(Circulation. 1997;96:550-555.)
© 1997 American Heart Association, Inc.
Articles |
Congenital Heart Defects
Natural Course and In Utero Development
From the Department of Obstetrics and Gynecology, Hadassah Medical Center, Mount Scopus, Jerusalem (S.Y.), and the Department of Obstetrics and Gynecology, Chaim Sheba Medical Center, Tel Hashomer, and Sackler School of Medicine, Tel Aviv University, Israel.
Correspondence to R. Achiron, MD, Department of Obstetrics and Gynecology, Chaim Sheba Medical Center, Tel Hashomer 52621, Israel.
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Abstract |
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Background Most congenital heart defects (CHDs) are diagnosed on targeted prenatal transvaginal (TVS) or transabdominal (TAS) ultrasonography during the early second trimester or at midgestation. Nevertheless, delayed diagnosis in some cardiac malformations still remains despite detailed echocardiographic examination. The present study was conducted to evaluate the evolution of fetal cardiac anomalies and assess their development in utero.
Methods and Results We retrospectively reviewed 22 050 pregnant women who were divided into two groups: 6924 who had initial TVSs at 13 to 16 weeks' gestation, followed by TASs at 20 to 22 weeks, and 15 126 who had initial TASs at 20 to 22 weeks. Both groups were subsequently examined in their third trimester. All newborns were examined by certified pediatricians. CHD was diagnosed in 168 babies: 66 in group A and 102 in group B. In group A, 42 malformations (64%) were detected at the first TVS examination, and 11 (17%) were found during the subsequent TAS. Three additional anomalies (4%) were found during the third trimester, and 10 malformations (15%) were detected postnatally. In group B, 80 malformations (78%) were detected in the initial examination at midtrimester, and an additional 7 (7%) were found in the third trimester, whereas 15 (15%) were diagnosed postnatally. The 10 anomalies (group A, n=3; group B, n=7) that were detected only during the third trimester comprised aortic stenosis (n=2), cardiac rhabdomyoma (n=2), subaortic stenosis (n=1), tetralogy of Fallot (n=1), aortic coarctation (n=1), sealed foramen ovale (n=1), ventricular septal defects (n=1), and hypertrophic cardiomyopathy (n=1).
Conclusions Although most fetal cardiac anomalies are detectable early in gestation, some may evolve in utero at different stages of pregnancy.
Key Words: heart defects, congenital • diagnosis, in utero
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Introduction |
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Congenital heart defects are the most common major congenital malformation, affect 8 of every 1000 live births, and account for >20% of perinatal deaths resulting from congenital malformations1 and more than half the deaths in childhood caused by lethal malformations.2 CHDs are 6.5 times more common than chromosomal abnormalities and 4 times more common than neural tube defects.3 There also is a high incidence of chromosomal abnormalities that accompany CHD,4 and the prenatal diagnosis of CHD is often considered an indication for fetal karyotyping.
Technical advances in ultrasound instrumentation and the introduction of the extended echocardiographic examination5 into routine prenatal scanning have significantly improved the diagnostic capabilities of ultrasound over the last decade, contributing to the accurate antenatal detection of CHD and cardiac arrhythmias. At the same time, cardiac anomalies are the most frequently overlooked lesions during prenatal ultrasonographic scanning.6 All the benefits of early prenatal diagnosis—such as counseling by a multidisciplinary team, evaluation for chromosomal abnormalities and extracardiac anomalies, the option for elective pregnancy termination, or planned delivery in an appropriate tertiary center—are withheld from the family if the diagnosis has been missed. Furthermore, with the current climate of obstetric malpractice claims, medico-legal aspects should also be taken into consideration. Even with the combination of advanced instrumentation and expert hands and eyes, some CHDs will not be detected during anomaly surveys performed during midgestation. Although prenatal diagnosis of severe and complex cardiac malformations is relatively common early in the course of gestation, it is mainly anomalies with more subtle anatomic distortion such as AS and VSDs that often escape diagnosis.7
Recently, scattered reports show growing evidence that progression of cardiac disease may occur and be observed in utero with advancing gestational age.8 9 10 11 12 13 14 15 Motivated by these observations, we undertook this study in an attempt to characterize and further clarify the development of cardiac defects in utero.
