Journal of Autism and Developmental Disorders

https://doi.org/10.1007/s10803-019-04235-2

ORIGINAL PAPER

Association Between Prematurity and Diagnosis of Neurodevelopment

Disorder: A Case–Control Study
Thaise C. B. Soncini1,2 · Gabriella Antunes Belotto3 · Alexandre P. Diaz4

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Abstract
The aim of this study is to investigate the association between prematurity and diagnosis of neurodevelopmental disorders
(ND) (attention deficit/hyperactivity disorder [ADHD] or autism spectrum disorder [ASD]) in Brazilian children and ado-
lescents. Case–control study based on medical records data from a specialized outpatient clinic. Prematurity was defined as
gestational age less than 37 weeks. Prematurity was independently associated with diagnosis of a ND (adjusted odds ratio
[AOR] 3.46, 95% CI 1.15 – 7.92), as well as with ADHD and ASD diagnosis after a multiple logistic regression analysis.
These findings from Brazilian patients are related to what is found in the literature worldwide. Efforts to modify risk factors,
such as prematurity, may impact incidence reduction of both ADHD and ASD.

Keywords  Neurodevelopmental disorders · Attention deficit disorder with hyperactivity · Autism spectrum disorder ·
Infant · Premature

Introduction The worldwide prevalence of ADHD is estimated at about

Among the psychiatric disorders generally diagnosed in
childhood and adolescence, neurodevelopmental disorders,
including autistic spectrum disorders (ASD) and attention
deficit/hyperactivity disorder (ADHD) (American Psychi-
atric Association 2013), have, in addition to an early age at
onset, significant functional impairment and family burden
(Faraone et al. 2015; Woolfenden et al. 2012).
* Alexandre P. Diaz
alexandrepaimdiaz@gmail.com
Thaise C. B. Soncini
thaisesoncini@hotmail.com
Gabriella Antunes Belotto
gabiiejba@gmail.com
1
Médica Pediatra, Maternidade Carmela Dutra, Florianópolis,
Santa Catarina, Brazil
2
Programa de Pós-graduação em Ciências da Saúde
da Universidade do Sul de Santa Catarina, Palhoça,
Santa Catarina, Brazil
3
Faculdade de Medicina, Universidade do Sul de Santa
Catarina, Palhoça, Santa Catarina, Brazil
4
Médico Psiquiatra, Hospital Universitário da Universidade
Federal de Santa Catarina, Rua Maria Flora Pausewang S/N,
Florianópolis, Santa Catarina CEP 88040‑900, Brazil
3.4% (Polanczyk et al. 2015) and most children will be diag-
nosed as adults (Faraone et al. 2015). It affects more boys
than girls (ratio of approximately 2.4:1) with a similar pro-
portion between the sexes in adulthood (Faraone et al. 2015).
In addition, in the long run it has been related to losses in the
marital relationship, separation, divorce, and legal problems,
such as seizures and imprisonment. Individuals with ADHD
also have a higher risk of using psychoactive substances and
early mortality (Faraone et al. 2015).
ASD has a prevalence of approximately 0.8%, which is
three times more common in males than in females. The
age of onset is generally before 5 years (Baxter et al. 2015).
Diagnostic classification is characterized by “persistent
deficits in social communication and in social interaction
in multiple contexts” (American Psychiatric Association
2013). The economic burden associated with autism in a
US study was close to that related to ADHD and greater
than that associated with stroke and systemic arterial hyper-
tension (Leigh and Du 2015). In regards to ASD, a meta-
analysis identified that the risk of mortality in patients diag-
nosed with autism is about three times greater than that for
non-diagnosed individuals of the same age group and sex
(Woolfenden et al. 2012).
In addition to the similar economic cost, ASD and
ADHD have high comorbidity (Canals et al. 2018; Vohra

