ORIGINAL

ARTICLES
Fetal Heart Defects and Measures of Cerebral Size
Mette Høj Lauridsen, MD, PhD1, Niels Uldbjerg, MD, DMSc2, Olav Bjørn Petersen, MD, PhD2,
Else Marie Vestergaard, MD, PhD3, Niels Bjerregaard Matthiesen, MD, PhD1,4, Tine Brink Henriksen, MD, PhD1,
John Rosendahl Østergaard, MD, PhD1, and Vibeke Elisabeth Hjortdal, MD, DMSc5

Objectives To estimate the association between fetal congenital heart defects (CHDs) and measures of brain size
throughout pregnancy, from the end of the first trimester to birth.
Study design The cohort consisted of all fetuses scanned in Western Denmark in 2012 and 2013. Anthropometric
measures in fetuses with isolated CHDs diagnosed within 12 months after birth were compared with those in the
fetuses without CHDs. Z-scores standardized to gestational age were calculated for first trimester biparietal diam-
eter, second trimester head circumference, fetal weight, birthweight, head circumference, and placental weight.
Results We obtained data from 63 349 pregnancies and identified 295 fetuses with isolated CHDs (major n = 145;
minor n = 150). The first trimester mean biparietal diameter Z-scores were not different between those with and
those without CHDs. The head circumference mean Z-score difference was 0.13 (95% CI, 0.24 to 0.01;
P = .03) in the second trimester and 0.22 (95% CI, 0.35 to 0.09; P < .001) at birth. Fetuses with univentricular
physiology or tetralogy of Fallot showed the most pronounced compromise in cerebral size.
Conclusions Our results suggest that the brain alterations inducing an increased risk of impaired neurodevelop-
ment in children with CHDs begin during pregnancy. Although fetuses with univentricular physiology or tetralogy of
Fallot exhibited the most pronounced compromise in cerebral size, we recommend neurodevelopmental follow-up
for all children with CHDs. (J Pediatr 2019;210:146-53).

C
ongenital heart defects (CHDs) affect 6-8 children per 1000 live births,1 and the risk of impaired neurodevelopment among
these children is well-established.2-11 The association between CHDs and small head size at birth is well-described,1,12,13
and impaired neurodevelopment has been associated with small head size at birth.14 Magnetic resonance imaging of the
fetal brain has been used to explore the potential explanations for these associations and has shown that fetuses with major CHDs
exhibit smaller cerebral volumes and delayed cerebral maturation,6,15-17 as well as a decrease in cerebral oxygen supply and tissue
oxygenation during late gestation.18,19 Recent studies have reported an increased risk of placental pathology and possibly pre-
eclampsia,20-22 as well as a reduced placental size at birth23 in women carrying a fetus with a CHD. Studies have reported indices
of impaired brain growth as early as mid-gestation in fetuses with prenatally detected CHDs.24,25
Most fetuses with isolated CHDs survive birth and heart surgery26,27; thus, the search for potential neuroprotective strategies
is increasingly relevant and has recently been expanded into fetal life.28 It is unknown at which time point during the course of
pregnancy the fetal heart defects may affect brain growth; thus, we aimed to estimate the association between fetal CHDs and
measures of fetal size and brain size throughout pregnancy, from the end of the first trimester to birth.

Methods
In this population-based cohort study, we included data on the fetuses and newborn children in Western Denmark (a total
population of 3 million) of pregnant women who attended at least 1 of the 2 pregnancy ultrasound scans between January
1, 2012, and December 31, 2013. We identified fetuses with CHDs defined as structural defects in the heart or intrathoracic
great vessels of actual or potential functional significance (modified from29) diagnosed during pregnancy or up to 12 months
after birth to include as many children with CHDs as possible.
All pregnant women in Denmark are offered 2 routine ultrasound scans free
of charge during pregnancy, a first trimester scan at a gestational age of 113/7 1
From the Department of Pediatrics and Adolescent
2
to 136/7 weeks that includes a risk assessment for chromosomal anomalies and Medicine, Department of Obstetrics and Gynecology,
3
and Department of Clinical Genetics, Aarhus University
a fetal anomaly scan at a gestational age of 180/7 to 216/7 weeks. These scans 4
Hospital, Aarhus; Pediatrics and Adolescent Medicine,
Hospital Unit West, Herning; and the Cardiothoracic 5

Research Department T, Aarhus University Hospital,

Aarhus, Denmark
The authors declare no conflicts of interest.
CHD Congenital heart defect Portions of this study were presented at the jENS (joint
HC Head circumference European Neonatal Societies) conference, October 31-
November 4, 2017, Vienna, Italy.
RAA Right aortic arch
VSD ventricular septal defect 0022-3476/$ - see front matter. ª 2019 Elsevier Inc. All rights reserved.
https://doi.org/10.1016/j.jpeds.2019.02.042