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Methods |
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Patients
In a retrospective study, the medical files of 22 050 women and their newborns of a mixed high- and low-risk population for CHD were evaluated. All women had attended the obstetrical ultrasound units of the Chaim Sheba Medical Center or Hadassah Mount Scopus University Hospital between January 1990 and January 1994 for a targeted scan of fetal anomalies. The mean age and parity of the women who made up the study group were 29.1 years (range, 16 to 47 years) and 2.4 (range, 0 to 13), respectively.
Ultrasonographic fetal anomaly survey has become common practice in our
country, and almost every pregnant woman currently undergoes at least
one such scan, normally TAS, performed about 20 to 22 weeks of
pregnancy. Major health insurance organizations are funding this
program. Although early TVS was previously performed primarily in
high-risk patients, today an increasing number of low-risk patients
voluntarily seek and undergo an early transvaginal examination. An
additional ultrasound examination is commonly performed during the
third trimester of pregnancy for evaluation of fetal growth and
well-being. Further examinations are performed for various obstetrical
conditions and complications when ultrasonography is indicated. Thus, a
total of 4961 women (22.5%) were referred because they were considered
to be at high risk for fetal anomalies because of (1) a child with a
structural anomaly (including CHD) in a previous pregnancy, (2) a
strong family history (parents or their first-degree relatives affected
by structural anomalies), (3) maternal age (>37 years), (4) abnormal
biochemical triple marker (maternal serum 
-fetoprotein, human
chorionic gonadotropin, and estriol) screening results, (5) maternal
diabetes, (6) maternal exposure to teratogenic drugs or conditions (eg,
viral disease) associated with a high risk for CHD, and (7) twin
pregnancies (507 pairs or 2.3% of the study group). Higher-order
multiplets were not included in our study. The low-risk population
consisted of 17 089 pregnant women (77.5%).
Third-trimester ultrasound scans were performed for such obstetrical indications as estimation of fetal weight, assessment of amniotic fluid and fetal well-being, and evaluation of fetal and maternal blood flow.
For TVS, the empty bladder technique was used, and 6.5- and 7.5-MHz
mechanical sector transducers (Elscint ESI-3000) were applied. A
3.5-MHz convex scanner (Elscint ESI-3000, Aloka SSD 650, or Acuson
128xP/10) was used for the transabdominal scan. Detailed biometric and
structural evaluations of all fetuses were undertaken. In all cases and
on all occasions, the extended fetal echocardiographic
examination was performed as previously described by our
group.5 First, the standard four-chamber view was
visualized, and once it was obtained, simple rotation of the probe
(
90°) along its axis brought the major great vessels into view,
allowing proper visualization of the left ventricle outlet, the short
axis of the right ventricle axis with the main pulmonary
artery, and the aortic arch and ductus. All sonographic examinations
were performed by two operators (Drs Achiron and Yagel), both
experienced in fetal echocardiography.
Approximately 1% of total examinations were incomplete or
unsatisfactory16 and were not included in our study.
Only patients in whom the diagnosis of fetal cardiac defects was missed during the initial echocardiographic examinations (early second-trimester TVS or midgestation TAS at 20 to 22 weeks' gestation) and diagnosed on subsequent ultrasonographic examinations during pregnancy or postnatally were evaluated for this study. The medical records—including reports, prints, and videotapes of initial ultrasound examinations and of scans performed on detection of an anomaly; autopsy reports (where available); and neonatal records of newborns—were evaluated.