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et al. 2017), share genetic (Rommelse et al. 2010) and
environmental risk factors (Faraone et al. 2015; Modab-
bernia et al. 2017), and apparently have common patho-
physiology (Ameis et al. 2016).
Among the environmental risk factors, Bhutta et al.
(2002) reported in a meta-analysis that premature infants
had a relative risk of 2.64 for diagnosis of ADHD. Sciber-
ras et al. (2017) reviewed the literature in order to iden-
tify risk factors for the same diagnosis. The authors found
that prematurity, especially extreme prematurity, had the
largest effect size in association with ADHD , consider-
ing all other prenatal risk factors. In relation to ASD, a
meta-analysis analyzed pre, peri, and post variables as risk
factors. Among perinatal factors, gestational age less than
36 weeks was associated with a relative risk of 1.31 for
diagnosis of autism (Wang et al. 2017). During the fetal
period, the brain begins its development, when there is
intense synaptic action and myelination of the axons (Nel-
son et al. 2011). In the third trimester of pregnancy, there
is also a significant increase in brain volume (Anderson
et al. 2004) and premature labor can interrupt the adequate
evolution of these events. In addition, clinical complica-
tions, such as hypoxia, intraventricular hemorrhage, and
periventricular leukomalacia may alter the adequate for-
mation of the prefrontal cortex and the neural network
(Vicari et al. 2004), which possibly underlies the behav-
ioral signs and symptoms found in neurodevelopmental
disorders.
In Brazil, few studies have studied the association
between prematurity and neurodevelopmental disorders such
as ASD and ADHD. In a prospective study with 80 neonates
in the city of Rio de Janeiro-RJ, Espírito Santo et al. (2009)
found that nearly half had behavioral problems suggestive
of ADHD at 4–5 years of age. Murray et al. (2016) evalu-
ated 3749 4-year-old children by a cohort of live births out
of a total of 4231 newborns from 2004 in Pelotas-RS. The
evaluation included attentional problems measured by the
Child’s attention sub-scale of the Child Behavior Checklist
(CBCL) (Achenbach and Ruffle 2000). In this study, ges-
tational age of 28 weeks or less was significantly associ-
ated with impairment in attention at four years of age (odds
ratio [OR] 11.01), as well as gestational age between 32
and 37 weeks (OR 1.37) (Murray et al. 2015). However,
after adjustment for maternal, family, demographic, gesta-
tional and perinatal variables, prematurity was not signifi-
cantly associated with diagnosis of ADHD in the Pelotas
cohort (Murray et al. 2016). In a meta-analysis, which have
included the aforementioned study of Murray et al. (2016),
the only from a middle income country, Franz et al. (2018)
have evaluated the risk of ADHD in preterm and low birth
weight newborns. The results showed that the more extreme
the situation, higher the risk of ADHD: for those extremely
preterm/extremely low birth weight, the OR for ADHD was
13
Journal of Autism and Developmental Disorders
4.05, while for those very preterm and very low birth weight
the OR was 2.25.
In the Brazilian Multicenter Study on Preterm Birth,
Passini et al. (2010, 2014) have investigated the prevalence
and variables associated with preterm birth. In addition to
the high overall prevalence rate of prematurity birth (12.3%),
the authors have found differences regarding distinct regions.
For instance, while for the southeast the prevalence rate was
11.1%, in the northeast region of the country the prevalence
rate was 14.7%, which probably reflects contrasting health
and economic conditions between these regions (Passini
et al. 2014). Despite the significant prevalence of prema-
turity in Brazil, which places the country as one of the ten
with the highest number of preterm births in the year of 2010
(Blencowe et al. 2012), we did not find national studies that
investigated the association between this exposure and ASD.
The aim of this study is to investigate the association
between prematurity and diagnosis of neurodevelopmental
disorders in Brazilian children and adolescents. Also, we
explore whether the findings are similar for ADHD and ASD
diagnosis separately.
Methods
Study Design and Participants
Case–Control Study
The sample consisted of children and adolescents aged 2 to
12 years old who were followed at the Pediatrics Polyclinic
Service of the University of Southern Santa Catarina (Uni-
versidade do Sul de Santa Catarina – UNISUL) between
2012 and 2017. The Pediatrics Polyclinic Service is located
in the municipality of Palhoça in the state of Santa Catarina
- Brazil and attends to about 450 children a month in an
outpatient public health system.
For the sample size calculation, we considered an alpha
of 5% and 80% power for detecting an association with an
odds ratio (OR) of at least 2.33 (Murray et al. 2016). We
used prematurity’s prevalence in the Brazilian general popu-
lation of 9.2% (Blencowe et al. 2012). From these data, the
sample size required per group was 190 participants (Faul
et al. 2007).
The cases included participants at Neuropaediatrics and/
or Psychiatry Ambulatory of Childhood and Adolescence
of the Pediatrics Polyclinic Service with clinical diagnosis
of ADHD and/or ASD registered in medical records and
at least five medical appointments during a minimum of 2
years of follow-up.
Controls consisted of children or adolescents who were
followed up at the General Pediatrics outpatient unit of