146

Downloaded for Anonymous User (n/a) at LOS ANGELES COUNTY DEPARTMENT OF HEALTH SERVICES from ClinicalKey.com by Elsevier on June 04, 2020.
For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved.
 Volume 210  July 2019

are attended by more than 90% of all pregnant women,30,31 septal defect (Table II and Figure 2). The remaining
and the data are stored in a local fetal medicine database fetuses were not considered in the subgroup analyses owing
(2004-2018 Astraia Software GmbH, Munich, Germany) to sparse data.
used by all obstetric departments in Denmark. All data are We compared measures of fetal anthropometry at 3
transferred to a nationwide database, the Danish Fetal Med- different time points during pregnancy (end of the first
icine Database.30 Women carrying fetuses with malforma- trimester, middle of the second trimester, and at birth).
tions, increased nuchal translucency, or increased risk of According to the national guidelines, the biparietal diam-
trisomy after the combined first trimester screening are eter at the first trimester scan (between a gestational age
offered invasive testing and high-resolution chromosomal of 113/7 and 136/7 weeks) was the preferred measure of
microarray or standard chromosome analysis. Fetuses and brain size. At the anomaly scan (gestational age of 180/7
children with suspected CHDs are referred to a tertiary center to 216/7 weeks), the HC was calculated based on the bipar-
at Aarhus University Hospital for further examination and ietal diameter and the occipital frontal diameter.39 The
counseling of their parents. estimated fetal weight was calculated according to the
Prenatal ultrasound biometrics, birthweight, and placental Hadlock formula.40
weight were obtained from the Danish Fetal Medicine Data- At birth, HC, weight, and length of the newborn and the
base. Head circumference (HC) and length at birth were ob- weight of the placenta are routinely measured within the first
tained from The Danish Medical Birth Registry.32 Using the hour of life.41 Data from all fetuses (live born, stillborn, and
personal identification number assigned to all live-born chil- aborted) were included in the analysis. Data were analyzed
dren and all citizens residing in Denmark (allowing unam- using Stata 13.1 (StataCorp, College Station, Texas).
biguous individual-level record linkage of all Danish The fetal and neonatal biometric data were converted into
registers33), we identified fetuses with CHDs by the integra- Z-scores using published normative data from large popula-
tion of four sources of data: the local Fetal Medicine Data- tions of healthy fetuses and children1,23,36,40 to account for
base, the local register of prenatal genetic test results, differences in gestational age at both the fetal scanning and
cardiac diagnoses from the Patient Administration System at birth.
Central Region Denmark, and the Danish Fetal Medicine The Student t test was used to calculate mean differences
Database. According to our definition of CHDs, arrhythmias, between groups. Mean differences are presented with 95%
cardiomyopathies, tumors, and minor anatomic abnormal- CIs and 2-sided P values at a 5% level of significance. The
ities, such as patent ductus arteriosus before 37 weeks of Wilcoxon rank-sum test was used to compare variables be-
gestation, persistent oval foramen, and pulmonary branch tween groups when the variables were not normally
stenosis, were not included. Individuals with diagnoses that distributed. The c2 test and the Fisher exact test were
could not be verified by the pathological records, second used to compare dichotomous variables. The association
opinion fetal ultrasound scan records, or postnatal ultra- between gestational age and brain size Z-scores was esti-
sound scan records (n = 4) were also excluded from the mated using linear regression with robust standard errors
CHD cohort. to account for repeated measurements within the same
The initial cohort consisted of 63 349 pregnancies fetus. For the graphic presentation, we included all avail-
including 412 fetuses (0.66%) with CHDs. Figure 1 able brain size Z-scores regardless of the gestational age
presents the delimitation of the final cohort.29,34 at the time of the scan. Gestational age was modeled using
If a woman was pregnant more than once during the 2-year restricted cubic splines with prespecified knots at 12, 20,
period, only data from the first of the pregnancies were and 38 weeks of gestation. The study was approved by
included. Owing to delays in registration, pregnancy out- the Danish Data Protection Agency (1-16-02-391-14) and
comes were not available for some of the fetuses scanned dur- Danish Health and Medicines authority (journal number
ing the last 6 months of the study period. 3-3013-516/1/).
Birth biometric data from children born before 30 weeks of
gestation were excluded owing to the lack of plausible refer- Results
ence values of birthweight and HC at this age as well as the
higher risk of associated maternal or fetal illness in these chil- The final cohort consisted of 57 785 fetuses, including 295 fe-
dren born very preterm.35 Observations deviating more than tuses with isolated CHDs (Table I and Figure 1); 145 of the
5 SD from the mean were excluded from the analyses in both included fetuses (49.1%) had isolated major CHDs (Table I),
groups.1,36 77 of these (53%) were diagnosed before birth. Forty-nine
CHDs were initially stratified into major and minor CHDs fetuses with isolated major CHDs were genetically tested,
(Table I) and further stratified into 6 subgroups: (1) 44 of whom had chromosomal microarray performed. The
univentricular (heart with any univentricular physiology women opted for termination of pregnancy in 29
including hypoplastic left heart syndrome), (2) Tetralogy of pregnancies with isolated major CHDs (Table I). The basic
Fallot, (3) transposition of the great arteries, (4) aortic characteristics and differences between individuals with and
obstructions (severe aortic stenosis, aortic atresia, without CHDs are depicted in Table III. Overall, the risk
hypoplastic aortic arch, and/or coarctation of the aortic of preterm birth was 5% in children without CHDs and
arch38), (5) ventricular septal defect (VSD), and (6) atrial 18.5% in children with CHDs.
147

Downloaded for Anonymous User (n/a) at LOS ANGELES COUNTY DEPARTMENT OF HEALTH SERVICES from ClinicalKey.com by Elsevier on June 04, 2020.
For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved.
THE JOURNAL OF PEDIATRICS  www.jpeds.com Volume 210

Figure 1. Delimitation of the ultrasound data and birth biometrics from the included fetuses with and without CHDs scanned
between January 1, 2012, and December 31, 2013.

