Heterotaxy Syndrome with Functional Single Ventricle: Does Prenatal Diagnosis Improve Survival? Meryl S. Cohen, MD, Amy H. Schultz, MD, Zhi-Yun Tian, MD, Denise D. Donaghue, RN, Paul M. Weinberg, MD, J. William Gaynor, MD, and Jack Rychik, MD Divisions of Cardiology and Cardiothoracic Surgery, Departments of Pediatrics and Surgery,The Cardiac Center at The Children’s Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania Background. Despite improved outcome for many sin- gle ventricle lesions, staged reconstruction for heterotaxy syndrome with a functional single ventricle continues to have a high mortality. Prenatal identification of hetero- taxy syndrome may improve long-term survival. Methods. Our database was reviewed from January 1996 to December 2004 for patients with heterotaxy syndrome. Assessment was made for prenatal diagnosis and echocardiographic characteristics of heterotaxy syn- drome. We sought to assess the accuracy of fetal echocar- diography in the diagnosis of heterotaxy syndrome and determine whether prenatal diagnosis and other risk factors have an impact on survival in patients with heterotaxy syndrome. Results. Of 81 patients that met criteria, 43 (53%) had prenatal diagnosis. Prenatal diagnosis had high specific- ity and positive predictive value for all findings but had low sensitivity for anomalous pulmonary veins. Among the 70 patients born alive, survival was 60% with median follow-up of 51.4 months (range, 6.5 to 109.7 months). Prenatal diagnosis did not improve survival (p 0.09). None of the 11 patients with complete heart block (CHB) survived past 3 months of age. Two patients underwent heart transplantation as their first intervention and have survived. CHB and anomalous pulmonary venous con- nection were associated with shorter duration of survival. Conclusions. Prenatal diagnosis of heterotaxy syn- drome does not improve survival in patients who un- dergo single ventricle reconstruction. The most potent risk factors for poor outcome (CHB, anomalous pulmo- nary veins) are likely not impacted by identification in utero. In light of the poor outcome, cardiac transplanta- tion as an initial therapy may be a viable option for some patients. (Ann Thorac Surg 2006;82:1629 –36) © 2006 by The Society of Thoracic Surgeons H eterotaxy syndrome is frequently associated with complex congenital cardiac defects including func- tional single ventricle, common atrioventricular canal, outflow obstruction, and systemic and pulmonary venous malformations [1– 4]. During the past 20 years, children with single ventricle lesions have had improved survival with the advent of early postnatal identification, innova- tive therapies, and staged surgical procedures culminat- ing in the Fontan circulation [5–10]. Despite better out- come for such lesions as hypoplastic left heart syndrome, patients with heterotaxy syndrome in association with a functional single ventricle who undergo single ventricle palliation continue to exhibit a high morbidity and mor- tality that has not significantly improved in the contem- porary era [5, 11–14]. Whether prenatal diagnosis of congenital heart disease has a beneficial impact on outcome has been controver- sial. Some studies have shown no incremental benefit in survival with prenatal diagnosis [15–17]; however, recent reports suggest that significant morbidity such as meta- bolic acidosis can be avoided if a prenatal diagnosis is made [15, 18]. Prenatal diagnosis allows for prompt administration of prostaglandin when ductal- dependency is suspected. This may contribute to im- proved outcome for the most severe forms of congenital heart disease, as recently demonstrated for infants diag- nosed prenatally with hypoplastic left heart syndrome [19]. However, factors specific to heterotaxy syndrome, such as complex anatomic substrate, congenital complete heart block (CHB), and extracardiac anomalies, may counteract these benefits and negatively affect survival regardless of prenatal recognition of disease [12, 20 –22]. The complexity of anatomy in heterotaxy syndrome, which commonly includes unbalanced atrioventricular canal with contralateral ventricular hypoplasia, complex systemic and pulmonary venous anatomy, and conotrun- cal abnormalities, frequently dictates a course of man- agement that culminates in a single ventricle reconstruc- tion. We hypothesized that patients with heterotaxy syndrome who require single ventricle reconstruction might have a better outcome when an accurate prenatal diagnosis is made. Accepted for publication May 11, 2006. Address correspondence to Dr Cohen, Division of Cardiology, The Children’s Hospital of Philadelphia, 34th St and Civic Center Blvd, Philadelphia, PA 19104; e-mail: [email protected]. © 2006 by The Society of Thoracic Surgeons 0003-4975/06/$32.00 Published by Elsevier Inc doi:10.1016/j.athoracsur.2006.05.039 CARDIOVASCULAR
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doi:10.1016/j.athoracsur.2006.05.039g s h t
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eterotaxy Syndrome with Functional Single entricle: Does Prenatal Diagnosis Improve urvival? eryl S. Cohen, MD, Amy H. Schultz, MD, Zhi-Yun Tian, MD, enise D. Donaghue, RN, Paul M. Weinberg, MD, J. William Gaynor, MD, and
ack Rychik, MD ivisions of Cardiology and Cardiothoracic Surgery, Departments of Pediatrics and Surgery,The Cardiac Center at The Children’s
ospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
t f P N s h s n
d d r n u t p
Background. Despite improved outcome for many sin- le ventricle lesions, staged reconstruction for heterotaxy yndrome with a functional single ventricle continues to ave a high mortality. Prenatal identification of hetero-
axy syndrome may improve long-term survival. Methods. Our database was reviewed from January
996 to December 2004 for patients with heterotaxy yndrome. Assessment was made for prenatal diagnosis nd echocardiographic characteristics of heterotaxy syn- rome. We sought to assess the accuracy of fetal echocar- iography in the diagnosis of heterotaxy syndrome and etermine whether prenatal diagnosis and other risk actors have an impact on survival in patients with eterotaxy syndrome. Results. Of 81 patients that met criteria, 43 (53%) had
renatal diagnosis. Prenatal diagnosis had high specific- ty and positive predictive value for all findings but had
ow sensitivity for anomalous pulmonary veins. Among
r b m a d p h n [ s h c r
w c s c a t s m d
hildren’s Hospital of Philadelphia, 34th St and Civic Center Blvd, hiladelphia, PA 19104; e-mail: [email protected].