the Pediatrics Polyclinic Service without a diagnosis of
Journal of Autism and Developmental Disorders
ADHD or ASD and also who had a minimum of 2 years of
follow-up.
Cases and controls were selected consecutively from the
most recent date of outpatient visit up to the total number of
participants according to the sample size.
Control patients with a medical record that had any of
the following search terms “isolation”, “little social inter-
action”, “agitation”, “hyperactivity”, “impulsiveness” or
“aggressiveness” were excluded from this study. Participants
were also excluded from the control group if their medical
records had at any time during follow-up a diagnostic record
or diagnostic suspicion of “mental retardation” or “intel-
lectual deficiency”.
The time of patients’ follow-up in the service for at least
2 years was established to increase the chance of: (1) iden-
tification by the physician of a possible neurodevelopmen-
tal disorder in the child or adolescent; (2) any behavioral
changes in the child or adolescent suggestive of ADHD or
ASD reported by parents or guardians.
Variables
Prematurity was considered as a newborn with less than
37 weeks of gestational age and birth weight categorized
from 2500 g. Sociodemographic variables collected included
maternal and paternal age at delivery, gender, parental mari-
tal status at time of data collection, and parental education
(categorized as primary/secondary or high/superior). In
addition to prematurity, gestational data included history of
gestational bleeding (as well as the trimester of gestational
bleeding), maternal infection, maternal hypertension, and
type of delivery (c-section or vaginal) and prenatal care.
Newborn characteristics consisted of cephalic perimeter,
Apgar score categorized from seven points, and history of
neonatal sepsis, neonatal seizure, cerebral hemorrhage, or
neonatal resuscitation. Breast-feeding was considered absent
if less than 3 months of duration. History of maternal smok-
ing, alcohol, or drug use and parents’ psychiatric history
were collected as clinical variables.
Procedures
Data collection occurred between 2017 July and October of
the same year and included sociodemographic, gestational,
newborn characteristics and clinical variables.
First, it was evaluated whether the participant had a his-
tory of at least 2 years of follow-up in the Pediatrics Poly-
clinic Service, in addition to a minimum of five visits. Par-
ticipants with diagnostic records of ASD and/or ADHD were
included in the “cases” group. Then, the medical records
of the cases were evaluated. All patient’s charts from the
neuropaediatrics and/or psychiatry ambulatory of childhood
and adolescence outpatient clinic with a diagnosis of ASD or
ADHD were selected. Records with absence of information
from at least one variable of interest were excluded. Cases
and controls were matched by gender.
Statistical Analysis
Data were tabulated and analyzed using the Statistical Pack-
age for the Social Sciences (SPSS), version 10.0. Qualitative
data were presented with relative and absolute frequencies
and quantitative data on measures of central tendency (mean
or median) and dispersion (standard deviation or interquar-
tile range), depending on normality of distribution, tested
according to the Kolmogorov–Smirnov test. Association
between outcome and exposure variables was tested using
the Chi square test (or Fisher’s exact test) and Student’s t test
(or Mann–Whitney, if non-parametric distribution) for cat-
egorical or continuous independent variables, respectively.
Those independent variables that presented with a probabil-
ity of association with the outcome with significance level of
less than or equal to 0.05 were included in a multiple logis-
tic regression model to evaluate adjustment of independent
effect of exposures on the outcome of interest. An associa-
tion after the final model of less than 0.05 was considered
statistically significant.
Results
In all, 380 children and adolescents were selected for the
study (190 cases and 190 controls). Among the cases, 313
medical records were evaluated. Of these, 3 participants’
guardian did not agree to participate in the study, in 11 diag-
nosis was not conclusive, and 109 medical records did not
have information for all variables according to our proto-
col. For the controls, 352 medical records were analyzed of
which 96 were excluded due to missing data, 64 because the
presented clinical history registered in the medical record
was within the exclusion criteria, and 2 because they did not
accept to participate in the study.
Among the cases, 77 (40.5%) had the diagnosis of ADHD
and 113 (59.5%) had ASD. 12 (6.3%) had a diagnosis of both
conditions. For the purpose of analysis, if both diagnosis
were present in the same child or adolescent (comorbidity),
we considered the main diagnosis recorded in the medical
record.
Regarding parental psychiatric history, within the cases,
57 participants had one (n = 44) or both (n = 6) parents with
a psychiatric disorder (for 7 of them, despite a positive
registry of psychiatric disorder in the medical report, the
diagnosis was not mentioned). The most registered psychi-
atric diagnosis in the parents of the cases were depression
(n = 26), bipolar disorder (n = 12) and ADHD (n = 7). Within
the controls, 10 participants had at least one parent with a
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 Journal of Autism and Developmental Disorders