At the first trimester ultrasound scan (median gestational (95% CI, 0.24 to 0.01; P = .03) between fetuses with
age of 125/7 weeks), the mean Z-score difference between fe- and those without CHDs. At birth, the mean HC Z-score dif-
tuses with and without CHDs was 0.03 (95% CI, 0.07 to ference was 0.22 (95% CI, 0.35 to 0.09; P < .001). The
0.13; P = .5). At the anomaly scan (median gestational age differences between fetuses with major CHDs and those
of 200/7 weeks), the mean HC Z-score difference was 0.13 without CHDs were even more pronounced, with a mean
148 Lauridsen et al

Downloaded for Anonymous User (n/a) at LOS ANGELES COUNTY DEPARTMENT OF HEALTH SERVICES from ClinicalKey.com by Elsevier on June 04, 2020.
For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved.
July 2019 ORIGINAL ARTICLES

Table I. The distribution of major and minor CHDs

Isolated CHDs, terminated Isolated CHDs born after 23
All CHDs Isolated CHDs pregnancy weeks of gestation
Minor
Atrial septal defect 58 41 0 (0) 41
VSD 83 70 0 (0) 70
Vascular ring 8 6 0 (0) 6
Mild pulmonary stenosis (no need for immediate intervention) 8 4 0 (0) 4
Mild hypoplasia or coarctation of the aortic arch 14 11 0 (0) 11
Patent arterial duct after 37 weeks of gestation 18 16 0 (0) 16
Other 3 2 0 (0) 2
Major
Transposition of the great arteries 21 19 0 (0) 19
Hypoplastic left heart syndrome 26 19 13 (68) 6
Univentricular, other 26 21 14 (67) 6
Tetralogy of Fallot 26 17 0 (0) 17
Atrioventricular septal defect 17 6 0 (0) 6
Total or partial anomalous pulmonary venous connection 7 6 0 (0) 6
Double outlet right ventricle 9 7 1 (14) 6
Pulmonary atresia or severe pulmonary stenosis 17 11 0 (0) 10
Aortic atresia or severe aortic stenosis 7 6 0 (0) 6
Severe mitral or tricuspid insufficiency 4 2 0 (0) 2
Congenitally corrected transposition of the great arteries 3 3 0 (0) 3
Severe hypoplasia or coarctation of the aortic arch 29 24 1 (4) 23
Other 5 4 0 (0) 4

All CHDs, Total number of fetuses with the different types of CHDs; Isolated CHDs, number of CHD fetuses after the exclusion of multifetal gestations, genetic syndromes, and/or major associated
malformations; Isolated CHDs, terminated pregnancy, number of isolated CHD pregnancies terminated (percentage); CHDs born after 23 weeks of gestational age, number of children with isolated
CHD born after 23 weeks of gestational age.
Modified from.37

HC Z-score difference of 0.22 (95% CI, 0.38 to 0.06; Overall, the HC Z-scores compared with the birthweight
P < .009) at the anomaly scan and 0.47 (95% CI, 0.67 Z-scores in newborns did not differ between those with
to 0.28; P < .001) at birth. In the subgroup analyses, new- and those without CHDs. However, in the subgroup analyses,
borns with univentricular physiology or Tetralogy of Fallot newborns with univentricular physiology had a smaller HC
had substantially smaller mean HC Z-scores at birth than in relation to birthweight. The mean Z-score difference in
newborns without CHDs (Table II). these newborns compared with infants without CHDs was
Regression analyses of the absolute continuous Z-score of 0.73 (95% CI, 1.31 to 0.15; P = .01). Newborns with
the head biometrics (biparietal diameter and HC; y axis) aortic obstructions had larger HCs in relation to the birth-
plotted against gestational age (x axis) illustrate that, espe- weight. The mean Z-score difference was 0.37 (95% CI,
cially fetuses with tetralogy of Fallot or univentricular phys- 0.01 to 0.74; P = .04).
iology, present early with decreased mean brain size Z- The mean placental weight Z-score difference between
scores compared with fetuses without CHDs. The differences newborns with and without CHDs was 0.21 (95% CI,
were statistically significant from the middle of the second 0.33 to 0.09; P < .001). Further details about placenta
trimester and onward (Figure 2). The scatter points below weight Z-score differences are provided in Table II.
each graph display the time points of available head size We found no statistically significant differences in HC Z-
measurements for those with (CHD) and without (no scores between individuals diagnosed with a CHD before
CHD) a heart defect. If there were gaps between the birth compared to after birth, either at the anomaly scan or
measurements of some of the heart defects, the continuous at birth.
curve is based on some degree of interpolation and the CI Only 12 children were born with univentricular physiology
is wider. after 23 weeks of gestation (Table I). We found no difference
The mean differences between fetuses with and those in HC Z-scores at the anomaly scan between those who were
without CHDs regarding fetal weight and birthweight Z- terminated and those who were not: 0.06 (95% CI, 1.03 to
scores were 0.17 (95% CI, 0.25 to 0.08; P < .001) 0.91; P = .9).
and 0.22 (95% CI, 0.34 to 0.10; P < .001), respec-
tively. The mean difference between birthweight Z-score Discussion
among fetuses with major CHDs compared with infants
without CHDs was 0.42 (95% CI, 0.59 to 0.24; In the present study, brain size in fetuses with isolated CHDs
P < .001). Of note, the estimated fetal weight Z-score was reduced at 20 weeks of gestation and onward, but not at
and the birthweight Z-scores in fetuses and newborns 12 weeks of gestation. This finding was more prominent in
with VSDs were significantly lower than those without fetuses with major CHDs, especially in those with univentric-
CHDs (Table II). ular physiology or Tetralogy of Fallot. In these subtypes, head
Fetal Heart Defects and Measures of Cerebral Size 149

