Keywords
cardiac abnormality - cardiac anomaly - conotruncal - noncardiac abnormalities - noncardiac
anomalies
Cardiac abnormalities are among the most common congenital malformations and are present
in an estimated 0.8% of live births.[1]
[2] In the United States, routine ultrasound has led to the prenatal detection of fetal
cardiac malformations, though recent publications describe only a 36 to 39% detection
rate for all congenital cardiac malformations.[3]
[4]
The etiology of congenital cardiac abnormalities is multifactorial, and risk factors
include family history, teratogen exposure, and pregestational diabetes.[5] There is also an association with chromosomal abnormalities[6]
[7] and single-gene disorders. Previous studies have reported on the rate and type of
extracardiac anomalies and aneuploidy identified in fetuses with cardiac anomalies,[8] and the prognosis with associated structural or genetic abnormalities is worse.
Cardiac anomalies are associated with structural anomalies such as gastrointestinal
or skeletal abnormalities that may be difficult to identify at the time of the anatomy
ultrasound.[9] The likelihood of extracardiac anomalies that are not sonographically apparent in
the setting of normal genetic testing is unclear.
Accurate prenatal diagnosis can improve perinatal and long-term outcome by optimizing
the timing of delivery and ensuring that delivery occurs at a tertiary care center
with advanced expertise in the management of these neonates.[6] Prenatal diagnosis of cardiac defects can also give the patient an opportunity to
consider terminating the pregnancy. Information about the likelihood of associated
anomalies that are not apparent in the second trimester could inform these important
medical decisions. Our objective was to determine the rate of unsuspected noncardiac
abnormalities in newborns suspected to have isolated cardiac abnormalities in the
second trimester.
Materials and Methods
We reviewed the obstetric ultrasound database from the Weill Cornell Medical Center
and identified fetuses with a suspected cardiac abnormality (other than isolated atrial
or ventricular septal defect) from January 2006 to November 2016. Isolated atrial
and ventricular septal defects were excluded because the majority do not have clinical
sequelae and most resolve spontaneously.[10]
[11] A detailed anatomical evaluation was performed in all patients in the second trimester,
and cases in which noncardiac structural abnormalities were identified were excluded.
Cardiac anomalies were categorized as either conotruncal or noncontruncal. Conotruncal
anomalies included truncus arteriosus, malposition of the great arteries, tetralogy
of Fallot, double-outlet right ventricle, and a ventricular septal defect with an
overriding aorta. Structural abnormalities were defined as those that required medical
or surgical intervention or had a substantial cosmetic or functional impact. All patients
underwent fetal echocardiography to confirm the cardiac abnormality. Genetic counseling
was offered to all patients, and cases with abnormal fetal or postnatal genetic testing
were excluded. Patients without postnatal confirmation of fetal echocardiography findings,
those who delivered at an outside institution, and those who underwent abortion were
also excluded.
Neonatal records were reviewed to confirm prenatal findings and postnatal genetic
testing and to identify anomalies not suspected in the second trimester. Postnatal
imaging studies were also reviewed to correlate with prenatal findings. Categorical
data were compared using Fisher's exact test and χ
2 analysis. Institutional Review Board approval was obtained.
Results
We identified 94 cases of isolated fetal cardiac abnormalities suspected on prenatal
ultrasound. There were 68 live births meeting the inclusion criteria, and all fetal
echo findings were confirmed postnatally. Conotruncal abnormalities were suspected
in 42 (61.8%) cases ([Table 1]). The most common conotruncal abnormalities were tetralogy of Fallot (20 cases;
47.6%) and transposition of the great arteries (11 cases; 29%). Of the nonconotruncal
abnormalities, the most common were aortic coarctation in isolation or with other
cardiac abnormalities (12 cases; 55%), and hypoplastic left or right heart (5 cases;
23%). Twenty-five patients had prenatal genetic testing through amniocentesis. All
25 had a karyotype, 15 (60%) had a microarray, and 4 (16%) had fluorescent in situ
hybridization specific for 22q11.2 deletion performed. Neonatal genetic testing was
performed on 20 of the 43 patients who did not have an amniocentesis. Neonatal genetic
testing included a karyotype in all cases and microarray in eight cases, all of which
were normal. Of the newborns who did not undergo genetic testing, none had any noncardiac
clinical features of DiGeorge's syndrome.
Table 1
Factors associated with unsuspected postnatal findings
|
No noncardiac findings identified postnatally (n = 63)
|
Noncardiac findings identified postnatally (n = 5)
|
p-Value
|
|
Maternal age[a]
|
32 [26–35]
|
30 [27–32]
|
0.81
|
|
Raceb
|
|
White
|
23
|
1
|
0.27
|
|
Black or African-American
|
6
|
2
|
|
Hispanic
|
8
|
−
|
|
Asian
|
6
|
−
|
|
Declined/other combinations, not described
|
20
|
2
|
|
BMI[a]
|
24 [22–29]
|
25 [22–26]
|
0.63
|
|
Single umbilical arteryb
|
8
|
0
|
0.40
|
|
Category of cardiac anomalyb
|
|
Conotruncal
|
37
|
5
|
0.07
|
|
Nonconotruncal
|
26
|
0
|
Abbreviation: BMI, body mass index.
a Data are presented as median [interquartile range]. bData are presented as number of cases.