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Results |
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During the 4-year study period, 22 050 women, including 507 women who had twins, had fetal cardiac ultrasonographic examinations. Group A comprised 6924 patients (31.4%) who were initially examined by TVS at 13 to 16 weeks' gestation, followed by TAS at 20 to 22 weeks in 6701 patients (97%). Third-trimester examination was performed in this group in 6579 patients (95%; Fig 1
). In group B,
15 126 patients (68.6%) had their initial examinations at
midgestation with TAS, and in 14 370 patients (95%), third-trimester
examinations were performed. A total of 1607 newborns (8.95%) were not
available for postnatal examination. Of the mothers of newborns lost to
follow-up, 801 were from group A, and 806 were from group B. One
hundred sixty-eight fetuses (7.6 of 1000) were diagnosed prenatally and
postnatally as having congenital cardiac anomalies. Sixty-six were from
group A, and 102 were from group B. Fig 2 describes the
accumulation of detection of cardiac malformations in group A on each
examination. The first TVS examination at 13 to 16 weeks revealed 42
malformations (64%). At midgestation, 81% of the malformations were
diagnosed because 11 new cases (17%) that had not been previously
diagnosed by TVS were evident on TAS. Examination in the third
trimester added 3 new cases (4%) that had not been previously
detected, bringing the total to 56 anomalies (85%) detected in utero.
In group B, 102 anomalies were found, 78% having been detected during
the first TAS at midgestation. This rate is comparable to the
accumulation rate of diagnosis in group A at the same gestational point
(Fig 2). In this group, third-trimester examination added 7% of
anomalies, again comparable to group A. In both groups, postnatal
examination added 15% of anomalies (P>.01,
2 test).
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Table 1 summarizes the types of 122 fetal cardiac
anomalies detected during the initial ultrasonographic examination in
both groups. These 122 cases represent 42 anomalies detected in
group A with TVS, and 80 of group B were diagnosed with TAS. Table 2 summarizes the type of cardiac anomalies detected at
subsequent ultrasonographic examinations. Eleven anomalies were
undetected in group A during the early TVS, and 10 anomalies (3 from
group A; 7 from group B) were undetected until the last in utero
third-trimester examination. Prenatal diagnosis of CHD was possible in
a total of 143 of 168 cases (85%).
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In 25 cases (15%; group A, n=10; group B, n=15), CHD was diagnosed
only postnatally. Table 3 outlines the types of
malformations and the number of diagnosed cases. In 15 cases, postnatal
evaluation revealed additional cardiac abnormalities. Of these 15
abnormalities, 4 were major and 11 were minor. The 4 major
abnormalities included transposition of the great arteries,
coarctation, and 2 cases with heterotoxic syndrome and mitral and
tricuspid stenoses. Seven cases had false-positive diagnoses,
which included VSD (n=3), coarctation of the aorta (n=2), and PS and
atrial septal defect (n=1). Chromosomal analysis was performed
in 85% of the cases. Fourteen (10%) abnormal karyotypes were
detected: trisomy 21 in 8, trisomy 18 in 4, trisomy 13 in 1, and
monosomy XO in 1. Two additional cases with trisomy 21 were detected
postnatally among those who had no in utero investigation. Ten cases
had additional extracardiac abnormalities. Twenty-five pregnancies were
terminated, and 15 fetuses died in utero; thus, the mortality of
fetuses in completed pregnancies was 28% (40 of 143). Twenty-five
newborns died postnatally; overall, 65 of 168 fetuses (39%) with
cardiac anomalies died. In 5 of the 103 surviving newborns, an
associated genetic syndrome was found.
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Discussion |
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Our study presents novel data regarding the natural course and development of CHD in a large fetal anomaly survey program. It is noteworthy that this study re-emphasizes the importance of an extended fetal echocardiographic examination performed by experienced obstetric ultrasonographers with an interest in fetal heart imaging. This inclusion facilitated a correct diagnosis in
80% of newborns with CHD early in the course of pregnancy. This
figure is comparable to previous reports by us5 and
others.17 18 Altogether, prenatal diagnosis of CHD was
possible in 85% of the population. However, of major importance is the
finding that a considerable portion (20%) of CHD, which includes a
wide range of cardiac malformations, may remain undetected even after
detailed and thorough echocardiographic examinations
have been performed by experienced operators during the first half of
pregnancy. Some of these anomalies, through their natural course,
develop ultrasonographic manifestations and become amenable to
diagnosis only later in the course of pregnancy or even after birth.