Downloaded for Anonymous User (n/a) at LOS ANGELES COUNTY DEPARTMENT OF HEALTH SERVICES from ClinicalKey.com by Elsevier on June 04, 2020.
For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved.
THE JOURNAL OF PEDIATRICS  www.jpeds.com Volume 210

size was significantly smaller from the early second trimester

Z-score mean difference

0.33 to 0.09)*

0.59 to 0.24)*

1.39 to 0.48)*

0.71 to 0.07)*

0.35 ( 0.59 to 0.12)*

and onwards.

(median gestational

0.21 to 0.12)

0.62 to 0.57)

0.37 to 0.49)
age 401/7 weeks)
Placental weight

0.32 (0.04 to 0.66)*

Previous studies have also associated major CHDs with
decreased cerebral size at mid gestation24,38,42; however, we
also report on cerebral measures before 20 weeks of gestation
in fetuses with major and minor CHDs.

0.21 (
0.04 (
0.41 (
0.03 (
0.94 (

0.39 (
0.06 (
We speculate whether the early onset of compromised ce-
rebral growth in fetuses with univentricular physiology or
Tetralogy of Fallot may be explained by intracardiac mixing
Z-score mean difference

0.73 ( 1.31 to 0.15)*

HC minus birth weight

(median gestational

0.04 ( 0.08 to 0.16)

0.03 ( 0.13 to 0.18)
0.05 ( 0.13 to 0.23)

0.00 ( 0.45 to 0.45)

0.29 ( 0.76 to 0.17)

0.20 ( 0.02 to 0.42)

0.06 ( 0.35 to 0.23)
of oxygenated and deoxygenated blood, leading to a state
age 401/7 weeks)

0.37 (0.01 to 0.74)*

of relative cerebral hypoxia.18,43 The early onset of deviations
in fetal and placental growth may, on the other hand, point
toward factors affecting both cardiogenesis and brain devel-
opment,44 such as genetic or epigenetic factors.
HC was smaller in newborns with isolated CHDs than in
Aortic obstructions, Aortic atresia/stenosis, aortic arch hypoplasia/coarctation; ASD, atrial septal defect; BPD, biparietal diameter; ToF, Tetralogy of Fallot; TGA, transposition of the great arteries.
newborns without CHDs. Newborns with major CHDs ac-
0.34 to 0.10)*

0.59 to 0.24)*

1.39 to 0.48)*

1.03 to 0.31)*

0.37 ( 0.60 to 0.13)*

Table II. Mean Z-score differences of brain, body, and placental size between individuals with and without CHDs

counted for the majority of this difference, confirming previ-

Birth weight Z-score

(median gestational

0.21 to 0.11)

0.62 to 0.56)

0.37 to 0.49)
age 401/7 weeks)

0.35 (0.04 to 0.66)*

mean difference

ous findings.1,45 In newborns and fetuses with CHDs, we also

found a smaller body size and that the placenta was smaller
(potentially adding to the risk of a relative hypoxic state in
utero46).
0.22 (
0.05 (

0.03 (
0.41 (

0.94 (

0.67 (
0.06 (

Aortic obstructions and VSDs were associated with

increased HC relative to birthweight. This anthropometric
pattern has previously been reported in newborns with a
1.245 to 0.43)*
0.35 to 0.09)*

1.48 to 0.21)*
0.67 to 0.28)*
(median gestational

VSD.1 During pregnancy, the flow across a VSD is minimal

difference at birth

0.20 to 0.14)

0.75 to 0.05)
0.66 to 0.35)

0.17 ( 0.42 to 0.07)

0.25 ( 0.07 to 0.56)
HC Z-score mean

age 401/7 weeks)

owing to pressure equilibration between the pulmonary

and systemic circulations. Intrauterine growth restriction in
fetuses without CHD, which has generally been associated
0.22 (
0.03 (

0.85 (

0.35 (
0.47 (

0.94 (
0.15 (

with an asymmetrically large head relative to body size, has

also been associated with lower left ventricular end-systolic
and end-diastolic diameters, as well as a smaller posterior
Z-score mean difference

0.25 to 0.08)*

0.79 to 0.22)*
0.41 to 0.15)*

0.22 ( 0.39 to 0.05)*

(median gestational age

wall diameter in both systole and diastole.47 Noteworthy is

Estimated fetal weight

at the anomaly scan

0.19 to 0.05)

0.47 to 0.22)

