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Pre-eclampsia is associated with increased
neurodevelopmental disorders in children
with congenital heart disease
Camilla Omann
1,2,
*, Camilla Nyboe
1,2
, Rasmus Kristensen
3
, Andreas Ernst
4
,
Cecilia Høst Ramlau-Hansen
4
, Charlotte Rask
2,5
, Ann Tabor
6
, J. William Gaynor
7
,
and Vibeke E. Hjortdal
3
1
Department of Cardiothoracic & Vascular Surgery, Aarhus University Hospital, Aarhus, Denmark;
2
Department of Clinical Medicine, Aarhus University, Aarhus, Denmark;
3
Department of Cardiothoracic Surgery, Copenhagen University Hospital, Copenhagen, Denmark;
4
Department of Public Health, Research Unit for Epidemiology, Aarhus University,
Aarhus, Denmark;
5
Department of Child and Adolescent Psychiatry, Aarhus University Hospital, Aarhus, Denmark;
6
Center of Fetal Medicine, Department of Obstetrics, Copenhagen
University Hospital Rigshospitalet, Copenhagen, Denmark; and
7
Division of Cardiothoracic Surgery, Children’s Hospital of Philadelphia, Philadelphia, PA, USA
Received 20 January 2022; revised 17 March 2022; accepted 24 March 2022; online publish-ahead-of-print 21 April 2022
Handling Editor: Edit Nagy
Aims Our primary aim was to examine whether exposure to pre-eclampsia increases the risk of neurodevelopmental disor-
ders in children born with congenital heart disease (CHD). Our secondary aim was to evaluate whether CHD and pre-
eclampsia may act in synergy and potentiate this risk.
Method
and results
Using population-based registries, we included all Danish children born with CHD between 1994 and 2017. Non-single-
tons and children born with a syndrome were excluded. Neurodevelopmental disorders including attention-deficit/hyper-
activity disorder, autism spectrum disorders, and tic disorders were identified with the use of the 10th edition of
International Classification of Disease (ICD-10) codes DF80–DF98. Using Cox proportional hazard regression, we esti-
mated the risk of neurodevelopmental disorders in children with CHD exposed to pre-eclampsia compared with those
with CHD not exposed to pre-eclampsia. The population consisted of 11 449 children born with CHD. Children exposed
to pre-eclampsia had an increased risk of neurodevelopmental disorders, hazard ratio: 1.84 (95% confidence interval:
1.39–2.42). Furthermore, a comparison cohort of 113 713 children with no CHD diagnoses were included. Using cumu-
lative incidence analyses with death as competing risk, we compared the risk of neurodevelopmental disorders if exposed
to pre-eclampsia among children with CHD and children without CHD. Exposure to pre-eclampsia drastically increased
the cumulative incidence of neurodevelopmental disorders in children born with CHD.
Conclusion Exposure to pre-eclampsia is associated with increased risk of neurodevelopmental disorders in children born with
CHD. CHD and pre-eclampsia may act in synergy and potentiate this effect. Clinicians should therefore be especially
attentive to neurodevelopmental problems in this vulnerable subgroup.
------------------------------------------------------------------------------------------------------------------------------------------------------------
* Corresponding author. Tel: +45 29401223, Email: camillaomann@clin.au.dk
© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/),
which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact
journals.permissions@oup.com
European Heart Journal Open (2022) 2,1–9
https://doi.org/10.1093/ehjopen/oeac027
ORIGINAL ARTICLE
Adult congenital heart disease
.........................................................................................................................................................................................
Graphical Abstract
Keywords Congenial heart disease •Pre-eclampsia •Neurodevelopment •Psychiatry •Foetus
Introduction
Over the past four decades, mortality in children born with a congeni-
tal heart disease (CHD) has dramatically decreased due to both
improved pre-natal diagnostics and post-natal treatment. There is a
growing population of adult survivors with CHD. With improved sur-
vival, there has been increasing recognition of the considerable risk of
neurodevelopmental problems in children and adults with CHD.
1–5
2C. Omann et al.
Studies have observed an association between being born with
CHD and an increased risk of psychiatric morbidity later in life, includ-
ing neurodevelopmental disorders like autism spectrum disorders,
attention-deficit/hyperactive disorders (ADHD), and tic disorder.
6
These findings apply to both major and minor heart defects.
