational age at birth to
estimate risk of intellectual disability associated with birth
at specific moments along the gestational course. We
investigated potential interactions between gestational age
and fetal growth using GEE models with a categorical
exposure variable to assess risk of intellectual disability
among those born at varying gestational duration (preterm/
term/post-term) and weight for gestational age
(small/appropriate/large) with statistical adjustment for confounders.
In a nested cohort of matched outcome-discordant
siblings we examined associations between continuously
varying gestational age and risk of intellectual disability
with conditional likelihood logistic regression models. This
allowed us to explore the potential influence of unobserved
familial traits, e.g. residual genetic risk/unmeasured
socioeconomic factors/parental health behaviors, which
may have confounded associations between gestational
length and risk of intellectual disability. If we were to
observe associations at the population level,
non-association within families would suggest confounding by these
shared familial traits. Conversely, replication of
population-level associations within families would suggest they
were robust against shared familial confounding, thereby
allowing stronger causal inference from our result [
statistically adjusted within-family associations for
nonshared confounding characteristics including sex, parity,
gestational diabetes, hypertension or preeclampsia, weight
for gestational age, maternal and paternal age, disposable
family income quintile, and parental educational
We compared characteristics for those with missing and
complete data to assess whether our estimates may have
been affected by selection bias (Table S2). To ensure that
the association between gestational age and intellectual
disability was not driven by presence of co-occurring
autism spectrum disorder or attention deficit hyperactivity
disorder (which are associated with intellectual disability
] and for which risk may also vary by gestational
]) we examined associations in a subset of the
cohort without a record of these conditions (Figure S1 and
Prevalence of intellectual disability without a common
genetic cause was estimated at 1% in our study population
(Fig. 1). Characteristics of the study cohort are described in
Table 1. Prevalence among those born at term gestation
was 0.9%. By contrast, 5.6% of children born extremely to
very preterm and 1.6% of those born very post-term had
Examining associations between gestational duration and
risk of intellectual disability in a model using a continuous
exposure variable with statistical adjustment for potential
confounders (Fig. 2), the adjusted odds ratio (aOR) for risk at
extremely preterm birth (at 24 weeks) was estimated at 14.54
[95% CI 11.46–18.44]. This risk decreased with gestational
age towards term (aOR32 weeks = 3.59 [3.22–4.01];
aOR37 weeks = 1.50 [1.38–1.63]; aOR38 weeks = 1.26
[1.16–1.37]; aOR39 weeks = 1.10 [1.04–1.17]) after which it
increased with gestational age post-term (aOR42 weeks =
1.16 [1.08–1.25]; aOR43 weeks = 1.41 [1.21–1.64];
aOR44 weeks = 1.71 [1.34–2.18]; aOR45 weeks = 2.07
We report associations using a categorical exposure
variable in an online supplement (Table S7). Irrespective of
gestational length, risk of intellectual disability was
greatest among those showing evidence of fetal growth
restriction (Table 2).
This difference was most pronounced in the preterm
group, but our results suggest risk of intellectual disability
was also increased among children born post-term and
growth-restricted. Associations between gestational length
and risk of intellectual disability persisted when we
repeated our analysis in a nested cohort of
outcome-discordant siblings (Fig. 3, Table S7).
In a subset of the cohort without a diagnosis of ASD or
ADHD, pre- and post-term birth remained associated with
increased risk of intellectual disability (Figure S1,
Table S3). Among those born at 21–31 completed weeks of
gestation, risk of intellectual disability was lesser when the
baby was delivered by Caesarean section, while Caesarean
birth was associated with greater risk than vaginal birth
between 37 and 41 weeks gestation (Table S4). There was
no consistent variation in risk due to unassisted versus
assisted delivery within gestational age categories
(Table S5). Importantly, risk of intellectual disability
associated with early or late birth remained when
considering those born in vaginal or unassisted deliveries
(Tables S4 and S5). Among those born between 37 and
41 weeks, risk of intellectual disability was greater when
birth was induced (Table S6). This effect existed
independently of the influence of fetal growth restriction or
other potential confounders. Finally, children born in
induced post-term deliveries were at greater risk of
intellectual disability than children born spontaneously at term,
while the increase in risk associated with spontaneous
postterm birth was lesser (Table S6).