psychiatric diagnosis, with depression and bipolar disorder association between prematurity and increased risk of psy-
the most frequent (n = 5 and n = 3, respectively). chiatric disorder at age 11 (OR 1.3, p = 0.04), in addition to
Table 1 shows the comparison between cases and controls a greater chance of diagnosis of mental disorder in the chil-
according to the investigated variables. Cases presented sig- dren of mothers who presented with depressive symptoms
nificantly higher frequency of not married parents (40% vs. during pregnancy. In this case, the risk was higher according
10.5%, p ≤ 0.001) and mothers with lower schooling (45.8% to severity of the psychiatric condition (high and chronic
vs. 34.7%, p = 0.03) (sociodemographic variables); higher symptomatology: OR 4.7, low-moderate symptomatology:
frequency of prematurity (17.9% vs. 6.3%, p ≤ 0.001), mater-
nal hypertension (14.2% vs. 5.8%, p = 0.006) (gestational
data); higher frequency of lower birth weight (13.7% vs. Table 1  Comparison between case (ADHD or ASD) and control par-
5.8%, p = 0.009) and higher frequency of exclusive breast- ticipants according to sociodemographic, gestational, newborn and
clinical characteristics
feeding for less than 3 months (42.6% vs. 30.5%, p = 0.01)
(newborn characteristics); higher frequency of alcohol use Variables Cases Controls p
(2.6% vs. 0; p = 0.02), illicit drugs (2.6% vs. 0; p = 0.02) and Sociodemographic
smoking (7.4% vs. 1.6%, p = 0.006) during gestation, as well  Male gender, n (%) 160 84.2 159 83.7 0.89
as higher history of psychiatric disorder in one of the parents  Maternal age, mean (SD) 26.7 6.1 27.0 7.0 0.63
(30% vs. 5.3%, p ≤ 0.001) (clinical variables) (Table 1).  Parental age, mean (SD) 30.8 8.0 30.1 7.9 0.41
Table 2 presents the comparisons with controls strati-  Marital status not married, n 76 40.0 39 10.5 ≤ 0.001
fied for each type of disorder. For participants diagnosed (%)
with ADHD, we found associations for the same variables,  Paternal education, n (%)
except for maternal schooling, hypertension during preg-   Primary/secondary 95 50.0 98 51.6 0.76
nancy, and breastfeeding time. However, the frequency of  Maternal education, n (%)
neonatal seizures in the cases was significantly higher when   Primary/secondary 87 45.8 66 34.7 0.03
compared to controls (2.6% vs. 0, respectively, p = 0.03). Gestational
For those diagnosed with ASD, there was also no associa-  Prematurity, n (%) 34 17.9 12 6.3 ≤ 0.001
tion with maternal schooling, birth weight, alcohol use, and  Gestacional bleeding, n (%) 45 23.7 45 23.7 ≤ 0.001
drug abuse compared to the analysis that included all cases.  Trimester of bleeding, n (%)
Tables 3, 4, and 5 illustrate multiple logistic regression   First trimester 30 66.7 32 71.1 0.84
analyses for neurodevelopmental disorders, ADHD, and   Second trimester 8 17.8 6 13.3
ASD, respectively. Prematurity and family history of psy-   Third trimester 7 15.6 7 15.6
chiatric disorders in parents had an independent association  Prenatal care, n (%) 189 99.5 190 100.0 0.32
with all three analyzed outcomes. Unmarried marital status  Number of visits, mean (SD) 5.9 0.6 5.8 0.7 0.66
and maternal smoking were also associated with diagnosis  Maternal infection, n (%) 48 25.3 44 23.3 0.63
of ADHD after multiple logistic regression (adjusted OR  Maternal hypertension, n (%) 27 14.2 11 5.8 0.006
2.69, p = 0.003 and adjusted OR 4.99, p = 0.03, respectively).  Delivery, n (%)
  C-section 94 49.5 91 47.9 0.76
  Vaginal 96 50.0 99 52.1
Discussion Newborn characteristics
 Birth weight < 2500 g, n (%) 26 13.7 11 5.8 0.009
In this study, prematurity was independently associated with  Cephalic perimeter, mean (SD) 34.1 1.9 34.5 1.7 0.08
diagnosis of neurodevelopmental disorders. The association  Apgar 5°min ≥ 7, n (%) 186 97.9 188 98.9 0.41
was maintained when the analysis was performed separately  Neonatal sepsis, n (%) 5 2.6 2 1.1 0.25
for the diagnoses of ADHD and ASD. In addition to pre-  Neonatal seizure, n (%) 3 1.6 0 0.0 0.08
maturity, a psychiatric family history in one of the parents  Cerebral hemorrhage, n (%) 1 0.5 0 0.0 0.32
was also associated with outcomes after multiple logistic  Neonatal resuscitation, n (%) 14 7.4 8 4.2 0.19
regression analysis.  Breast feeding < 3 months, n 81 42.6 58 30.5 0.01
In a cohort study conducted in the city of Pelotas-RS, (%)
La Maison et al. (2018) evaluated 3562 children at 11 years Clinical
of age from 4231 live births. In this study, 13.2% of ado-  Maternal smoking, n (%) 14 7.4 3 1.6 0.006
lescents had at least one psychiatric diagnosis according to  Alcohol use, n (%) 5 2.6 0 0.0 0.02
the fifth edition of the Diagnostic and Statistical Manual of  Illicit drug use, n (%) 5 2.6 0 0.0 0.02
Mental Disorders (DSM-5) (American Psychiatric Associa-  Parents’ psychiatric history, 57 30.0 10 5.3 ≤ 0.001
n (%)
tion 2013). In the adjusted analysis, the authors found an