6,7
The association between CHD and neurodevelopmental disorders is
not easily explained, but a main determinant appears to be impaired cere-
bral development in utero.
1,4,8
The underlying aetiological mechanisms are
likely multifactorial with hypoxia as a proposed leading cause.
9–11
Inducing additional hypoxia in an already oxygen-deprived brain, as
seen in children with CHD, could therefore worsen the potential risk
of neurodevelopmental problems. In the case of pre-eclampsia and
an impaired placental function, the foetus may be exposed to add-
itional hypoxia. Pre-eclampsia is an independent risk factor for neu-
rodevelopmental disorders
12–14
and pre-eclampsia and placental
abnormalities have been shown to be overrepresented in pregnan-
cies with foetuses with CHD.
15–17
However, we do not know if
the exposure to pre-eclampsia further increases the risk of neurode-
velopmental disorders when born with CHD.
Our primary aim was to evaluate whether exposure to pre-
eclampsia in foetal life increased the risk of neurodevelopmental disor-
ders in all Danish children born with CHD between 1994 and 2017.
Our secondary aim was to examine whether CHD and pre-eclampsia
may act in synergy. We hypothesized that pre-eclampsia potentiates
the risk of neurodevelopmental disorders in children with CHD.
Methods
Data source
We conducted a nationwide population-based registry study. The Danish
health care system is free of charge and equally accessible to all citizens.
Each Danish citizen has since 1968 received a unique personal identification
number. Several national registries can be linked using this unique number
as this unique identifying number is included as a variable in most regis-
ters.
18
Data included in this study were obtained from numerous national
registries, including the following: The Danish National Patient Registry
(DNPR), The Danish Cytogenetic Central Registry (DCCR), The Danish
Medical Birth Registry, The Danish National Patient Register on
Psychiatric Admissions, and The Family Sociogroup Registry.
Study population
The study population consisted of children diagnosed with CHD and
born between 1 January 1994 and 31 December 2017 in Denmark.
Considering our secondary aim of examining whether CHD and pre-
eclampsia may act in synergy, we created a comparison cohort of 10 ran-
domly drawn age- and gender-matched individuals without CHD for
each CHD patient. This comparison cohort was drawn based on the
same exclusion criteria as applied to the CHD population.
CHD diagnosis
We used the DNPR to identify all Danish children diagnosed with CHD
between 1994 and 2017. The DNPR contains information from the out-
patient setting and on all hospital admissions including date of admission
and discharge, surgical procedures, hospital of admission, and discharge
diagnoses coded according to the International Classification of
Disease (ICD). The 10th edition of the ICD has been used since 1994,
hence, the cut-off at 1994 for our study period of interest. The following
ICD-10 codes, including sub-codes, were used to identify CHD diagnosis:
DQ20–DQ26. The CHD diagnoses were grouped into two hierarchical
categories, major and minor, according to severity of the CHD based on
definitions described in previous studies.
19
If a child had more than one
CHD diagnosis, the most severe CHD diagnosis given at the earliest
point in time was included. Similar to earlier studies, only children with
a CHD diagnosis issued at a University Hospital were included in order
to increase the diagnostic validity.
14
Exclusion criteria
Childrenborn with one of the following syndromes wereidentified and ex-
cluded based on information obtained from the DCCR: Trisomy 13,
Trisomy 18, Trisomy 21, Turner Syndrome(45, X), Klinefelter
Syndrome(47, XXY), DiGeorge Syndrome (22q11 deletion), and
Williams-Beuren Syndrome. The DCCR is a nationwide register to which
all chromosome analyses performed in Denmark since 1960 are reported.
Non-singletons were excluded with the use of The Danish Medical
Birth Registry. This registry links mother and child and contains informa-
tion on a large number of variables regarding maternal characteristics,
pregnancy, and childbirth. Individuals who were not included in the
Danish Medical Birth Registry, for example, due to adoption from an-
other country or immigration, were likewise excluded.
Exposure
Exposure was defined as being born by a mother diagnosed with pre-
eclampsia, eclampsia, or HELLP syndrome in the index pregnancy. The
diagnostic criteria for pre-eclampsia is the presence of gestational hyper-
tension (blood pressure ≥140 mmHg systolic and/or ≥90 mmHg dia-
stolic after Gestational Week 20 in women, who were normotensive
pre-pregnancy) with associated newly emerged proteinuria and/or signs
of organ dysfunction.