There were five (7.4%) newborns with one or more major abnormalities not identified
in the second trimester ([Table 2]). There were no associated findings, such as a single umbilical artery, in any of
these cases. Three newborns had an imperforate anus. One newborn had left hydronephrosis
and an absent right lung. Another newborn had hemifacial microsomia and fused ribs.
All five newborns with unsuspected anomalies were in the group with suspected conotruncal
anomalies, with an 11.9% rate of unsuspected anomalies versus 0% in those with nonconotruncal
cardiac anomalies (p = 0.15). There was no association of maternal age, body mass index, ethnicity, or
single umbilical artery with unsuspected postnatal findings ([Table 1]).
Table 2
Suspected isolated cardiac anomalies and postnatal findings
|
Case
|
Suspected cardiac anomaly
|
Neonatal sex
|
Was prenatal genetic testing performed?
|
Was postnatal genetic testing performed?
|
Postnatal findings
|
|
1
|
Tetralogy of Fallot, large ventricular septal defect, hypoplastic pulmonary arteries
|
Male
|
No
|
No
|
Imperforate anus
VATER
|
|
2
|
Dextroversion, transposition of the great arteries, ventricular septal defect
|
Male
|
No
|
Yes, karyotype, microarray (all normal)
|
Left hydronephrosis, right hemivertebrae, absent right lung
|
|
3
|
Tetralogy of Fallot
|
Male
|
No
|
Yes, karyotype, microarray (all normal)
|
Imperforate anus
|
|
4
|
Tetralogy of Fallot
|
Female
|
Yes, karyotype (normal)
|
Yes, karyotype, microarray (all normal)
|
Imperforate anus, rectovaginal fistula
|
|
5
|
Double-outlet right ventricle, ventricular septal defect, overriding aorta
|
Male
|
No
|
Yes, karyotype microarray (all normal)
|
Torticollis, hemifacial microsomia, right fused ribs, left hemivertebrae at T9
|
Abbreviation: VATER, vertebral anomalies, anal atresia, tracheoesophageal fistula,
esophageal atresia, and renal and radial anomalies.
Four of the five cases with unsuspected major anomalies underwent postnatal genetic
testing including karyotype and microarray, which were normal. One case did not undergo
postnatal genetic testing, and this case was the only one associated with a defined
syndrome. In this case (case 1), the findings were consistent with VATER (vertebral
anomalies, anal atresia, tracheoesophageal fistula, esophageal atresia, and renal
and radial anomalies).
Comment
Major noncardiac findings not suspected in the second trimester were not uncommon,
particularly among newborns with conotruncal anomalies. The difference in rates of
unsuspected findings in conotruncal versus other cardiac anomalies (11.9% vs 0%) was
not statistically significant, though posthoc power analysis indicates that we only
had 41.8% power to discern such a difference. Our study is unlike other studies characterizing
the frequency of associated anomalies in fetuses with cardiac anomalies, as we included
only cases with no sonographic evidence of associated anomalies at the time of prenatal
diagnosis.
Conotruncal anomalies are a category of cardiac abnormalities characterized by a defect
in the conotruncal septum and include truncus arteriosus, malposition of the great
arteries, tetralogy of Fallot, double-outlet right ventricle, and a ventricular septal
defect with an overriding aorta.[12] Published studies describe high rates of associated noncardiac anomalies, with a
considerably worse prognosis in these cases.[7]
[12] Unlike our study, however, these studies included cases with anomalies detected
in utero as well as those fetuses with chromosomal abnormalities. As our study excluded
such cases, the rate of associated anomalies in our study population was considerably
lower.
While the absence of associated genetic or major structural abnormalities apparent
in utero is reassuring, patients should be aware of the possibility that major structural
abnormalities could be identified after birth. As such abnormalities could be associated
with a poorer prognosis, this information could inform decisions regarding continuing
versus terminating an affected pregnancy. Third-trimester ultrasound to look for evidence
of associated anomalies could be considered; however, some anomalies such as an imperforate
anus, the most common unsuspected anomaly in this series, is rarely identified in
utero.[13]
A limitation of the study was the relatively small number of cases, as a large proportion
of fetuses with cardiac anomalies have associated genetic or structural abnormalities
identified in utero, and many patients in our population do not continue pregnancies
after the diagnosis of major fetal cardiac anomalies. Another limitation is that genetic
testing was not performed on all cases. While we acknowledge the possibility of undiagnosed
genetic conditions in our study group, some patients with cardiac anomalies diagnosed
by ultrasound decline genetic testing. As counseling these patients about the possibility
of unsuspected structural anomalies is important, our data may be relevant to these
patients. We also acknowledge that genetic testing has advanced considerably since
the beginning of our study period and that many anomalies formerly considered isolated
may now be recognized to have an associated genetic abnormality.
Among the strengths of this analysis was the single-institution design, which allowed
us to compare prenatal and postnatal findings with precision. Detailed anatomical
fetal evaluation was performed in all cases under a uniform imaging protocol. Neonatal
follow-up was available in all cases, and all patients had fetal and neonatal echocardiography
performed in the same pediatric cardiology unit.
In summary, patients with a suspected isolated fetal cardiac anomaly on ultrasound
should be aware of the possibility of other major structural abnormalities, especially
in cases of conotruncal anomalies. Our results provide a different perspective on
apparently isolated cardiac anomalies. While neonatal prognosis largely depends on
the severity of the cardiac anomaly, the outcome may also depend on the presence and
severity of associated noncardiac findings.