2006 by The Society of Thoracic Surgeons ublished by Elsevier Inc
he 70 patients born alive, survival was 60% with median ollow-up of 51.4 months (range, 6.5 to 109.7 months). renatal diagnosis did not improve survival (p 0.09). one of the 11 patients with complete heart block (CHB)
urvived past 3 months of age. Two patients underwent eart transplantation as their first intervention and have urvived. CHB and anomalous pulmonary venous con- ection were associated with shorter duration of survival. Conclusions. Prenatal diagnosis of heterotaxy syn-
rome does not improve survival in patients who un- ergo single ventricle reconstruction. The most potent isk factors for poor outcome (CHB, anomalous pulmo- ary veins) are likely not impacted by identification in tero. In light of the poor outcome, cardiac transplanta-
ion as an initial therapy may be a viable option for some atients.
(Ann Thorac Surg 2006;82:1629–36)
© 2006 by The Society of Thoracic Surgeons
eterotaxy syndrome is frequently associated with complex congenital cardiac defects including func-
ional single ventricle, common atrioventricular canal, utflow obstruction, and systemic and pulmonary venous alformations [1–4]. During the past 20 years, children ith single ventricle lesions have had improved survival ith the advent of early postnatal identification, innova-
ive therapies, and staged surgical procedures culminat- ng in the Fontan circulation [5–10]. Despite better out- ome for such lesions as hypoplastic left heart syndrome, atients with heterotaxy syndrome in association with a
unctional single ventricle who undergo single ventricle alliation continue to exhibit a high morbidity and mor-
ality that has not significantly improved in the contem- orary era [5, 11–14]. Whether prenatal diagnosis of congenital heart disease
as a beneficial impact on outcome has been controver- ial. Some studies have shown no incremental benefit in urvival with prenatal diagnosis [15–17]; however, recent
ccepted for publication May 11, 2006.
ddress correspondence to Dr Cohen, Division of Cardiology, The
eports suggest that significant morbidity such as meta- olic acidosis can be avoided if a prenatal diagnosis is ade [15, 18]. Prenatal diagnosis allows for prompt
dministration of prostaglandin when ductal- ependency is suspected. This may contribute to im- roved outcome for the most severe forms of congenital eart disease, as recently demonstrated for infants diag- osed prenatally with hypoplastic left heart syndrome
19]. However, factors specific to heterotaxy syndrome, uch as complex anatomic substrate, congenital complete eart block (CHB), and extracardiac anomalies, may ounteract these benefits and negatively affect survival egardless of prenatal recognition of disease [12, 20–22].
The complexity of anatomy in heterotaxy syndrome, hich commonly includes unbalanced atrioventricular
anal with contralateral ventricular hypoplasia, complex ystemic and pulmonary venous anatomy, and conotrun- al abnormalities, frequently dictates a course of man- gement that culminates in a single ventricle reconstruc- ion. We hypothesized that patients with heterotaxy yndrome who require single ventricle reconstruction ight have a better outcome when an accurate prenatal
iagnosis is made.
P
fi s p s s a t c a
p d f e c v b c
u V s s u t e a
e b b g p 4 fi a v t t f
f u h p t
S T s w T t
h a j s S p d t o h
c b a s t f r k f s t o o n
r m n w
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1630 COHEN ET AL Ann Thorac Surg PRENATAL DIAGNOSIS OF HETEROTAXY SYNDROME 2006;82:1629–36
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With this in mind, we sought to assess the accuracy of etal echocardiography in the diagnosis of heterotaxy yndrome, with particular emphasis on anatomic vari- bles that may negatively affect surgical outcome, such as otal anomalous pulmonary venous connection (TAPVC) nd atrioventricular valve regurgitation. We also sought o determine whether prenatal diagnosis improved sur- ival in this highest-risk group and to assess the risk actors for mortality.