20
Using the Danish Medical Birth Registry, we iden-
tified all mothers of children born with CHD and not excluded due to the
criteria mentioned above. With the use of the DNPR, the following
ICD-10 codes were used to identify pre-eclampsia including HELLP syn-
drome in the mother: DO11, DO14, DO140, DO141, DO142, DO149,
DO15, DO151, DO152, and DO159. Both primary and secondary diag-
noses were included. To ensure correct linkage of the mother and child
the diagnosis of pre-eclampsia, eclampsia or HELLP syndrome had to be
given between 200 days before and 60 days after birth of the index child,
and by definition the foetus had to be 20 weeks of gestation or more at
the time of diagnosis. Early-onset pre-eclampsia was defined as pre-
eclampsia diagnosed between 20 and 33 weeks of gestation.
Late-onset pre-eclampsia was defined as pre-eclampsia diagnosed during
or after 34 weeks of gestation.
Exposure limited to exclusively gestational hypertension was consid-
ered in a sub-analysis comparing children exposed exclusively to gesta-
tional hypertension to children not exposed to any type of
hypertension. Gestational hypertension was identified with the use of
the following ICD-10 codes: DO13, DO139, DO16, and DO169.
Outcomes: neurodevelopmental disorders
The outcome was defined as being diagnosed with a neurodevelopmen-
tal disorder including attention disorder, autism spectrum disorders, and
tic disorders within the available follow-up period. If a child had one or
more of these included diagnoses during this time period, only the first
given diagnosis was included as an event.
These neurodevelopmental disorders were identified with the use of
the DNPR and the Danish National Patient Register on Psychiatric
Admissions using the following ICD-10 codes: DF80–DF98.
DF80–DF89 covers Disorders of Psychological Development, of which
DF84 including sub-diagnoses accounted for autism. DF90–DF98 covers
Behavioural and Emotional Disorders with onset usually occurring in
Pre-eclampsia is associated with increased neurodevelopmental disorders 3
childhood and adolescence of which DF90 including sub-diagnosis and
DF98.8 covers attention disorders and DF95 accounted for tic disorders.
Additional variables
Using a directed acyclic graph, the socioeconomic status (SES) was consid-
ered a confounder in the association between CHD and neurodevelop-
mental disorders, whereas pre-term birth may act as intermediate factor.
The SES was obtained based on the family SES as most children in-
cluded in the study did not yet have their own individual status in the reg-
isters. This was done with the use of The Family Sociogroup Registry. In
this registry, the parent with the highest income in the family determines
the total family SES. The highest achieved family SES over time was used.
All children and parents of a family unit were assigned the same unique
family ID. This allowed for us to identify the family unit of each included
child. We categorised the family SES into four groups (Groups 1–4) of
hierarchical descending SES. Group 1 included business owners and em-
ployees with a high income, Group 2 accounted for employees with mid-
dle or low income, Group 3 included students and unemployed, and
Group 4 accounted for others.
Gestational age (GA) at birth was identified using The Danish Medical
Birth Registry. We categorised pre-term birth into two groups. Group 1
contained all pre-term births, defined as being born with a GA at delivery
of ,37 weeks. Group 2 contained only early pre-term births, defined as
being born with a GA at delivery of ,34 weeks.
Data analysis
Direct comparison between groups were done using students t-test if
data were continuous. For binomial data, the chi-square test was used.
When comparing exposed children to unexposed children in the popu-
lation of children born with CHD, we used Cox proportional regression
analysis to compute hazard ratio (HR). This was done for the first hos-
pital contact (inpatient or outpatient contacts in the hospital) with a diag-
nosis for neurodevelopmental disorders registered, with follow-up
beginning at the time of birth using age as the underlying scale. This stat-
istical method was chosen in order to account for the lack of complete
follow-up in all children. All analyses were adjusted for SES.
All statistical tests presumed a significance level of 5%. Furthermore,
we compared the potential effect of exposure to pre-eclampsia between
a population of children born with CHD and a population of children
born with no CHD in order to examine whether CHD and pre-
eclampsia may act in synergy. To account for the great difference in
the risk of death among the two populations,
21
Fine and Gray competing
risk regression was used to estimate the cumulative incidence of neuro-
developmental disorders among exposed and unexposed children born
with and without CHD.