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Journal of Autism and Developmental Disorders

Table 2  Stratified bivariate Variables ADHD p ASD p

analysis for each disorder
according to sociodemographic, No Yes No Yes
gestational, newborn and
clinical characteristics Sociodemographic
 Male gender, n (%) 160 (84.2) 59 (76.6) 0.14 160 (84.2) 100 (88.5) 0.30
 Maternal age, mean (SD) 27.0 (7.0) 27.0 (6.1) 0.82 27.0 (6.7) 26.4 (6.2) 0.47
 Parental age, mean (SD) 30.1 (7.9) 29.9 (7.7) 0.54 30.1 (7.8) 31.3 (8.1) 0.15
 Marital status not married, n (%) 39 (20.5) 33 (42.9) ≤ 0.001 39 (20.5) 43 (38.1) 0.001
 Paternal education, n (%)
  Primary/secondary 98 (51.6) 42 (54.5) 0.46 98 (51.6) 53 (46.9) 0.43
 Maternal education, n (%)
  Primary/secondary 66 (34.7) 35 (45.5) 0.10 66 (34.7) 52 (46.0) 0.05
Gestational
 Prematurity, n (%) 12 (6.3) 15 (19.5) 0.001 12 (6.3) 19 (16.8) 0.004
 Gestational bleeding, n (%) 45 (23.7) 18 (23.4) 0.96 45 (23.7) 27 (23.9) 0.97
 Trimester of bleeding, n (%) 0.92 0.81
  First trimester 32 (71.1) 13 (72.2) 32 (71.1) 17 (63.0)
  Second trimester 6 (13.3) 3 (16.7) 6 (13.3) 5 (18.5)
  Third trimester 7 (15.6) 2 (11.1) 7 (15.6) 5 (18.5)
 Prenatal care, n (%) 302 (99.7) 77 (100.0) – 190 (100.0) 112 (99.1) 0.19
 Maternal infection, n (%) 44 (23.2) 18 (23.4) 0.97 44 (23.2) 30 (26.5) 0.51
 Maternal hypertension, n (%) 11 (5.8) 9 (11.7) 0.10 11 (5.8) 18 (15.9) 0.004
 Delivery, n (%)
  C-section 91 (47.9) 41 (53.2) 0.43 91 (47.9) 53 (46.9) 0.87
  Vaginal 99 (52.1) 36 (46.8) 99 (52.1) 60 (53.1)
 Number of visits, mean (SD) 5.8 (0.7) 5.9 (0.5) 0.54 5.8 (0.7) 5.8 (0.6) 0.96
Newborn characteristics
 Birth weight < 2.500 g, n (%) 11 (5.8) 13 (16.9) 0.004 11 (5.8) 13 (11.5) 0.07
 Apgar 5° min ≥ 7, n (%) 188 (98.9) 74 (96.1) 0.12 188 (98.9) 112 (99.1) 0.69
 Neonatal sepsis, n (%) 2 (1.1) 3 (3.9) 0.12 2 (1.1) 2 (1.8) 0.63
 Neonatal seizure, n (%) 0 (0.0) 2 (2.6) 0.03 0 (0.0) 1 (0.9) 0.37
 Cerebral hemorrhage, n (%) 0 (0.0) 0 (0.0) – 0 (0.0) 1 (0.9) 0.37
 Neonatal resuscitation, n (%) 8 (4.2) 6 (7.8) 0.23 8 (4.2) 8 (7.1) 0.30
 Breast feeding < 3 months, n (%) 58 (30.5) 32 (41.6) 0.08 58 (30.5) 49 (43.4) 0.02
 Cephalic perimeter, mean (SD) 34.4 (1.7) 33.9 (3.7) 0.07 34.3 (1.9) 34.3 (1.6) 0.96
Clinical
 Maternal smoking, n (%) 3 (1.6) 7 (9.1) 0.003 3 (1.6) 7 (6.2) 0.04
 Alcohol use, n (%) 0 (0.0) 3 (3.9) 0.006 0 (0.0) 2 (1.8) 0.14
 Illicit drug use, n (%) 0 (0.0) 2 (2.6) 0.03 0 (0.0) 3 (2.7) 0.05
 Parent’s psychiatric history, n (%) 10 (5.3) 27 (35.1) ≤ 0.001 180 (94.7) 83 (73.5) 0.001