0.45 to 0.08)
0.28 to 0.41)

0.10 ( 0.12 to 0.32)

the decreased fetal weight already at the second trimester

200/7 weeks)

scan, and the low placental weight and weight at birth in chil-
dren with VSDs in the present as well as in a previous study.23
Even though a VSD is usually considered to be a minor CHD,
0.17 (
0.07 (

0.51 (

0.18 (
0.28 (

0.13 (
0.07 (

we speculate that the presence of a VSD may alter the func-

tion of the heart during fetal life.
We do not know whether the brain suffers less if the body
0.24 to 0.01)*

0.38 to 0.06)*
(median gestational

0.20 to 0.12)

0.55 to 0.12)
0.73 to 0.18)

0.43 to 0.27)
0.68 to 0.20)

0.15 ( 0.38 to 0.07)

0.11 ( 0.21 to 0.40)

and the head are equally affected by reduced growth. Fetal

HC Z-score mean

age 200/7 weeks)

difference at the
anomaly scan

brain-sparing physiology (reduced resistance to cerebral

flow) has been associated with impaired neurodevelopment
in children with CHDs,48,49 and a low birthweight is reported
0.13 (
0.04 (
0.22 (
0.21 (
0.27 (

0.08 (
0.24 (

to be a risk factor for impaired neurodevelopment.50 Conse-

quently, we are unable to determine whether neurodevelop-
ment may be better in children with CHDs who are
0.07 to 0.13)
0.03 to 0.25)
0.19 to 0.09)
0.18 to 0.38)
0.51 to 0.27)

0.36 to 0.27)
0.40 to 0.47)

0.10 ( 0.10 to 0.30)

0.04 ( 0.22 to 0.30)
(median gestational
age of 125/7 weeks)
first trimester scan
BPD Z-score mean

symmetrically small than in those where only the head is

difference at the

small.
We found a prevalence of CHDs of 6.6 per 1000 births
(including live births, still births, and termination of preg-
0.03 (

0.10 (
0.11 (
0.05 (

0.12 (

0.05 (
0.04 (

nancies). Previous publications reported a birth prevalence

between 5.4 and 15.3 per 1000 births.1,37,51 The higher risk
of preterm birth in individuals with CHDs observed in our
obstructions
Univentricular

study has previously been reported.34 Children with a patent

Minor CHDs
Major CHDs
Categories
All CHDs

ductus arteriosus born before 37 weeks of gestation were

Aortic

*P < .05.
ASD
VSD
TGA

excluded from our analyses; nonetheless, a patent ductus ar-

ToF

teriosus screening program in children born very preterm

150 Lauridsen et al

Downloaded for Anonymous User (n/a) at LOS ANGELES COUNTY DEPARTMENT OF HEALTH SERVICES from ClinicalKey.com by Elsevier on June 04, 2020.
For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved.
July 2019 ORIGINAL ARTICLES

Figure 2. Mean continuous Z-scores of head biometrics (y axis) plotted against gestational age (x axis) in individuals without
(solid line) and with (dashed lines) a CHD. Grey area, CIs. Grey dots, time points of available head size measurements for those
with (CHD) and without (no CHD) a heart defect. Aortic obstruction, Aortic atresia/stenosis, aortic arch hypoplasia, or coarctation;
ASD, atrial septal defect; TGA, transposition of the great arteries.

may have induced detection bias owing to the finding of fetuses owing to genetic or chromosomal anomalies, 95
small septal defects that otherwise would not have been (66%) of those with isolated major CHDs were not geneti-
found.52 cally tested. Because information was lacking, there may
A limitation of our study and prior studies in this field is have been unknown factors (maternal characteristics, life-
that we cannot exclude confounding caused by genetic muta- style, and obstetric and medical history) resulting in residual
tions and epigenetic alterations. Even though we excluded 50 confounding.53-56 The majority of the missing newborn

Table III. Basic characteristics and differences between individuals with and without CHDs
No CHD Isolated CHD Difference
5/7 2/7 0/7 4/7 2/7 0/7
Gestational age at the first trimester scan, weeks 12 (12 to 13 ) 12 (12 to 13 )
Median BPD, mm 21.8 (20.1 to 23.3) 21.6 (20.0 to 23.3)
Correction of gestational age at the first scan, days +1 ( 2 to 3) 0 ( 3 to 2) *
Gestational age at the anomaly scan, weeks 200/7 (195/7 to 202/7) 200/7 (194/7 to 203/7)
Median HC at the anomaly scan, mm 171.4 (166.0 to 176.9) 170.7 (164.5 to 177.2)
Gestational age at birth, weeks 401/7 (390/7 to 410/7) 392/7 (375/7 to 404/7) *
HC at birth, cm 35 (34 to 36) 34 (33 to 36) *
Birth weight, g 3530 (3190 to 3860) 3260 (2800 to 3655) *
Placental weight, g 660 (570 to 760) 600 (500 to 720) *

Values are median (IQR). Medians are compared using the Wilcoxon rank-sum test.
BPD, Biparietal diameter.
*P < .05.