Data cleaning and analysis was conducted by the use of Statistics
Denmark’s encrypted online data service (Forskerservice). For statistical
analyses, Stata Statistical Software, release 15 (StataCorp LP, TX, USA)
was used.
Results
Primary aim: examine whether exposure
to pre-eclampsia increases the risk of
neurodevelopmental disorders in
children born with CHD
We identified 16 799 children born with CHD between 1 January
1994 and 31 December 2017 in the DNPR (Figure 1). Of these,
773 children had a syndrome and were excluded. Furthermore,
615 children were missing in the Danish Medical Birth Registry and
1247 non-singletons were excluded. After exclusion of children,
who did not receive their CHD diagnosis at a university hospital, a
total of 11 449 children with CHD were included in the study.
Median follow-up time was 11.0 years (range 0.02–23.9 years).
Baseline characteristic of children with CHD included in the study
are shown in Table 1. No overall differences were observed between
children exposed to pre-eclampsia, eclampsia or HELLP syndrome
compared with unexposed children regarding distribution of sex,
year of birth, or SES. More children exposed to pre-eclampsia
were born pre-term.
No differences were found between the distribution of the individual
subtypes of CHD between exposed and unexposed children (Table 2).
In total, 57 children born with CHD and exposed to pre-eclampsia were
diagnosed with a neurodevelopmental disorder, whereas 929 unex-
posed CHD children had a neurodevelopmental disorder. The distribu-
tion of the individual neurodevelopmental disorders can be found in
Supplementary material online, supplementary material 1.Thedistribu-
tion of neurodevelopmental disorders based on CHD status can be
found in Supplementary material online, supplementary material 2.
In the population of children born with CHD, children exposed to
pre-eclampsia had a higher risk of neurodevelopmental disorders com-
pared with unexposed children, HR: 1.84 [95% confidence interval (CI):
1.23–2.42] (Table 3). Children exposed to exclusively gestational hyper-
tension did not have a higher risk of neurodevelopmentaldisorderscom-
pared with unexposed children, HR: 1.05 (95% CI: 0.77–1.43).
When adjusting for all pre-term births (GA at delivery of ,37 weeks),
the HR decreased to 1.65 (95% CI: 1.24–2.18) suggesting that some ef-
fect, however not all, could have been mediated through pre-term birth.
No additional effect was observed when adjusting for early pre-term
(GA at delivery of ,34 weeks), HR: 1.63 (95% CI: 1.22–2.16).
When excluding CHD children diagnosed with only a patent ductus
arteriosus, the risk of neurodevelopmental disorders between exposed
and unexposed CHD children was HR: 1.67 (95% CI: 1.25–2.25).
Furthermore, we found in this population of children born with
CHD, that if exposed to early-onset pre-eclampsia the risk of neuro-
developmental disorders was higher than if exposed to late-onset
pre-eclampsia (Table 4).
The HR of neurodevelopmental disorders was higher in male chil-
dren born with CHD than in female children born with CHD and ex-
posed to pre-eclampsia (Table 3). When considering the type of
CHD, we found that the HR of neurodevelopmental disorders was
higher between exposed and unexposed children born with a minor
CHD than between exposed and unexposed children born with a
major CHD (Table 3).
Mortality rates during the follow-up period between children born
with a minor CHD and children born with a major CHD can be
found in Supplementary material online, supplementary material 3.
We found that 82.8% of the children born with a major CHD
were alive at the end of follow-up compared with 98.3% in the group
of children born with a minor CHD.
Secondary aim: examine whether CHD
and pre-eclampsia may act in synergy
A comparison cohort of 113 713 children with no CHD diagnoses
were included. No overall differences were found in baseline charac-
teristics between the population of children born with CHD
4C. Omann et al.
Figure 1 The number of children born with CHD included in the study.
Pre-eclampsia is associated with increased neurodevelopmental disorders 5
compared with the population of children born with no CHD.
Baseline characteristic of this population stratified on exposure to
pre-eclampsia can be found in Supplementary material online,
supplementary material 4.
From Figure 2, we see that children with CHD and exposed to pre-
eclampsia had a drastically higher cumulative incidence of neurodeve-
lopmental disorders over time compared with unexposed CHD chil-
dren but also compared with both exposed and unexposed children
with no CHD.