atients and Methods
pproval for review of existing data was obtained in arch 2005 from the Institutional Review Board at The hildren’s Hospital of Philadelphia, with individual con-
ent waived. We reviewed the fetal echocardiographic atabase at The Children’s Hospital of Philadelphia from
anuary 1996 to December 2004 for all patients with a renatal diagnosis of heterotaxy syndrome. The surgical and echocardiographic databases identi-
ed all patients with a postnatal diagnosis of heterotaxy yndrome in the same time period. The diagnosis in each atient was defined by evidence of combination of situs olitus and situs inversus or midline liver, or both; ystemic or pulmonary venous anomalies, or both, char- cteristic of the disease; confirmation of splenic dysfunc- ion after birth, when possible; and the association of ommon atrioventricular canal with conotruncal bnormalities [1, 2]. Because accurate prenatal determination of atrial ap-
endage anatomy is often not possible, patients were esignated as having asplenia or polysplenia syndrome
rom the typical characteristic findings of these two ntities or splenic anatomy, or both. Patients were in- luded if they had a diagnosis destined for a single entricle reconstructive strategy with intent to perform a idirectional Glenn shunt and subsequent Fontan ompletion
All fetal echocardiographic studies were performed sing an Acuson Sequoia ultrasound system (Mountain iew, CA) with appropriate transducers for the mother’s
ize/body habitus and fetal gestational age. Postnatal tudies were performed on a Philips 2500 5500 or 7500 ltrasound system (Andover, MA) using appropriate
ransducers for patient size. All prenatal and postnatal chocardiographic reports, surgical operative notes, and utopsy reports (when performed) were reviewed. To determine accuracy of prenatal diagnosis, the pres-
nce of systemic or pulmonary venous anomalies, or oth; systemic or pulmonary outflow tract obstruction, or oth; and the presence of significant (moderate or reater) atrioventricular valve regurgitation were com- ared on the prenatal and postnatal echocardiogram for 3 subjects with a prenatal diagnosis. TAPVC was de- ned as a confluence connecting to an extracardiac site, nd all cases had evidence of at least mild pulmonary enous obstruction at birth. Accuracy of prenatal predic- ion of postnatal ductal-dependent circulation to sys- emic or pulmonary circulations was also assessed. If the
etus survived to birth, medical records were reviewed t
or sex, type of surgery, survival, and date of last follow- p. The frequency of anatomic variables associated with eterotaxy syndrome was assessed on the prenatal and ostnatal echocardiograms to determine if the popula-
ions were similar.
tatistical Analysis o assess accuracy of prenatal diagnosis, sensitivity, pecificity, and positive and negative predictive value ere calculated for each identified characteristic finding. he postnatal echocardiograms and the surgical opera-
ive notes were used as the gold standard for comparison. Univariate comparisons between subsets of the co-
ort were made using 2 tests or the Fisher exact test if ny expected value was less than 5. Among the sub- ects born alive, we examined the relationship between urvival and potential risk factors for poor outcome. urvival-time analysis was performed using the Cox roportional hazards model. We excluded prenatally iagnosed subjects who did not survive to birth from
he survival analysis because of the unknown number f fetal deaths in those without prenatal recognition of eart disease. For purposes of analysis, 2 patients who underwent
ardiac transplantation were considered nonsurvivors ecause they had heart disease considered “untreatable” nd would have died without a transplant. Duration of urvival was defined as birth to death, cardiac transplan- ation, or last known follow-up. Variables were selected or testing in the Cox proportional hazard model from the esults of the univariate analysis, clinical experience, and nown associations in the literature. The potential risk actors assessed for the model were prenatal diagnosis, ex, type of first surgical intervention, and presence of he following cardiac abnormalities: CHB, TAPVC, type f outflow tract obstruction, dextrocardia, and moderate r greater atrioventricular valve regurgitation at the post- atal study. Nested models were compared with the likelihood
atio test. The most parsimonious model that maintained aximal explanatory power was selected. Prenatal diag-
osis was then added back to this model to determine hether it added any explanatory power. Univariate analyses were performed using STATA 7.0
STATA Corp, College Station, TX). Cox proportional azard model was performed using SAS 9.1 (SAS Insti-
ute, Inc, Cary, NC). Statistical significance was defined s p 0.05.
esults
emographics and Spectrum of Disease f 7964 fetal echocardiographic studies performed from
anuary 1996 to December 2004, 699 (8.8%) fetuses had ongenital heart disease, and 43 (6.2%) were identified ith heterotaxy syndrome with functional single ventri-
le. Identification of heterotaxy syndrome was made at a ean gestational age of 23 4.2 weeks. During the same
ime period, 38 patients with heterotaxy syndrome with
f t n m p p 2
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1631Ann Thorac Surg COHEN ET AL 2006;82:1629–36 PRENATAL DIAGNOSIS OF HETEROTAXY SYNDROME
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unctional single ventricle were diagnosed after birth. For he study population of 81 patients, 54.3% were boys, and one were born before 35 weeks’ gestation. Significantly ore patients with heterotaxy syndrome were identified
renatally during the latter time frame of the study eriod (2001–2004) than the earlier time frame (1996– 000, 62.3% vs 21.6%, p 0.001).
The spectrum of anatomic findings for prenatal and ostnatal diagnosis is summarized in Table 1. TAPVC as more frequently observed in those with prenatal iagnosis (p 0.05). CHB was also more common in the renatally diagnosed group but did not reach statistical ignificance (p 0.20).