OR 1.7). Smoking during pregnancy was also associated
with mental disorder risk during adolescence. On the other
hand, greater maternal schooling was protective. ADHD and
ASD were diagnosed in 4.0% (144) and 0.4% (15) of the
cohort participants, respectively (La Maison et al. 2018).
Although the analysis did not investigate risk factors for spe-
cific disorders, findings from this cohort are in line with our
results, that is, for an association between prematurity and
psychiatric disorders.
Blencowe et al. (2013) performed a systematic review
and meta-analysis to estimate risk of neurodevelopmental
impairment from preterm births, including behavioral
changes such as difficulties in social interaction, socializa-
tion, attention, and hyperactivity. Of the nearly 10 million
live births in 2010 in Latin America and the Caribbean,
8.5% were premature. Of these, 91.7% (780,700) survived,
of which 45,700 (5.8%) and 30,500 (3.9%) presented mild
and severe neurodevelopmental losses, respectively (Blen-
cowe et al. 2013). The frequency of health risk was higher
when gestational age was lower: worldwide, 52% of those
born under 28 weeks, 24% of those born between 28 and
31  weeks, and 5% of preterm infants born between 32

13
 Journal of Autism and Developmental Disorders

Table 3  Adjusted analysis related to associated factors to neurodevel- less than 28 weeks, which limited the stratification of our
opment disorders analysis to potentially higher preterm infants.
Variable AOR (95% CI) p Schieve et  al. (2016) used population data from the
United States to investigate the association between prema-
Sociodemographic
turity and neurodevelopmental disorders, including ADHD,
 Marital status not married 2.18 (1.31–3.06) 0.003
ASD, learning, and conduct disorders. The authors collected
 High/superior maternal education 0.62 (0.39–0.99) 0.047
data related to psychiatric diagnosis, prematurity, low birth
Gestational
weight, as well as age, sex, ethnicity, maternal schooling,
 Prematurity 3.46 (1.15–7.92) 0.003
and mother’s age at the time of the child’s birth. 13.9% of
 Maternal hypertension 1.35 (0.59–3.06) 0.48
the sample of 74,565 children and adolescents between 3 and
Newborn characteristics
17 years of age presented with at least one neurodevelop-
 Birth weight < 2500 g 1.14 (0.46–2.88) 0.77
mental disorder. ADHD was diagnosed in 8.2% and ASD in
 Breast feeding < 3 months 1.18 (0.73–1.92) 0.48
1.9% of the participants. Both disorders were associated with
Clinical
prematurity even considering only those with normal birth
 Maternal smoking 2.77 (0.71–10.70) 0.14
weight, whose alteration has already been reported in the
 Parent’s psychiatric history 6.43 (3.09–13.40) ≤ 0.001
literature as a risk factor for neurodevelopmental disorders
(Hack et al. 2009; Losh et al. 2012; Szatmari et al. 1990).
However, the population attributable fraction, which can be
Table 4  Adjusted analysis related to associated factors to ADHD understood as the proportion of the disease that would be