Discussion
In this large nationwide population-based registry study, the overall
risk of neurodevelopmental disorders was higher in children with
CHD exposed to pre-eclampsia compared with children unexposed
to pre-eclampsia. The risk of neurodevelopmental disorders among
children born with CHD of mothers with pre-eclampsia appeared to
depend on the onset of pre-eclampsia, as CHD children exposed to
early-onset pre-eclampsia had a higher risk of neurodevelopmental
disorders than CHD children exposed to late-onset pre-eclampsia.
We also found a higher risk of neurodevelopmental disorders in
males born with CHD and exposed to pre-eclampsia than female
with the same exposure, suggesting effect modification by sex.
.................................................................................
Table 1 Baseline characteristics of children born
with CHD
Pre-eclampsia
n=502 (4.4%)
No
pre-eclampsia
P-value
n=10 947
(95.6%)
Male sex, n(%) 271 (54.0) 5581 (51.0) 0.19
Surgery for CHD,
n(%)
156 (31.1) 3503 (32.0) 0.66
Small for GA, n(%) 52 (10.4) 1226 (11.2) 0.56
Pre-term birth, n(%)
Term: GA ≥37
weeks
273 (54.4) 9142 (83.5) ,0.001
Group 1: GA ,37
weeks
223 (44.4) 1590 (14.5) ,0.001
Group 2: GA ,34
weeks
149 (33.3) 776 (7.1) ,0.001
Missing 6 (1.2) 215 (2.0) ,0.001
Maternal age, mean
(95% CI)
29.7 (29.2–30.2) 29.5 (29.8–29.9) 0.57
Year of birth, n(%) 152 (30.3) 3506 (32.0) 0.02
1994–2001 156 (31.1) 3841 (35.1)
2002–2009 194 (38.6) 3600 (32.9)
2010–2017
Socioeconomic status,
n(%)
Group 1: Low 119 (23.7) 2650 (24.2) 0.92
Group 2: Lower
middle
257 (51.2) 5440 (49.7) 0.03
Group 3: Higher
middle
87 (17.3) 1887 (17.2)
Group 4: High 9 (2.0) 212 (1.9)
Missing 30 (6.5) 758 (6.9)
Length of follow-up,
median
(interquartile range)
11.0 (5.4–17.2) 9.3 (4.6–16.8)
.............................................
.................................................................................
Table 2 Distribution of the individual types of
CHD stratified by exposure status
CHD
Pre-eclampsia,
n(%)
No
pre-eclampsia,
n(%)
P-value
Minor CHD 372 (82.9) 8810 (80.1) 0.19
VSD 109 (24.3) 3024 (27.5)
CoA 16 (3.6) 389 (3.5)
Aortic valve
disease
17 (3.8) 466 (4.2)
Pulmonary valve
disease
35 (7.8) 934 (8.5)
MV disease 11 (2.4) 392 (3.6)
PAPVD ,5 29 (0.3)
ASD 104 (23.2) 2272 (20.7)
PDA 76 (16.9) 1055 (9.6)
Simple
miscellaneous
,5 46 (0.4)
Major CHD 77 (17.1) 2190 (19.9) 0.19
UVH ,5 92 (0.8)
TAC ,5 56 (0.5)
I/HAA ,5 114 (1.0)
TGA 19 (4.2) 525 (4.8)
AVSD 19 (4.2) 486 (4.4)
TAPVD ,5 162 (1.5)
PA ,5 63 (0.6)
TOF ,5 69 (0.6)
Ebsteins
anomaly
15 (3.3) 341 (3.1)
Tricuspid valve
disease
,5 51 (0.5)
Eisenmeger
syndrome
,5 49 (0.4)
Complex
miscellaneous
,5 232 (2.1)
VSD, ventricular septal defect; CoA, coarctatio aortae; MV disease, mitral valve
disease; PAPVD, partial anomalous pulmonary venous drainage; ASD, arterial
septal defect; PDA, patent ductus arteriosus; UVH, univentricular heart; TAC,
truncus arteriosus communis; I/HAA, interrupted/hypoplastic aortic arch; TGA,
transposition of the great arteries; AVSD, artrioventricular septal defect; TAPVD,
total anomalous pulmonary venous drainage; PA, pulmonary atresia; TOF,
Tetralogy of Fallot.
6C. Omann et al.
Furthermore, the severity of the heart disease was found to inversely
modify the risk of neurodevelopmental disorders as the risk of neu-
rodevelopmental disorders was higher between exposed and unex-
posed children born with a minor CHD than between exposed and
unexposed children born with a major CHD.