able 1. Prevalence of Anatomic Cardiac Variables in atients with Prenatal and Postnatal Diagnosis of eterotaxy Syndrome
natomic Variables
Prenatal Diagnosis
olysplenia 17 (39.5) 13 (34.2) extrocardia 14 (32.5) 14 (36.8)
nterrupted inferior vena cava 15 (34.9) 8 (21.0) ilateral superior vena cavaa 14 (43.7) 25 (65.8) bsent right superior vena cavaa 4 (12.5) 7 (18.4) otal anomalous pulmonary venous return (extracardiac)ab
14 (43.8) 8 (21.1)
ommon atrioventricular canal defect 31 (72.1) 30 (78.9) ypoplastic left heart syndrome (and variants)
9 (20.9) 3 (7.9)
ouble outlet right ventricle 13 (30.2) 17 (44.7) -looped ventricle with conotruncal defecta
5 (15.6) 8 (21)
13 (30.2) 13 (34.2)
ulmonary outflow obstruction 33 (76.7) 28 (73.7) ystemic outflow obstruction 9 (20.9) 6 (15.8) ilateral outflow obstruction 1 (2.3) 0 (0) bnormal arch sidednessa 11 (34.3) 16 (42.1) omplete heart block 8 (18.6) 3 (7.9)
For these diagnoses, the 11 patients with fetal demise were excluded rom the prenatal diagnosis group because confirmation of the defect ould not be made on postnatal echocardiogram. b p 0.05. All other values were not significant.
able 2. Accuracy of Prenatal Diagnosis of Heterotaxy Syndr chocardiographic Diagnosis
Systemic Venous
Anomaly
ensitivity 54.5 50.0 pecificity 90.0 100 ositive predictive value 92.3 100 egative predictive value 47.4 72.0
VVR moderate or greater atrioventricular valve regurgitation.
ccuracy of Prenatal Diagnosis he accuracy of prenatal diagnosis of heterotaxy syn- rome compared with postnatal echocardiographic diag- osis (and surgical or autopsy confirmation) is presented
n Table 2. Sensitivity and negative predictive value were oor for the diagnosis of systemic and pulmonary venous nomalies in utero; however, specificity and positive redictive value were excellent for all variables. Despite
he poor sensitivity, there was no difference in outcome or those fetal patients with TAPVC if the diagnosis was
ade prenatally or postnatally (Fisher exact test, p NS). renatal diagnosis of systemic and pulmonary outflow bstruction as well as predicting ductal-dependency was ery accurate. Prenatal echocardiography was also accu- ate for identification of significant atrioventricular valve egurgitation that continued to be significant after birth; owever, several patients with no significant atrioven-
ricular valve regurgitation before birth had significant egurgitation after birth and before surgical intervention.
utcome verall survival for the 81 patients with heterotaxy syn- rome (including fetal deaths) was 51.8%, and their utcomes are shown in Figure 1. If fetal death is included, atients with a prenatal diagnosis had worse outcome
han those with a postnatal diagnosis (2, p 0.025). here were 11 fetal deaths: 7 died in utero and four regnancies were terminated. Four of the 7 fetuses that ied in utero had CHB, making it the only risk factor ssociated with fetal death (p 0.02), and all 4 with CHB ad hydrops fetalis. Only 1 fetus (with CHB) that died in tero had significant atrioventricular valve regurgitation. ix of the fetuses that died in utero had polysplenia yndrome (of which 4 also had CHB) and 5 had asplenia yndrome.
Of the 68 live-born patients destined for Fontan pro- edure, 39 (57.3%) were alive at a median follow-up of 1.4 months (range, 6.5 to 109.7 months; Fig 2). Patients orn alive with polysplenia syndrome had a higher ortality rate than those with asplenia syndrome (2, p
.05). Of the 29 patients who died after birth (15 with renatal diagnosis, 14 with postnatal diagnosis), 6 (20.7%) ied before cardiac surgical intervention (although 2 of
hese 6 had pacemaker implantation for CHB), 19 (65.5%) ied after the initial surgical procedure, and 4 (13.8%) ied after a bidirectional Glenn shunt. No late deaths
for the 32 Patients Who Had Both Prenatal and Postnatal
temic tflow ruction
Obstruction AVVR Ductal-Dependency
00 100 28.6 100 00 100 100 100 00 100 100 100 00 100 83.3 100
ome
o t w c t m u a F i
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1632 COHEN ET AL Ann Thorac Surg PRENATAL DIAGNOSIS OF HETEROTAXY SYNDROME 2006;82:1629–36
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ccurred after the Fontan operation. No patient is known o have died from extracardiac disease, except for one ho died shortly after birth. This patient had multiple
ongenital anomalies and the parents declined interven- ion. Of the survivors, 2 Fontan patients presently have
ild pulmonary venous obstruction and 2 have not ndergone bidirectional Glenn shunt because of severe bnormalities (biliary atresia, poor anatomic substrate for ontan physiology) that preclude further cardiac surgical
ntervention. In light of the poor outcome, the therapeutic strategy
or some patients was changed during the study period. wo patients with particularly severe disease—1 with evere atrioventricular valve regurgitation and severely nbalanced atrioventricular canal, the other with single entricle, pulmonary atresia and obstructed TAPVC— ere listed for cardiac transplantation at birth. Both nderwent successful cardiac transplantation within the rst 5 months of life and have survived to 32 and 33 onths.
isk Factors Associated With Outcome he Cox proportional hazard model, without adjusting
or other risk factors, showed that prenatal diagnosis was
ig 2. Survival curve for all 68 live-born patients with heterotaxy yndrome destined for Fontan operation. Solid circles all live-born
atients in the study; shaded areas 95% confidence intervals. S
ot associated with longer duration of survival (p 0.09; ig 3). Univariate relationships between failure to survive nd potential risk factors among patients who survived to erm are summarized in Table 3. Significant atrioventric- lar valve regurgitation at birth and CHB were associated ith poor outcome, whereas dextrocardia was associated ith better survival. The best-fitting Cox proportion hazard model relating
uration of survival to potential risk factors is summa- ized in Table 4. In this analysis, which includes the 70 atients who survived to term, CHB and TAPVC were ignificant risk factors. All patients with CHB died by 3 onths of age. Twelve (54.4%) of the 22 live-born patients ith TAPVC did not survive. After accounting for these
isk factors, there was no association between duration of urvival and either prenatal diagnosis (p 0.50) or ignificant atrioventricular valve regurgitation (p 0.50).