Although scattered case reports in the literature have described
variations in the appearance of CHD in utero with advancing
gestation,8 9 10 11 12 13 14 15 our study is the first to address this
issue directly. Fetal anomalies can vary in appearance over time, and the fetal heart provides a critical example for this notion. Although comprehensive fetal cardiac anatomy can be assessed by the end of the first trimester,16 alterations in chamber size, minute VSDs, and differences in size between the great vessels may not become apparent until later in fetal or neonatal life. An apparently normal appearance at any stage of pregnancy does not exclude a major heart defect, and it seems likely that some defects may be amenable to diagnosis only after birth. As seen from our series, the natural histories of the hypoplastic heart syndrome, AC, endocardial fibroelastosis secondary to AS, PS, TOF, and cardiac tumors all serve as fine examples for this phenomenon. All these anomalies have been described as indistinguishable from normal at 13 to 22 weeks' gestation but were subsequently diagnosed during follow-up scans performed later in pregnancy or after birth.
Our understanding of the rate of evolution in utero and of the unexpectedly variable appearance of certain cardiac defects at the time of diagnosis is fragmentary and incomplete. Any attempt to explain this phenomenon would be difficult, and at the moment, all assumptions are yet to be proved by careful future studies. When fetal echocardiography is performed by experts, the causes for delayed diagnosis of fetal cardiac anomalies may be classified into three major categories: limited resolution, which may be related to both instrumentation and fetal size and position (category A); progression of lesions in utero, leading to late onset cardiac malformation (category B); and erroneous diagnosis (category C).
Category A
Although VSDs can be readily diagnosed in
utero,19 they are probably the most commonly missed
lesions during prenatal echocardiographic
examinations.7 20 The small size of most of these lesions
is apparently beyond the resolution of most currently available
gray-scale ultrasound scanners. Therefore, the prenatal diagnosis of
VSD is often very difficult if not impossible. Moreover, in many cases,
VSDs can undergo spontaneous closure during pregnancy or shortly after
birth,7 21 which makes the rate of undiagnosed lesions
even higher. In our series, 68% of VSD lesions were undetected.
However, new higher-frequency tranducers (5 to 7 MHz) and color
Doppler may enhance the diagnosis of some cases with VSD.
Category B
Observations made by us and others8 9 10 11 12 13 14 15 have indicated
that some lesions tend to undergo progression in utero. Examples for
such lesions include major vessel stenosis and
ventricular outflow tract obstruction. These forms of
obstructive outflow tract lesions may not be obvious in the first half
of pregnancy, mainly because the process of arrest of growth in
narrowing the vessel is not significant enough to be detected by
bidimensional ultrasound scanning. For example, AS tends to be a
progressive disease. Late appearance of this defect postnatally or
during childhood is well documented.22 Similarly, mild PS
diagnosed early in the second trimester may progress to critical PS and
hypoplasia of the right ventricle, or alternatively in cases in which
the pulmonic valve and right ventricle appeared normal on early fetal
echocardiography, serious PS developed by the end
of pregnancy.23 Hypoplasia of the aortic arch and
pulmonary arteries can develop with AC and TOF, respectively.