To our knowledge, no studies have yet investigated how a preg-
nancy complicated by pre-eclampsia affects the neurodevelopment
in a population of children born with CHD. The relationship between
the CHD, pre-eclampsia, and neurodevelopmental outcomes is com-
plex. CHD causes abnormal brain development, in part due to de-
creased cerebral oxygen delivery. Placental dysfunction expressed
as pre-eclampsia may exacerbate this. The association between ma-
ternal pre-eclampsia and offspring CHD is well documented,
15,22,23
and particularly early-onset pre-eclampsia is associated with
CHD.
15
There may be shared genetic mechanisms between pre-
eclampsia and CHD, especially in angiogenic genes,
24,25
however
this remains uncertain. It is therefore difficult to disentangle the po-
tential causal pathways between CHD, pre-eclampsia, and neurode-
velopmental disorders.
In this study, exposure to pre-eclampsia was associated with a fur-
ther increase in the risk of neurodevelopmental disorders in children
born with CHD. Exposure to pre-eclampsia drastically increased the
cumulative incidence of neurodevelopmental disorders in children
born with CHD compared with the cumulative incidence of neuro-
developmental disorders among exposed and unexposed children
born with no CHD. This could potentially indicate that CHD and
pre-eclampsia may act in synergy and thereby potentiate the risk
of neurodevelopmental disorders in children born with CHD.
Furthermore, we saw that children born with CHD but not ex-
posed to pre-eclampsia had a higher incidence of neurodevelopmen-
tal disorders compared with children born with no CHD yet
exposed to pre-eclampsia. As previously mentioned, the underlying
aetiological mechanisms are likely multifactorial. Hypoxia in foetal
life is likely a leading cause, but other factors including genetics could
be of importance.
We saw that exposure to early-onset pre-eclampsia increased the
risk of neurodevelopmental disorders when compared with expos-
ure to late-onset pre-eclampsia. Considering this impact of the timing
of the onset of pre-ecplampsia on neurodevelopmental it is there-
fore important to distinguish between early and late-onset pre-
eclampsia in this population of children born with CHD.
Exposure to pre-eclampsia heightens the risk of being born pre-
mature. Being born pre-term increases the risk of neurodevelop-
mental problems and could potentially be the underlying cause for
neurodevelopmental disorders in this population. However, we
find that only a very limited effect is mediated through pre-term
birth, indicating that pre-eclampsia acts independently as a risk factor
for neurodevelopmental disorders in children born with CHD.
It is well-known that major CHD is associated with neurodeve-
lopmental complications in children.
9,26
However, recent studies
from our group also demonstrate an association between being
born with a minor CHD and an increased risk of lifetime psychiatric
morbidity.
5,7
Our data support the importance of not neglecting
those with a minor CHD, as they also seem to be vulnerable to
the exposure of pre-eclampsia in terms of neurodevelopmental dis-
orders. Children born with a minor CHD in this study seem to be
relatively more vulnerable pre-eclampsia compared with children
born with a major CHD. This paradox may occur because major
CHDs are already severely compromised in circulation and oxygen-
ation, and pre-eclampsia contributes with little or no extra measur-
able effect on this. Another important factor is live birth bias where
the higher survival rate among minor CHD generate a larger group
of patients who can live to experience neurodevelopmental pro-
blems. Furthermore, children born with a major CHD have a higher
mortality than children born with a minor CHD. Therefore, it could
potentially be the case, that children born with a major CHD does
not live long enough to get a diagnosis of neurodevelopmental
disorders.
The higher psychiatric morbidity in males vs. females has previous-
ly been observed in the general population as well as in a population
of children with CHD.
6
We also observed that neurodevelopment in
males with CHD was more vulnerable to the exposure of pre-
eclampsia. If a male with CHD was exposed to pre-eclampsia he
had a higher risk of neurodevelopmental disorders compared with
males with CHD who were not exposed to pre-eclampsia. We did
not find the same important difference in females with CHD.
.................................
.................................................................................
Table 3 Risk of neurodevelopmental disorders in
children with CHD according to sex and type of
CHD.