Fig 1. Flow diagram of outcome of all patients diagnosed with hetero- taxy syndrome with functional sin- gle ventricle. TOP termination of pregnancy, BDG bidirectional Glenn shunt.
ig 3. Cox proportional hazard model of overall survival from birth or patients with prenatal (open circles) versus postnatal (solid cir- les) diagnosis without adjustment for any other risk factors. Pa- ients with fetal death are excluded from the analysis (p 0.09).
haded areas 95% confidence intervals.
C
I O s c v p t d d s f ( f p s s l o
s r a i s a n d
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R C f p p c m d p C
i c p i e p s t p c w a
a t q S c t o
T
P
H h
1633Ann Thorac Surg COHEN ET AL 2006;82:1629–36 PRENATAL DIAGNOSIS OF HETEROTAXY SYNDROME
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omment
mpact of Prenatal Diagnosis ur study shows that prenatal diagnosis of heterotaxy
yndrome in patients destined to undergo single ventri- le reconstruction does not significantly improve sur- ival. This remains true even after adjusting for other otential risk factors. Several likely reasons account for
his poor overall prognosis. Infants with heterotaxy syn- rome typically have very complex congenital heart isease with multiple risk factors for poor outcome. The everity of disease is demonstrated by the high rate of etal death. Of the 43 fetuses with prenatal diagnosis, 7 16.2%) did not survive to term. The natural history of etal congenital heart disease has been previously re- orted. In these studies, fetal death is frequently ob- erved because of hemodynamic abnormalities such as ignificant atrioventricular valve regurgitation, ventricu- ar dysfunction, or arrhythmias resulting in low cardiac utput [20–26]. Previous reports of prenatal diagnosis of heterotaxy
yndrome have suggested that prognosis is poor despite ecognition in utero [27–29]. Lim and colleagues [29], who ssessed a group of patients with left and right atrial somerism, reported that prenatal diagnosis did not affect urvival even if immediate and aggressive care was given…
p i l
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eterotaxy Syndrome with Functional Single entricle: Does Prenatal Diagnosis Improve urvival? eryl S. Cohen, MD, Amy H. Schultz, MD, Zhi-Yun Tian, MD, enise D. Donaghue, RN, Paul M. Weinberg, MD, J. William Gaynor, MD, and
ack Rychik, MD ivisions of Cardiology and Cardiothoracic Surgery, Departments of Pediatrics and Surgery,The Cardiac Center at The Children’s
ospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
t f P N s h s n
d d r n u t p
Background. Despite improved outcome for many sin- le ventricle lesions, staged reconstruction for heterotaxy yndrome with a functional single ventricle continues to ave a high mortality. Prenatal identification of hetero-
axy syndrome may improve long-term survival. Methods. Our database was reviewed from January
996 to December 2004 for patients with heterotaxy yndrome. Assessment was made for prenatal diagnosis nd echocardiographic characteristics of heterotaxy syn- rome. We sought to assess the accuracy of fetal echocar- iography in the diagnosis of heterotaxy syndrome and etermine whether prenatal diagnosis and other risk actors have an impact on survival in patients with eterotaxy syndrome. Results. Of 81 patients that met criteria, 43 (53%) had
renatal diagnosis. Prenatal diagnosis had high specific- ty and positive predictive value for all findings but had
ow sensitivity for anomalous pulmonary veins. Among
r b m a d p h n [ s h c r
w c s c a t s m d
hildren’s Hospital of Philadelphia, 34th St and Civic Center Blvd, hiladelphia, PA 19104; e-mail: [email protected].
2006 by The Society of Thoracic Surgeons ublished by Elsevier Inc
he 70 patients born alive, survival was 60% with median ollow-up of 51.4 months (range, 6.5 to 109.7 months). renatal diagnosis did not improve survival (p 0.09). one of the 11 patients with complete heart block (CHB)
urvived past 3 months of age. Two patients underwent eart transplantation as their first intervention and have urvived. CHB and anomalous pulmonary venous con- ection were associated with shorter duration of survival. Conclusions. Prenatal diagnosis of heterotaxy syn-
rome does not improve survival in patients who un- ergo single ventricle reconstruction. The most potent isk factors for poor outcome (CHB, anomalous pulmo- ary veins) are likely not impacted by identification in tero. In light of the poor outcome, cardiac transplanta-
ion as an initial therapy may be a viable option for some atients.