Variable AOR (95% CI) p
prevented in the population if the risk factor was eliminated
(Rezende and Eluf-Neto 2016) (for example, if all children
Sociodemographic were born full term), was different for ADHD and ASD,
 Marital status not married 2.69 (1.41–5.13) 0.003 2.5% and 5.3%, respectively, suggesting a greater impact of
Gestational prematurity for autism spectrum disorders (Schieve et al.
 Prematurity 3.08 (1.08–8.87) 0.04 2016).
Newborn characteristics Few national studies have investigated the association
 Birth weight < 2500 g 1.58 (0.51–4.87) 0.42 between prematurity and neurodevelopmental disorders.
Clinical Fezer et al. (2017), through a review of medical records,
 Maternal smoking 4.99 (1.12–22.26) 0.03 found a frequency of prematurity in children diagnosed with
 Parent’s psychiatric history 9.18 (4.01–21.01) ≤ 0.001 ASD higher than that reported in the general population.
ADHD-related behaviors were found in almost half of a
sample of 80 premature infants at 4–5 years of age evalu-
ated by Espírito Santo et al. (2009). However, a study pub-
Table 5  Adjusted analysis related to associated factors to ASD
lished in 2016 by Murray et al. (2016) did not identify an
Variable AOR (95% CI) p association between prematurity and ADHD for the Brazil-
Sociodemographic ian cohort, different from that found for the British Avon
 Marital status not married 1.98 (1.12–3.48) 0.09 Longitudinal Study of Parents and Children (ALSPAC) (OR
Gestational 2.33) as stated by the authors.
 Prematurity 2.93 (1.28–6.70) 0.01 Brain magnetic resonance imaging in neonates born less
 Maternal hypertension 0.54 (0.22–1.29) 0.17 than 32 weeks gestation found a small lesion of white matter
Newborn characteristics in 58% of participants; moderate in 15%, and severe damage
 Breast feeding < 3 months 1.31 (0.77–2.23) 0.32 in 3% (Woodward et al. 2011). Such alterations may under-
Clinical lie the behavioral and cognitive changes found in children
 Maternal smoking 2.67 (0.60–11.78) 0.19 and adolescents with neurodevelopmental disorders, with
 Parent’s psychiatric history 5.41 (2.45–11.92) 0.001 severity associated with extent of brain lesions. Prematu-
rity, in addition to the physiological consequences associated
with a more vulnerable organism, can alter the connectiv-
ity between cerebral structures such as cortex-orbito-frontal
and 36 weeks have some degree of neurodevelopmental circuit connections that are associated with reward learn-
impairment (Blencowe et al. 2013). In our study, 46 par- ing, context verification, and socio-emotional processing.
ticipants (12.1%) were premature, of whom only 4 were Cortico-cortical connections, which play an important role
born with less than 32 weeks of gestation, 3 (6.5%) born in language, problem solving, and social behavior, may also
between 28 and 31 weeks, and 1 (2.2%) was born with be compromised (Fischi-Gomez et al. 2015).