In this large population-based study, we found a greater
risk of intellectual disability without a common genetic
cause among preterm and post-term births compared with
term births. Risk also varied within the term period and
was lowest when the child was born at 40–41 completed
weeks’ gestation. These associations were evident in
analyses using the full sample, as well as in a nested cohort
of matched outcome-discordant siblings. Risk of
intellectual disability was greatest among those showing evidence
of fetal growth restriction, especially when born before or
after term. To our knowledge, this is the first
total-population study to estimate risk of intellectual disability
without a common genetic cause over the entire range of
gestation using high-quality prospectively measured data.
In addition to a range of measured confounders, this study
explored the influence of unmeasured familial effects using
a matched sibling design. This allowed us to take into
account unmeasured familial confounding of the
association between intellectual disability and gestational length,
as these traits are heritable within families [
10, 41, 42
There were several limitations. First, 5% of the study
cohort had missing data on gestational age at birth or other
covariates. Although we cannot know with certainty how
these exclusions may have affected our result, sensitivity
analyses suggest that our estimates may have been
conservative as we may have excluded preterm children with
higher prevalence of intellectual disability (Table S2).
Second, we did not have information on whether
gestational length was calculated by the mother’s report of her
last menstrual period or based on ultrasound measurement
in specific pregnancies. As our sample includes births from
1984 onwards, it is likely that there is greater measurement
error in earlier cohort years, where gestational length
would have been estimated by last menstrual period for a
larger proportion of pregnancies. This may have resulted in
overestimation of rates of post-term birth [
underestimation of population-level [
] and within-family
] between gestational length and later risk
of intellectual disability. Third, while the matched-sibling
design provides a powerful method to examine the
influence of shared confounding, it is more sensitive than
traditional methods to confounders not perfectly shared by the
siblings. Selection based on exposure-discordance could
also prompt discordance in terms of non-shared
confounding characteristics, which may bias the within-family
]. The size and direction of such bias depends on
the similarity or dissimilarity of matched siblings in terms
of exposure and confounding characteristics [
that measurement error in the gestational age variable
would have downwardly biased our estimate of the
withinGestational durationa/weight-for-gestational age
Percentage of the cohort
aPreterm was defined as birth \ 37 completed weeks of gestation. Term birth was defined as birth between 37 and 41 completed weeks of
gestation. Post-term birth was defined as birth at C 42 completed weeks of gestation
bFetal growth categories were defined as small-for-gestational age [in the lowest decile of the gestational age-specific birthweight distribution],
appropriate-for-gestational age [in the 11th to 90th decile of the gestational age-specific birthweight distribution] and large-for-gestational age [in
the upper decile of the gestational age-specific birthweight distribution]
cPopulation-level associations were estimated using a generalized estimating equations model with a logit link, and adjusted statistically for year
of birth, child sex, parity, gestational hypertension or preeclampsia, gestational diabetes, maternal and paternal age, maternal and paternal
psychiatric history, maternal and paternal country of birth, family disposable income quintile at birth, and parental educational attainment at birth
dNumber and percentage of ID cases within gestational duration/fetal growth category
eNumber of observations within gestational duration/fetal growth category
fN = 499,621
family effect, additional bias due to sibling non-shared
confounding would have either offset this downward bias
or further enhanced it. Fourth, there may be bias due to
omitted non-shared confounding characteristics in our
matched sibling analyses. For example, it is possible that
prenatal infection [
], maternal obesity [
], or use of
drugs or alcohol  may have influenced gestational
length and resulted in greater risk of offspring intellectual
disability in as far as these factors were present in one
pregnancy but not the other.
The mechanisms underlying our findings are likely to
differ depending on whether birth occurred before or after
the due date. With regards to preterm birth, perturbations in
development of the fetal brain because of shortened
gestation can increase risk for longer-term
neurodevelopmental problems [
]. Our findings for preterm
smallfor-gestational age children would suggest that these
effects might become particularly apparent if the fetus is
already growth-restricted. After birth, further injury to the
brain could result from respiratory support for preterm
infants with immature pulmonary function .
Mechanisms linking post-term birth with later risk of intellectual
disability might involve placental deterioration or
insufficiency causing fetal hypoxia or nutritional deficiencies
], which in turn could result in injury to the fetal brain.
Meconium aspiration, which is more common in post-term
], may result in neonatal asphyxia thereby
incurring risk for brain injury and later neurodevelopmental
Our finding of associations among those born in
unassisted or vaginal deliveries suggested that adverse obstetric
circumstances did not explain the higher risk of intellectual
disability associated with birth at \ 37 or [ 42 weeks.