(Ann Thorac Surg 2006;82:1629–36)
© 2006 by The Society of Thoracic Surgeons
eterotaxy syndrome is frequently associated with complex congenital cardiac defects including func-
ional single ventricle, common atrioventricular canal, utflow obstruction, and systemic and pulmonary venous alformations [1–4]. During the past 20 years, children ith single ventricle lesions have had improved survival ith the advent of early postnatal identification, innova-
ive therapies, and staged surgical procedures culminat- ng in the Fontan circulation [5–10]. Despite better out- ome for such lesions as hypoplastic left heart syndrome, atients with heterotaxy syndrome in association with a
unctional single ventricle who undergo single ventricle alliation continue to exhibit a high morbidity and mor-
ality that has not significantly improved in the contem- orary era [5, 11–14]. Whether prenatal diagnosis of congenital heart disease
as a beneficial impact on outcome has been controver- ial. Some studies have shown no incremental benefit in urvival with prenatal diagnosis [15–17]; however, recent
ccepted for publication May 11, 2006.
ddress correspondence to Dr Cohen, Division of Cardiology, The
eports suggest that significant morbidity such as meta- olic acidosis can be avoided if a prenatal diagnosis is ade [15, 18]. Prenatal diagnosis allows for prompt
dministration of prostaglandin when ductal- ependency is suspected. This may contribute to im- roved outcome for the most severe forms of congenital eart disease, as recently demonstrated for infants diag- osed prenatally with hypoplastic left heart syndrome
19]. However, factors specific to heterotaxy syndrome, uch as complex anatomic substrate, congenital complete eart block (CHB), and extracardiac anomalies, may ounteract these benefits and negatively affect survival egardless of prenatal recognition of disease [12, 20–22].
The complexity of anatomy in heterotaxy syndrome, hich commonly includes unbalanced atrioventricular
anal with contralateral ventricular hypoplasia, complex ystemic and pulmonary venous anatomy, and conotrun- al abnormalities, frequently dictates a course of man- gement that culminates in a single ventricle reconstruc- ion. We hypothesized that patients with heterotaxy yndrome who require single ventricle reconstruction ight have a better outcome when an accurate prenatal
iagnosis is made.
P
fi s p s s a t c a
p d f e c v b c
u V s s u t e a
e b b g p 4 fi a v t t f
f u h p t
S T s w T t
h a j s S p d t o h
c b a s t f r k f s t o o n
r m n w
D O J c w c m
1630 COHEN ET AL Ann Thorac Surg PRENATAL DIAGNOSIS OF HETEROTAXY SYNDROME 2006;82:1629–36
C A
R D
IO V
A S
C U
L A
R
With this in mind, we sought to assess the accuracy of etal echocardiography in the diagnosis of heterotaxy yndrome, with particular emphasis on anatomic vari- bles that may negatively affect surgical outcome, such as otal anomalous pulmonary venous connection (TAPVC) nd atrioventricular valve regurgitation. We also sought o determine whether prenatal diagnosis improved sur- ival in this highest-risk group and to assess the risk actors for mortality.
atients and Methods
pproval for review of existing data was obtained in arch 2005 from the Institutional Review Board at The hildren’s Hospital of Philadelphia, with individual con-
ent waived. We reviewed the fetal echocardiographic atabase at The Children’s Hospital of Philadelphia from
anuary 1996 to December 2004 for all patients with a renatal diagnosis of heterotaxy syndrome. The surgical and echocardiographic databases identi-
ed all patients with a postnatal diagnosis of heterotaxy yndrome in the same time period. The diagnosis in each atient was defined by evidence of combination of situs olitus and situs inversus or midline liver, or both; ystemic or pulmonary venous anomalies, or both, char- cteristic of the disease; confirmation of splenic dysfunc- ion after birth, when possible; and the association of ommon atrioventricular canal with conotruncal bnormalities [1, 2]. Because accurate prenatal determination of atrial ap-
endage anatomy is often not possible, patients were esignated as having asplenia or polysplenia syndrome
rom the typical characteristic findings of these two ntities or splenic anatomy, or both. Patients were in- luded if they had a diagnosis destined for a single entricle reconstructive strategy with intent to perform a idirectional Glenn shunt and subsequent Fontan ompletion
All fetal echocardiographic studies were performed sing an Acuson Sequoia ultrasound system (Mountain iew, CA) with appropriate transducers for the mother’s
ize/body habitus and fetal gestational age. Postnatal tudies were performed on a Philips 2500 5500 or 7500 ltrasound system (Andover, MA) using appropriate
ransducers for patient size. All prenatal and postnatal chocardiographic reports, surgical operative notes, and utopsy reports (when performed) were reviewed. To determine accuracy of prenatal diagnosis, the pres-
nce of systemic or pulmonary venous anomalies, or oth; systemic or pulmonary outflow tract obstruction, or oth; and the presence of significant (moderate or reater) atrioventricular valve regurgitation were com- ared on the prenatal and postnatal echocardiogram for 3 subjects with a prenatal diagnosis. TAPVC was de- ned as a confluence connecting to an extracardiac site, nd all cases had evidence of at least mild pulmonary enous obstruction at birth. Accuracy of prenatal predic- ion of postnatal ductal-dependent circulation to sys- emic or pulmonary circulations was also assessed. If the
etus survived to birth, medical records were reviewed t
or sex, type of surgery, survival, and date of last follow- p. The frequency of anatomic variables associated with eterotaxy syndrome was assessed on the prenatal and ostnatal echocardiograms to determine if the popula-
ions were similar.