Fetal Heart Defects and Measures of Cerebral Size 151

Downloaded for Anonymous User (n/a) at LOS ANGELES COUNTY DEPARTMENT OF HEALTH SERVICES from ClinicalKey.com by Elsevier on June 04, 2020.
For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved.
THE JOURNAL OF PEDIATRICS  www.jpeds.com Volume 210

biometric data originated from fetuses scanned during the 9. Gardiner HM. Head start for heart babies: perspectives on neurodeve-
last 6 months of the study period. These data are likely to lopmental outcome. Ultrasound Obstet Gynecol 2009;34:616-7.
10. Olsen M, Hjortdal VE, Mortensen LH, Christensen TD, Sorensen HT,
be missing at random, and are thus unlikely to have intro-
Pedersen L. Educational achievement among long-term survivors of
duced bias. In fetuses with univentricular physiology, the congenital heart defects: a Danish population-based follow-up study.
HC Z-scores at 20 weeks of gestation did not differ according Cardiol Young 2011;21:197-203.
to whether the child was later born alive. Consequently, we 11. Olsen M, Sorensen HT, Hjortdal VE, Christensen TD, Pedersen L.
consider the risk of selection bias to be limited. HC Z-scores Congenital heart defects and developmental and other psychiatric
disorders: a Danish nationwide cohort study. Circulation 2011;124:
measured at birth in fetuses with CHDs were not statistically
1706-12.
different in those diagnosed before and those diagnosed after 12. Cheong JL, Thompson DK, Spittle AJ, Potter CR, Walsh JM, Burnett AC,
birth. Nonetheless, some degree of measurement error and et al. Brain volumes at term-equivalent age are associated with 2-year
information bias cannot be ruled out. It is a major strength neurodevelopment in moderate and late preterm children. J Pediatr
of the present study that we were able to include measure- 2016;174:91-7.e1.
13. Hallioglu O, Gurer G, Bozlu G, Karpuz D, Makharoblidze K, Okuyaz C.
ments as early as 12 weeks of gestation, linking later diagnoses
evaluation of neurodevelopment using Bayley-III in children with
during pregnancy as well as postnatal diagnoses of both ma- cyanotic or hemodynamically impaired congenital heart disease. Conge-
jor and minor CHDs with early prenatal measures. nit Heart Dis 2015;10:537-41.
Measures of brain size in fetuses with isolated CHDs begin 14. Matos SM, Sarmento S, Moreira S, Pereira MM, Quintas J, Peixoto B,
to deviate from those of fetuses without CHDs during the et al. Impact of fetal development on neurocognitive performance of ad-
olescents with cyanotic and acyanotic congenital heart disease. Congenit
second trimester. Fetuses with major CHDs and especially
Heart Dis 2014;9:373-81.
those with univentricular physiology or tetralogy of Fallot ex- 15. Jowett V, Allsop J, Fox M, Kyriakopoulou V, Rutherford M, Gardiner H.
hibited the earliest and most pronounced compromise in ce- Brain growth is impaired in fetuses with congenital heart disease-MR
rebral growth. We recommend neurodevelopmental follow- volumetric assessment of the fetal brain. Cardiol Young
up of all children with CHDs. n 2013;23(Suppl):S15.
16. Zeng S, Zhou QC, Zhou JW, Li M, Long C, Peng QH. Volume of intra-
cranial structures on three-dimensional ultrasound in fetuses with
We thank research nurse Vibeke Laursen for her assistance in obtaining congenital heart disease. Ultrasound Obstet Gynecol 2015;46:174-81.
the relevant data from the medical records. We thank Aarhus Univer- 17. Limperopoulos C, Tworetzky W, McElhinney DB, Newburger JW,
sity for supporting this work. Brown DW, Robertson RL Jr, et al. Brain volume and metabolism in fe-
tuses with congenital heart disease: evaluation with quantitative mag-
Submitted for publication Nov 13, 2018; last revision received Jan 14, 2019; netic resonance imaging and spectroscopy. Circulation 2010;121:26-33.
accepted Feb 27, 2019. 18. Sun L, Macgowan CK, Sled JG, Yoo SJ, Manlhiot C, Porayette P, et al.