13
Journal of Autism and Developmental Disorders
The association between prematurity and mental health
problems can be partly explained by the adverse conditions
that the developing brain undergoes, both intrauterine and
after birth. However, factors such as socioeconomic cir-
cumstances, family structure, and other environmental
factors may also play an important role in determining
mental health risks, albeit to a lesser degree for term chil-
dren (Singh et al. 2013). Problems in childhood mental
health may be related to genetic (Lee et al. 2013), as well
as other biological factors (prematurity, malnutrition, low
birth weight) (Franz et al. 2018; Peter et al. 2016; Wang
et al. 2017). In the present study, the proportion of parental
psychiatry diagnosis among the cases was significantly
higher comparing with controls (30% vs. 5.3%). Interest-
ingly, most of the disorders reported were mood disor-
ders, which could reflect not only the high prevalence of
them in the population, but also the shared genetic etiol-
ogy between major depression, bipolar disorder, ASD and
ADHD (Lee et al. 2013).
This study has some limitations that should be
addressed. Studies such as ours suffer from limitations in
medical records, in which parental psychiatric disorders
were self-reported. It should be added that the records
in medical records were not controlled according to the
study protocol, since they were done according to clini-
cal practice, and may still suffer from the memory bias of
the professional who made the records. Prematurity and
family psychiatric history have been independently asso-
ciated with neurodevelopmental disorders in children and
adolescents. Despite similar findings in the international
literature, this work reinforces this association. Efforts to
modify risk factors such as prematurity, as well as increas-
ing effective care for premature infants, can have an impact
on the reduction of disorders diagnosed in childhood and
adolescence that are related to significant individual, fam-
ily, and social burden. Finally, transdiagnostic endophe-
notypes as outcomes could provide better neurobiological
and mechanistic insights into the relationship between pre-
maturity and neurodevelopmental disorders (Insel et al.
2010).
Author Contributions  All authors contributed to the study conception
and design. Material preparation, data collection and analysis were
performed by TCBS, GAB and APD. The first draft of the manuscript
was written by TCBS and all authors commented on previous versions
of the manuscript. All authors read and approved the final manuscript.
Funding  There is no external funding for this study.
Compliance with Ethical Standards 
Ethics Approval  The protocol study was approved by the Human
Research Ethics Committee of the UNISUL submitted through Plata-
forma Brasil.
Informed Consent  All data were collected from participant’s medi-
cal records. After authorization by the legal custodian of the medical
records, the investigator contacted the legal participant’s guardian for
signing the inform consent. The inform consent signature was allowed
to be dispensed after two unsuccessful telephone contact attempts made
by the investigators on different occasions.
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