tatistical Analysis o assess accuracy of prenatal diagnosis, sensitivity, pecificity, and positive and negative predictive value ere calculated for each identified characteristic finding. he postnatal echocardiograms and the surgical opera-
ive notes were used as the gold standard for comparison. Univariate comparisons between subsets of the co-
ort were made using 2 tests or the Fisher exact test if ny expected value was less than 5. Among the sub- ects born alive, we examined the relationship between urvival and potential risk factors for poor outcome. urvival-time analysis was performed using the Cox roportional hazards model. We excluded prenatally iagnosed subjects who did not survive to birth from
he survival analysis because of the unknown number f fetal deaths in those without prenatal recognition of eart disease. For purposes of analysis, 2 patients who underwent
ardiac transplantation were considered nonsurvivors ecause they had heart disease considered “untreatable” nd would have died without a transplant. Duration of urvival was defined as birth to death, cardiac transplan- ation, or last known follow-up. Variables were selected or testing in the Cox proportional hazard model from the esults of the univariate analysis, clinical experience, and nown associations in the literature. The potential risk actors assessed for the model were prenatal diagnosis, ex, type of first surgical intervention, and presence of he following cardiac abnormalities: CHB, TAPVC, type f outflow tract obstruction, dextrocardia, and moderate r greater atrioventricular valve regurgitation at the post- atal study. Nested models were compared with the likelihood
atio test. The most parsimonious model that maintained aximal explanatory power was selected. Prenatal diag-
osis was then added back to this model to determine hether it added any explanatory power. Univariate analyses were performed using STATA 7.0
STATA Corp, College Station, TX). Cox proportional azard model was performed using SAS 9.1 (SAS Insti-
ute, Inc, Cary, NC). Statistical significance was defined s p 0.05.
esults
emographics and Spectrum of Disease f 7964 fetal echocardiographic studies performed from
anuary 1996 to December 2004, 699 (8.8%) fetuses had ongenital heart disease, and 43 (6.2%) were identified ith heterotaxy syndrome with functional single ventri-
le. Identification of heterotaxy syndrome was made at a ean gestational age of 23 4.2 weeks. During the same
ime period, 38 patients with heterotaxy syndrome with
f t n m p p 2
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O O d o p t T p d a h u S s s
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unctional single ventricle were diagnosed after birth. For he study population of 81 patients, 54.3% were boys, and one were born before 35 weeks’ gestation. Significantly ore patients with heterotaxy syndrome were identified
renatally during the latter time frame of the study eriod (2001–2004) than the earlier time frame (1996– 000, 62.3% vs 21.6%, p 0.001).
The spectrum of anatomic findings for prenatal and ostnatal diagnosis is summarized in Table 1. TAPVC as more frequently observed in those with prenatal iagnosis (p 0.05). CHB was also more common in the renatally diagnosed group but did not reach statistical ignificance (p 0.20).
able 1. Prevalence of Anatomic Cardiac Variables in atients with Prenatal and Postnatal Diagnosis of eterotaxy Syndrome
natomic Variables
Prenatal Diagnosis
olysplenia 17 (39.5) 13 (34.2) extrocardia 14 (32.5) 14 (36.8)
nterrupted inferior vena cava 15 (34.9) 8 (21.0) ilateral superior vena cavaa 14 (43.7) 25 (65.8) bsent right superior vena cavaa 4 (12.5) 7 (18.4) otal anomalous pulmonary venous return (extracardiac)ab
14 (43.8) 8 (21.1)
ommon atrioventricular canal defect 31 (72.1) 30 (78.9) ypoplastic left heart syndrome (and variants)
9 (20.9) 3 (7.9)
ouble outlet right ventricle 13 (30.2) 17 (44.7) -looped ventricle with conotruncal defecta
5 (15.6) 8 (21)
13 (30.2) 13 (34.2)
ulmonary outflow obstruction 33 (76.7) 28 (73.7) ystemic outflow obstruction 9 (20.9) 6 (15.8) ilateral outflow obstruction 1 (2.3) 0 (0) bnormal arch sidednessa 11 (34.3) 16 (42.1) omplete heart block 8 (18.6) 3 (7.9)
For these diagnoses, the 11 patients with fetal demise were excluded rom the prenatal diagnosis group because confirmation of the defect ould not be made on postnatal echocardiogram. b p 0.05. All other values were not significant.
able 2. Accuracy of Prenatal Diagnosis of Heterotaxy Syndr chocardiographic Diagnosis
Systemic Venous
Anomaly
ensitivity 54.5 50.0 pecificity 90.0 100 ositive predictive value 92.3 100 egative predictive value 47.4 72.0
VVR moderate or greater atrioventricular valve regurgitation.
ccuracy of Prenatal Diagnosis he accuracy of prenatal diagnosis of heterotaxy syn- rome compared with postnatal echocardiographic diag- osis (and surgical or autopsy confirmation) is presented
n Table 2. Sensitivity and negative predictive value were oor for the diagnosis of systemic and pulmonary venous nomalies in utero; however, specificity and positive redictive value were excellent for all variables. Despite
he poor sensitivity, there was no difference in outcome or those fetal patients with TAPVC if the diagnosis was
ade prenatally or postnatally (Fisher exact test, p NS). renatal diagnosis of systemic and pulmonary outflow bstruction as well as predicting ductal-dependency was ery accurate. Prenatal echocardiography was also accu- ate for identification of significant atrioventricular valve egurgitation that continued to be significant after birth; owever, several patients with no significant atrioven-
ricular valve regurgitation before birth had significant egurgitation after birth and before surgical intervention.
utcome verall survival for the 81 patients with heterotaxy syn- rome (including fetal deaths) was 51.8%, and their utcomes are shown in Figure 1. If fetal death is included, atients with a prenatal diagnosis had worse outcome
han those with a postnatal diagnosis (2, p 0.025). here were 11 fetal deaths: 7 died in utero and four regnancies were terminated. Four of the 7 fetuses that ied in utero had CHB, making it the only risk factor ssociated with fetal death (p 0.02), and all 4 with CHB ad hydrops fetalis. Only 1 fetus (with CHB) that died in tero had significant atrioventricular valve regurgitation. ix of the fetuses that died in utero had polysplenia yndrome (of which 4 also had CHB) and 5 had asplenia yndrome.