The late development of left and right ventricular outflow
tract lesions may render this group of CHD discernible only in the
second or even third trimester. A proposed
pathophysiological mechanism for the development of
AC includes primarily reduced blood flow through the aortic arch. This
causes its gradual hypoplasia in utero or aberrant ductal tissue,
leading to lassoing of the aorta in a juxtaductal position and
constricting the aorta during ductal closure, which may explain the
development of AC after birth.24
Several reports in the literature have emphasized the phenomenon of progression of lesions in utero. Allan et al8 9 described two cases of left heart obstructive disease, one with discrete AC and one with AS. The anatomy of the defects changed unfavorably during gestation to become a coarctation with severe hypoplasia of the aortic arch and a hypoplastic left heart syndrome, respectively. Marasini et al11 reported the evolution in utero of two cases of obstructive left heart disease with ventricular hypoplasia. Thus, in some forms of the hypoplastic left heart syndrome, the left ventricle can be of normal size or even dilated in early pregnancy. This may indicate that the more subtle signs of poor left ventricular contraction could be overlooked in a routine four-chamber view during the anomaly survey. The variable sonographic spectrum of fetal cardiac hypoplasia has been described by McGahan et al.25
The delayed diagnosis of TOF, as we understand it, may also be caused by a combination of limited ultrasonographic resolution early in the course of pregnancy with in utero progression of the typical lesions. Some investigators26 believe that the pathophysiology of TOF involves arrest of pulmonary artery development accompanied by dynamic dilatation and mal-location of the aorta. These changes develop during pregnancy and after birth and may easily be overlooked during the early stages of pregnancy.
In our series of CHDs, we also noted that some lesions tend to acquire a typical late-onset appearance. Endocardial fibroelastosis,27 fetal cardiac rhabdomyoma,28 hypertrophic cardiomyopathy,29 and ventricular aneurysm30 all serve as fine examples of the late-onset appearance of fetal cardiac pathology. Endocardial fibroelastosis is an excellent example of cardiac lesion that may develop and present at any time in utero. A debate is currently under way as to whether endocardial fibroelastosis is a primary or secondary disease, and coxsackievirus or mumps virus infections have been suggested. Therefore, the appearance of fetal endocardial fibroelastosis, following normal fetal cardiac evaluation, supports the hypotheses that this peculiar cardiac lesion may be secondary and that its appearance depends on the time of possible in utero infection. Alternatively, its initial manifestations may be subtle; therefore, the possibility exists that they escape early diagnosis. However, in two cases, we had the unique opportunity to review the video records retrospectively, and in both cases we could not detect any abnormality during the early second trimester of pregnancy.12 Fetal cardiac rhabdomyoma is another example of congenital cardiac disease that evolves in utero. In two fetuses, rhabdomyomas were detected during the third trimester after a normal echographic examination during the first half of pregnancy. The fact that in both fetuses the lesions were not detected early in the pregnancy but only during the third trimester clearly indicated that rhabdomyoma may develop during gestation, infancy, and childhood.28 Regarding cardiomyopathy, no data exist on the natural history of this anomaly during fetal life. However, Sonesson et al29 described one anecdotal case of its development during gestation. They showed that ventricular hypertrophy was not evident on first examination at 23 weeks but became evident only at the second examination 12 weeks later, at 35 weeks.
Premature closure of the foramen ovale is another interesting abnormality that may develop later in gestation and may even escape accurate in utero diagnosis. Although most cases with premature closure of the foramen ovale will present as hypoplastic left heart,31 some may show normal- or nearly normal-sized left heart.32 The authors explained that in these cases, late closure of the foramen ovale resulted in normal development of the left atrium and ventricle and concluded that the left heart may not be hypoplastic, as has been assumed previously in cases of premature closure of the foramen ovale. Recently, we evaluated a case that at postmortem was diagnosed as having a sealed foramen ovale that escaped accurate diagnosis during in utero echocardiographic examination. Despite the knowledge of the pathology when the videotape recorded prenatally was reviewed, we were unable to recognize the constricted foramen ovale. The only possible hint of this abnormality that could be detected from the video: instead of having a normal flapping motion, the foramen ovale showed ballooning into the left atrium, where a clear color filling the aneurysmal flap that reached the surface of the mitral valve was noted.33
Category C
Critical review of this series may suggest that the main reason
for late diagnosis of fetal cardiac malformation during pregnancy
should be attributed to erroneous diagnosis. Moreover, our ability to
obtain a correct diagnosis on the initial scan was compromised because
pulsed and color Doppler studies were not included in our cardiac
evaluation protocol. However, we believe that careful analysis
of the diagnosed and "missed" cases proves that the main reason
for late diagnosis stems from evolution and the late appearance of some
heart defects.