Furthermore, our findings suggest that risk of intellectual
disability increases with induction of labor at further
postterm gestation, although these estimates are likely to be
biased by the higher risk nature of induced pregnancies as a
whole (Table S6). Risk of intellectual disability may have
also increased with advancing post-term gestational age
when delivery started spontaneously, although our data
may have been underpowered to detect these subtler effects
(Table S6). Importantly, due to the observational nature of
our study, and given that the decision to induce labor will
be informed by other factors than gestational length alone,
we cannot infer from our data whether the risks associated
with post-term delivery could be curtailed by induction of
labor around term. This question will therefore be better
answered by randomized studies designed specifically for
the purpose of comparing outcomes of children induced at
late term with those born post-term by expectant
]. Finally, the generalisability of our findings may
vary with regional differences in practice regarding the
management of pre- or post-term pregnancy and in the
quality of obstetric and neonatal care.
Our findings are consistent with other studies examining
risk of cognitive deficit in relation to birth before or after
term gestational duration [
12, 16–19, 58–64
]. These studies
suggest there may be increased risk of intellectual
], special educational needs [
17, 62, 63
poorer performance in school [
12, 18, 58, 60, 63
] and lower
IQ in childhood [
] or adulthood [
children are born before or after term. Furthermore, our
findings are consistent with those of other studies
investigating variation within the term period and reporting that
birth at 40–41 weeks’ gestation was optimal in relation to
IQ scores at age six [
], risk of special educational needs
in primary or secondary school [
], and end-of-secondary
school performance outcomes [
]. The independent risk
of intellectual disability associated with being born
smallfor-gestational age is consistent with earlier studies
examining other outcomes for fetal growth-restriction in
infants born at preterm or post-term gestational duration
16, 58, 65, 66
In conclusion, our findings suggest that delivery at
nonoptimal gestational age is associated with greater risk of
intellectual disability in offspring in the absence of
common genetic causes. This association existed independently
of a range of measured potential confounders as well as
unmeasured confounding from shared familial factors.
While this study cannot provide conclusive evidence for
causality, our use of a matched sibling design helped to
address confounding due to unmeasured shared familial
factors, thereby providing a better estimate of the causal
effect than in studies using traditional methods for dealing
with confounding. As birth at non-optimal gestational
duration may be linked causally with greater risk of
intellectual disability, it is important that the mechanisms
underlying these associations are elucidated because of
their relevance to clinical practice concerning elective
delivery within the term period and the mitigation of risk in
children who are born post-term. Our work highlights the
need for randomized controlled studies to establish whether
offspring neurodevelopmental outcomes would improve if
women in post-term pregnancies were routinely induced.
Acknowledgements This work was supported by the Baily Thomas
Charitable Fund [TRUST/RNA/AC/KW/3115/5780]. This work was
also supported by the NIHR Biomedical Research Centre at the
University of Bristol. The funders had no role in study design, data
collection and analysis, decision to publish, or preparation of the
manuscript. All views expressed in this paper are of the authors and
not necessarily of the funders or the organisations they represent.
Compliance with ethical standards
Conflict of interest statement The authors declare having no
Ethical approval Ethical approval for this study was granted by the
research ethics committee at Karolinska Institute [2010/1185-31/5
and 2013/1118-32], allowing record linkage without personal consent
when the confidentiality of the individuals is maintained. The
personal identity of participants was replaced with a serial number before
the research group were given access to these data.
Open Access This article is distributed under the terms of the Creative
Commons Attribution 4.0 International License (http://creative
commons.org/licenses/by/4.0/), which permits unrestricted use,
distribution, and reproduction in any medium, provided you give appropriate
credit to the original author(s) and the source, provide a link to the
Creative Commons license, and indicate if changes were made.
Centre for Academic Mental Health, Population Health
Sciences, Bristol Medical School, University of Bristol,
Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK
Centre for Women’s Mental Health, Manchester Academic
Health Sciences Centre, Institute of Brain Behaviour and
Mental Health, University of Manchester, 3rd Floor Jean
McFarlane Building, Oxford Road, Manchester M13 9PL,
Manchester Mental Health and Social Care Trust, Chorlton
House, 70 Manchester Road, Manchester M21 9UN, UK
Department of Public Health Sciences, Karolinska Institutet,
171 77 Stockholm, Sweden
Centre for Epidemiology and Community Medicine,
Stockholm County Council, 171 29 Solna, Sweden
Maternal and Fetal Health Research Centre, Manchester
Academic Health Sciences Centre, Institute for Human
Development, University of Manchester, St Mary’s Hospital,
Oxford Road, Manchester M13 0WL, UK
Department of Epidemiology and Biostatistics, A.J. Drexel
Autism Institute, Drexel University School of Public Health,
Philadelphia, PA, USA
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