Of the 68 live-born patients destined for Fontan pro- edure, 39 (57.3%) were alive at a median follow-up of 1.4 months (range, 6.5 to 109.7 months; Fig 2). Patients orn alive with polysplenia syndrome had a higher ortality rate than those with asplenia syndrome (2, p
.05). Of the 29 patients who died after birth (15 with renatal diagnosis, 14 with postnatal diagnosis), 6 (20.7%) ied before cardiac surgical intervention (although 2 of
hese 6 had pacemaker implantation for CHB), 19 (65.5%) ied after the initial surgical procedure, and 4 (13.8%) ied after a bidirectional Glenn shunt. No late deaths
for the 32 Patients Who Had Both Prenatal and Postnatal
temic tflow ruction
Obstruction AVVR Ductal-Dependency
00 100 28.6 100 00 100 100 100 00 100 100 100 00 100 83.3 100
ome
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1632 COHEN ET AL Ann Thorac Surg PRENATAL DIAGNOSIS OF HETEROTAXY SYNDROME 2006;82:1629–36
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ccurred after the Fontan operation. No patient is known o have died from extracardiac disease, except for one ho died shortly after birth. This patient had multiple
ongenital anomalies and the parents declined interven- ion. Of the survivors, 2 Fontan patients presently have
ild pulmonary venous obstruction and 2 have not ndergone bidirectional Glenn shunt because of severe bnormalities (biliary atresia, poor anatomic substrate for ontan physiology) that preclude further cardiac surgical
ntervention. In light of the poor outcome, the therapeutic strategy
or some patients was changed during the study period. wo patients with particularly severe disease—1 with evere atrioventricular valve regurgitation and severely nbalanced atrioventricular canal, the other with single entricle, pulmonary atresia and obstructed TAPVC— ere listed for cardiac transplantation at birth. Both nderwent successful cardiac transplantation within the rst 5 months of life and have survived to 32 and 33 onths.
isk Factors Associated With Outcome he Cox proportional hazard model, without adjusting
or other risk factors, showed that prenatal diagnosis was
ig 2. Survival curve for all 68 live-born patients with heterotaxy yndrome destined for Fontan operation. Solid circles all live-born
atients in the study; shaded areas 95% confidence intervals. S
ot associated with longer duration of survival (p 0.09; ig 3). Univariate relationships between failure to survive nd potential risk factors among patients who survived to erm are summarized in Table 3. Significant atrioventric- lar valve regurgitation at birth and CHB were associated ith poor outcome, whereas dextrocardia was associated ith better survival. The best-fitting Cox proportion hazard model relating
uration of survival to potential risk factors is summa- ized in Table 4. In this analysis, which includes the 70 atients who survived to term, CHB and TAPVC were ignificant risk factors. All patients with CHB died by 3 onths of age. Twelve (54.4%) of the 22 live-born patients ith TAPVC did not survive. After accounting for these
isk factors, there was no association between duration of urvival and either prenatal diagnosis (p 0.50) or ignificant atrioventricular valve regurgitation (p 0.50).
Fig 1. Flow diagram of outcome of all patients diagnosed with hetero- taxy syndrome with functional sin- gle ventricle. TOP termination of pregnancy, BDG bidirectional Glenn shunt.
ig 3. Cox proportional hazard model of overall survival from birth or patients with prenatal (open circles) versus postnatal (solid cir- les) diagnosis without adjustment for any other risk factors. Pa- ients with fetal death are excluded from the analysis (p 0.09).
haded areas 95% confidence intervals.
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T
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1633Ann Thorac Surg COHEN ET AL 2006;82:1629–36 PRENATAL DIAGNOSIS OF HETEROTAXY SYNDROME
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omment
mpact of Prenatal Diagnosis ur study shows that prenatal diagnosis of heterotaxy
yndrome in patients destined to undergo single ventri- le reconstruction does not significantly improve sur- ival. This remains true even after adjusting for other otential risk factors. Several likely reasons account for
his poor overall prognosis. Infants with heterotaxy syn- rome typically have very complex congenital heart isease with multiple risk factors for poor outcome. The everity of disease is demonstrated by the high rate of etal death. Of the 43 fetuses with prenatal diagnosis, 7 16.2%) did not survive to term. The natural history of etal congenital heart disease has been previously re- orted. In these studies, fetal death is frequently ob- erved because of hemodynamic abnormalities such as ignificant atrioventricular valve regurgitation, ventricu- ar dysfunction, or arrhythmias resulting in low cardiac utput [20–26]. Previous reports of prenatal diagnosis of heterotaxy
yndrome have suggested that prognosis is poor despite ecognition in utero [27–29]. Lim and colleagues [29], who ssessed a group of patients with left and right atrial somerism, reported that prenatal diagnosis did not affect urvival even if immediate and aggressive care was given…
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