Transposition of the great vessels, AV canal, heterotaxy syndrome, double outlet of the right ventricle, total anomalous pulmonary venous connection, truncus arteriosus, and Ebstein anomaly are cardiac malformations that do not evolve from a normal-looking heart during pregnancy. Of this long list, only 1 case (AV canal) of 39 was missed by the initial scan, proving the quality and accuracy of our routine initial examinations.
Most of the isolated VSDs (68%) were not detected prenatally. Along with the above theory, we believe that most were overlooked because of technical reasons (category A) and should not be ascribed to operator error.
We use pulsed and color Doppler analysis only in cases of
suspected fetal cardiac anomalies. We are fully aware of the value of
Doppler studies in diagnosing fetal cardiac anomalies, and we were
among the first to describe its place in this field.34
However, like others,35 36 37 we showed that the main
advantage of Doppler analysis is in facilitation and
confirmation of an accurate diagnosis of cardiac malformations in
suspected cases. Moreover, analysis of our overlooked cases
(Table 2
) reveals that in most instances (ie, major vessel and
ventricular outlet stenosis), abnormal flow
patterns could be evident only in advanced stages of the disease,
because fetal intracardiac shunts preclude early development of
pressure gradients. In addition, because of the extra time required for
reasonable Doppler fetal heart assessment, its routine use is not
feasible.
Our ability to accurately identify subtle and complicated fetal cardiac anomalies and the nature of the initially undiagnosed cases led us to conclude that in most of the overlooked cases (except those in category A), the missed cardiac anomaly evolved during fetal life and therefore could not always be diagnosed by the initial or subsequent prenatal scan.
The concept that early TVS cannot replace the mid-gestation abdominal scan in the detection of congenital anomalies is now well established.15 38 39 In a recent study reported by our group,15 536 women at high risk for birth defects were examined by TVS at 13 to 16 weeks' gestation and by a subsequent abdominal sonogram at 20 to 22 weeks. Eight of 46 cases with anomalies (including cases with heart defects) not detected by early TVS were diagnosed by abdominal sonography at mid-gestation. This notion is re-emphasized by the current series; 17% of cardiac anomalies were not detected by early midtrimester TVS.
Special attention should be given to the stage of pregnancy in which fetal heart examination is performed. Early screening by TVS should be followed by a backup transabdominal scan at midgestation. Nevertheless, the value of early TVS is that it detects 64% of CHDs; therefore, there is a unique opportunity for early genetic counseling and pregnancy termination based on ultrasonic findings, subjects that are beyond the scope of this work.
Third-trimester ultrasound examination does not include detailed fetal echocardiography. However, in 10 cases a brief glance at the fetal heart by our experienced operators was enough to raise suspicion of an abnormality. This was followed by a comprehensive cardiac evaluation. Whether routine third-trimester fetal echocardiography (impossible in our institutions because of financial, personal, and technical difficulties) would further reduce the rate of undiagnosed cases with cardiac malformations is a matter of speculation.
Conclusions
Our study presents novel data and information regarding the in
utero development of heart defects. Fetal cardiac anomalies can vary in
appearance at different stages of fetal development and may evolve in
utero during the entire course of pregnancy. About 20% of CHDs may not
be identified by a comprehensive fetal
echocardiographic examination during the early
second-trimester TVS or midgestation TAS. The early second-trimester
TVS echocardiographic examination should always be
followed by a midgestation scan, which facilitates detection of an
additional 17% of cardiac anomalies that would not have been evident
at the beginning of the second trimester. Further examinations during
the late second or third trimester of pregnancy may increase the
detection rate of CHD, but until the issue of cost-effectiveness is
clarified, they currently are recommended only for high-risk
patients.
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Selected Abbreviations and Acronyms |
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Received October 24, 1996; revision received January 22, 1997; accepted February 11, 1997.
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