CHD children exposed
to PE vs. CHD children
unexposed to PE
HR (95% CI) P-value
Risk of neurodevelopmental disorders
Overall 1.84 (1.39–2.42) ,0.001
Female 1.29 (0.77–2.17) 0.33
Male 2.19 (1.59–3.04) ,0.001
Major CHD 1.44 (0.70–2.94) 0.32
Minor CHD 1.90 (1.41–2.57) ,0.001
Adjusted for socioeconomic status.
PE, pre-eclampsia.
.........................
.................................................................................
Table 4 Risk of neurodevelopmental disorders
among children with CHD according to the onset of
pre-eclampsia
Onset of
pre-eclampsia
No
pre-eclampsia
Early
onset
Late
onset
Total (N) 11 001 179 264
Risk of
neurodevelopmental
disorders
1.0 (reference) 2.3
(1.58–
3.35)
1.54
(01.05–
2.26)
HR (95% CI)
Adjusted for socioeconomic status.
Pre-eclampsia is associated with increased neurodevelopmental disorders 7
It is well-known that autism spectrum disorders and ADHD in
general are more frequent in men albeit it is discussed whether
females are potentially underdiagnosed. This may be caused by
the symptoms of autism and ADHD being expressed different
and in more hidden ways among girls than boys.
27
It is therefore
important to be cautious when interpreting these gender-specific
findings.
Limitations
The Danish registries provides us a great opportunity to include
large populations with long follow-up times. However, registry-
based studies are limited by the accuracy of the diagnostic coding.
In order to account for inaccurate diagnoses, we only included
CHD diagnoses issued at a University Hospital. Agergaard
et al.
28
found that diagnoses obtained from the four University
Hospitals matched the discharge diagnoses in the patient’s clinical
records in 98% of the cases and that the DNPR diagnosis was a
true reflection of the patient’s actual malformation in 90% of the
cases. The diagnosis for pre-eclampsia has a positive predictive va-
lue 74.4%.
29
In the Danish Psychiatric Central Research Registry,
86.8% of hyperkinetic disorders fulfilled the diagnostic criteria
30
and 94% of the cases with autism could be confirmed.
31
Another limitation is the fact that, as previously mentioned, it is
difficult to disentangle the causal pathways between CHD, pre-
eclampsia and neurodevelopmental disorders. To lower the risk
of introducing colliders stratification bias we have kept adjust-
ments to a minimum and thereby reduced the risk of adjusting
for covariates that open biasing pathways.
Conclusion
Due to improvements in surgical and medical techniques, children
born with CHD are highly likely to survive and thereby grow into
adults with CHD. However, it has become clear that even though
the heart disease may not be lethal these children potentially face
a life with considerable neurodevelopmental problems. In this study,
we demonstrated that exposure to pre-eclampsia increased the al-
ready existing risk of neurodevelopmental disorders in children
born with a CHD. We urge clinicians to be particularly attentive to
these vulnerable children for timely diagnosis and treatment of neu-
rodevelopmental problems in order to improve their prognosis and
quality of life.
Figure 2 Cumulative incidence of neurodevelopmental disorders with death as competing risk between four groups: (i) children born with CHD
and exposed to pre-eclampsia, (ii) children born with CHD but not exposed to pre-eclampsia, (iii) children with no CHD but exposed to pre-
eclampsia, and (iv) children with no CHD and not exposed to pre-eclampsia.
8C. Omann et al.
Lead author biography
Camilla Omann, MD, is a PhD fellow at
the Department of Cardiothoracic
and Vascular Surgery, Aarhus
University Hospital, Aarhus,
Denmark. She specializes in mater-
nal–fetal interactions in congenital
heart disease, investigating the com-
plex relationship between the mater-
nal–fetal environment and
neurodevelopmental outcomes. She
has used her great experience with
more methods to examine this field of research. Camilla has both na-
tional and international research collaborations, and she has with great
success presented her previous work at numerous conferences.
Data availability
The data underlying this article were provided by Statistics Denmark un-
der licence. Data will be shared on request to the corresponding author
with permission of Statistics Denmark.
Supplementary material
Supplementary material is available at European Heart Journal Open
online.
Acknowledgement
We thank Dr Nis Brix, MD, PhD, from Department of Public Health,
Section for Epidemiology, Aarhus University, Aarhus, Denmark for
his great help with epidemiologic guidance.
Funding
This work was funded by Aarhus University Research Foundation,
Region Midtjyllands Sundheds-videnskabelige Forskningsfond, and
Childrens Hospital of Philadelphia (CHOP).
Conflict of interest: None declared.
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