Reprint requests: Mette Høj Lauridsen, MD, PhD, Department of Pediatrics Reduced fetal cerebral oxygen consumption is associated with smaller
and Adolescent Medicine, Aarhus University Hospital, Palle Juul Jensens brain size in fetuses with congenital heart disease. Circulation
Boulevard 99, 8200 Aarhus N, Denmark. E-mail: [email protected] 2015;131:1313-23.
19. Lauridsen MH, Uldbjerg N, Henriksen TB, Petersen OB, Stausbol-
Gron B, Matthiesen NB, et al. cerebral oxygenation measurements by
References magnetic resonance imaging in fetuses with and without heart defects.
1. Matthiesen NB, Henriksen TB, Gaynor JW, Agergaard P, Bach CC, Circ Cardiovasc Imaging 2017;10:e006459.
Hjortdal VE, et al. Congenital heart defects and indices of fetal cerebral 20. Ruiz A, Ferrer Q, Sanchez O, Ribera I, Arevalo S, Alomar O, et al.
growth in a nationwide cohort of 924 422 liveborn infants. Circulation Placenta-related complications in women carrying a foetus with congen-
2016 9;133:566-75. ital heart disease. J Matern Fetal Neonatal Med 2016;8:1-5.
2. Bean Jaworski JL, Flynn T, Burnham N, Chittams JL, Sammarco T, 21. Thilaganathan B. Preeclampsia and fetal congenital heart defects:
Gerdes M, et al. Rates of autism and potential risk factors in children spurious association or maternal confounding? Circulation 2017;136:
with congenital heart defects. Congenit Heart Dis 2017;12:421-9. 49-51.
3. Khalil A, Suff N, Thilaganathan B, Hurrell A, Cooper D, Carvalho JS. 22. Auger N, Fraser WD, Healy-Profitos J, Arbour L. Association between
Brain abnormalities and neurodevelopmental delay in congenital heart preeclampsia and congenital heart defects. JAMA 2015;314:1588-98.
disease: systematic review and meta-analysis. Ultrasound Obstet Gynecol 23. Matthiesen NB, Henriksen TB, Agergaard P, Gaynor JW, Bach CC,
2014;43:14-24. Hjortdal VE, et al. Congenital heart defects and indices of placental
4. Dimitropoulos A, McQuillen PS, Sethi V, Moosa A, Chau V, Xu D, et al. and fetal growth in a nationwide study of 924 422 liveborn infants. Cir-
Brain injury and development in newborns with critical congenital heart culation 2016;134:1546-56.
disease. Neurology 2013;81:241-8. 24. Ruiz A, Cruz-Lemini M, Masoller N, Sanz-Cortes M, Ferrer Q, Ribera I,
5. Martinez-Biarge M, Jowett VC, Cowan FM, Wusthoff CJ. Neurodeve- et al. Longitudinal changes in fetal biometry and cerebroplacental hemo-
lopmental outcome in children with congenital heart disease. Semin dynamics in fetuses with congenital heart disease. Ultrasound Obstet Gy-
Fetal Neonatal Med 2013;18:279-85. necol 2017;49:379-86.
6. Owen M, Shevell M, Donofrio M, Majnemer A, McCarter R, Vezina G, 25. Turan S, Rosenbloom JI, Hussein M, Berg C, Gembruch U, Baschat AA,
et al. Brain volume and neurobehavior in newborns with complex et al. Longitudinal analysis of head and somatic growth in fetuses with
congenital heart defects. J Pediatr 2014;164:1121-7.e1. congenital heart defects. J Clin Ultrasound 2017;45:96-104.
7. Marino BS, Lipkin PH, Newburger JW, Peacock G, Gerdes M, 26. Larsen SH, Olsen M, Emmertsen K, Hjortdal VE. Interventional treat-
Gaynor JW, et al. Neurodevelopmental outcomes in children with ment of patients with congenital heart disease: nationwide Danish expe-
congenital heart disease: evaluation and management: a scientific state- rience over 39 years. J Am Coll Cardiol 2017;69:2725-32.
ment from the American Heart Association. Circulation 2012;126: 27. Oster ME, Lee KA, Honein MA, Riehle-Colarusso T, Shin M, Correa A.
1143-72. Temporal trends in survival among infants with critical congenital heart
8. Donofrio M, Duplessis A, Limperopoulos C. Impact of congenital heart defects. Pediatrics 2013;131:e1502-8.
disease on fetal brain development and injury. Curr Opin Pediatr 28. Porayette P, Madathil S, Sun L, Jaeggi E, Grosse-Wortmann L, Yoo SJ,
2011;23:502-11. et al. MRI reveals hemodynamic changes with acute maternal

152 Lauridsen et al

Downloaded for Anonymous User (n/a) at LOS ANGELES COUNTY DEPARTMENT OF HEALTH SERVICES from ClinicalKey.com by Elsevier on June 04, 2020.
For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved.
July 2019 ORIGINAL ARTICLES

hyperoxygenation in human fetuses with and without congenital heart 44. Barkovich AJ, Guerrini R, Kuzniecky RI, Jackson GD, Dobyns WB. A
disease. Prenat Diagn 2016;36:274-81. developmental and genetic classification for malformations of cortical
29. Mitchell SC, Korones SB, Berendes HW. Congenital heart disease in development: update 2012. Brain 2012;135:1348-69.
56,109 births. Incidence and natural history. Circulation 1971;43:323- 45. Barbu D, Mert I, Kruger M, Bahado-Singh RO. Evidence of fetal central
32. nervous system injury in isolated congenital heart defects: microcephaly
30. Ekelund CK, Kopp TI, Tabor A, Petersen OB. The Danish Fetal Medicine at birth. Am J Obstet Gynecol 2009;201. 43.e1-e7.
database. Clin Epidemiol 2016;8:479-83. 46. Miller SL, Huppi PS, Mallard C. The consequences of fetal growth re-
31. Crombag NM, Vellinga YE, Kluijfhout SA, Bryant LD, Ward PA, Ie- striction on brain structure and neurodevelopmental outcome. J Physiol
dema-Kuiper R, et al. Explaining variation in Down’s syndrome 2016;594:807-23.
screening uptake: comparing the Netherlands with England and 47. Cinar B, Sert A, Gokmen Z, Aypar E, Aslan E, Odabas D. Left ventricular
Denmark using documentary analysis and expert stakeholder interviews. dimensions, systolic functions, and mass in term neonates with symmet-
BMC Health Serv Res 2014;14:437. ric and asymmetric intrauterine growth restriction. Cardiol Young
32. Knudsen LB, Olsen J. The Danish Medical Birth Registry. Dan Med Bull 2015;25:301-7.
1998;45:320-3. 48. Masoller N, Sanz-CorteS M, Crispi F, Gomez O, Bennasar M, Egana-
33. Schmidt M, Pedersen L, Sorensen HT. The Danish Civil Registration Sys- Ugrinovic G, et al. Mid-gestation brain Doppler and head biometry in
tem as a tool in epidemiology. Eur J Epidemiol 2014;29:541-9. fetuses with congenital heart disease predict abnormal brain develop-
34. Lindinger A, Schwedler G, Hense HW. Prevalence of congenital heart de- ment at birth. Ultrasound Obstet Gynecol 2016;47:65-73.
fects in newborns in Germany: results of the first registration year of the 49. Williams IA, Tarullo AR, Grieve PG, Wilpers A, Vignola EF, Myers MM,
PAN Study (July 2006 to June 2007). Klin Padiatr 2010;222:321-6. et al. Fetal cerebrovascular resistance and neonatal EEG predict 18-
35. Swanson JR, Sinkin RA. Early births and congenital birth defects: a com- month neurodevelopmental outcome in infants with congenital heart
plex interaction. Clin Perinatol 2013;40:629-44. disease. Ultrasound Obstet Gynecol 2012;40:304-9.
36. Snijders RJ, Nicolaides KH. Fetal biometry at 14-40 weeks’ gestation. Ul- 50. Gaynor JW, Stopp C, Wypij D, Andropoulos DB, Atallah J, Atz AM, et al.
trasound Obstet Gynecol 1994;4:34-48. Neurodevelopmental outcomes after cardiac surgery in infancy. Pediat-
37. Dolk H, Loane M, Garne E. European Surveillance of Congenital Anom- rics 2015;135:816-25.
alies (EUROCAT) Working Group. Congenital heart defects in Europe: 51. Jorgensen DE, Vejlstrup N, Jorgensen C, Maroun LL, Steensberg J,
prevalence and perinatal mortality, 2000 to 2005. Circulation 2011;123: Hessellund A, et al. Prenatal detection of congenital heart disease in a
841-9. low risk population undergoing first and second trimester screening.
38. Jansen FA, van Zwet EW, Rijlaarsdam ME, Pajkrt E, van Velzen CL, Prenat Diagn 2015;35:325-30.
Zuurveen HR, et al. Head growth in fetuses with isolated congenital 52. Garne E, Olsen MS, Johnsen SP, Hjortdal V, Andersen HO, Nissen H,
heart defects: lack of influence of aortic arch flow and ascending aorta et al. How do we define congenital heart defects for scientific studies?
oxygen saturation. Ultrasound Obstet Gynecol 2016;48:357-64. Congenit Heart Dis 2012;7:46-9.
39. Chitty LS, Altman DG, Henderson A, Campbell S. Charts of fetal size: 2. 53. Grigoriadis S, VonderPorten EH, Mamisashvili L, Tomlinson G,
Head measurements. Br J Obstet Gynaecol 1994;101:35-43. Dennis CL, Koren G, et al. The impact of maternal depression during
40. Marsal K, Persson PH, Larsen T, Lilja H, Selbing A, Sultan B. Intrauterine pregnancy on perinatal outcomes: a systematic review and meta-analysis.
growth curves based on ultrasonically estimated foetal weights. Acta Pae- J Clin Psychiatry 2013;74:e321-41.
diatr 1996;85:843-8. 54. Oyen N, Diaz LJ, Leirgul E, Boyd HA, Priest J, Mathiesen ER, et al. Pre-
41. Arendt LH, Ramlau-Hansen CH, Wilcox AJ, Henriksen TB, Olsen J, pregnancy diabetes and offspring risk of congenital heart disease: a
Lindhard MS. Placental weight and male genital anomalies: a nationwide nationwide cohort study. Circulation 2016;133:2243-53.
Danish cohort study. Am J Epidemiol 2016;183:1122-8. 55. Jimenez-Solem E, Andersen JT, Petersen M, Broedbaek K, Jensen JK,
42. Masoller N, Martinez JM, Gomez O, Bennasar M, Crispi F, Sanz M, et al. Afzal S, et al. Exposure to selective serotonin reuptake inhibitors and the
Evidence of second trimester changes in head biometry and brain perfu- risk of congenital malformations: a nationwide cohort study. BMJ Open
sion in fetuses with congenital heart disease. Ultrasound Obstet Gynecol 2012;2. https://doi.org/10.1136/bmjopen-2012-001148. Print 2012.
2014;44:182-7. 56. Liu S, Joseph KS, Lisonkova S, Rouleau J, Van den Hof M, Sauve R,
43. Rosenthal GL. Patterns of prenatal growth among infants with cardio- et al. Association between maternal chronic conditions and congen-
vascular malformations: possible fetal hemodynamic effects. Am J Epide- ital heart defects: a population-based cohort study. Circulation
miol 1996;143:505-13. 2013;128:583-9.

Fetal Heart Defects and Measures of Cerebral Size 153

Downloaded for Anonymous User (n/a) at LOS ANGELES COUNTY DEPARTMENT OF HEALTH SERVICES from ClinicalKey.com by Elsevier on June 04, 2020.
For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved.