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Spectrum and Outcome of Primary Cardiomyopathies Diagnosed During Fetal Life
JACC: HEART FAILURE
VOL. 2, NO. 4, 2014
ª 2014 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
ISSN 2213-1779/$36.00
PUBLISHED BY ELSEVIER INC.
http://dx.doi.org/10.1016/j.jchf.2014.02.010
Spectrum and Outcome of Primary Cardiomyopathies Diagnosed During Fetal Life Roland Weber, MD,* Paul Kantor, MD,y David Chitayat, MD,z Mark K. Friedberg, MD,* Fraser Golding, MD,* Luc Mertens, MD, PHD,* Lynne E. Nield, MD,* Greg Ryan, MB,x Mike Seed, MD,* Shi-Joon Yoo, MD,* Cedric Manlhiot, BSC,* Edgar Jaeggi, MD*
ABSTRACT OBJECTIVES The purpose of this study was to determine the phenotypic presentation, causes, and outcome of fetal cardiomyopathy (CM) and to identify early predictors of outcome. BACKGROUND Although prenatal diagnosis is possible, there is a paucity of information about fetal CM. METHODS This was a retrospective review of 61 consecutive fetal cases with a diagnosis of CM at a single center between 2000 and 2012. RESULTS Nonhypertrophic CM (NHCM) was diagnosed in 40 and hypertrophic CM (HCM) in 21 fetuses at 24.7 5.7 gestational weeks. Etiologies included familial (13%), inflammatory (15%), and genetic-metabolic (28%) disorders, whereas 44% were idiopathic. The pregnancy was terminated in 13 of 61 cases (21%). Transplantation-free survival from diagnosis to 1 month and 1 year of life for actively managed patients was better in those with NHCM (n ¼ 31; 58% and 58%, respectively) compared with those with HCM (n ¼ 17; 35% and 18%, respectively; hazard ratio [HR]: 0.44; 95% confidence interval [CI]: 0.12 to 0.72; p ¼ 0.007). Baseline echocardiographic variables associated with mortality in actively managed patients included ventricular septal thickness (HR: 1.21 per z-score increment; 95% CI: 1.07 to 1.36; p ¼ 0.002), cardiothoracic area ratio (HR: 1.06 per percent increment; 95% CI: 1.02 to 1.10; p ¼ 0.006), $3 abnormal diastolic Doppler flow indexes (HR: 1.44; 95% CI: 1.07 to 1.95; p ¼ 0.02), gestational age at CM diagnosis (HR: 0.91 per week increment; 95% CI: 0.83 to 0.99; p ¼ 0.03), and, for fetuses in sinus rhythm, a lower cardiovascular profile score (HR: 1.45 per point decrease; 95% CI: 1.16 to 1.79; p ¼ 0.001). CONCLUSIONS Fetal CM originates from a broad spectrum of etiologies and is associated with substantial mortality. Early echocardiographic findings appear useful in predicting adverse perinatal outcomes. (J Am Coll Cardiol HF 2014;2:403–11) © 2014 by the American College of Cardiology Foundation.
C
ardiomyopathies (CMs) encompass a spec-
cardiac transplantation in infants (1,7). The condition
trum of heart muscle disorders that affect
is rarely diagnosed prenatally, and there is little
cardiac filling, contraction, or both, in the
knowledge of the disease spectrum and outcome
absence of correctible anatomic and/or hemodynamic
when detected prenatally. In a study that predated
abnormalities (1). Most children present with a
this research, Pedra et al. (8) reported 55 fetuses
dilated or hypertrophic phenotype (2–4) without an
with a hypertrophic (n ¼ 33) or dilated (n ¼ 22) pheno-
identifiable genetic, familial, infectious, or metabolic
type, diagnosed at The Hospital for Sick Children in
cause (5,6). CM is the most common indication for
Toronto, Ontario, Canada between 1990 and 1999.
From the *Fetal Cardiac Program, Labatt Family Heart Center, The Hospital for Sick Children, Toronto, Ontario, Canada; yHeart Failure Program, Labatt Family Heart Center, The Hospital for Sick Children, Toronto, Ontario, Canada; zPrenatal Diagnosis and Medical Genetics Programs, Mount Sinai Hospital; University of Toronto, Toronto, Ontario, Canada; and the xFetal Medicine Unit, Mount Sinai Hospital; University of Toronto, Toronto, Ontario, Canada. The authors have reported that they have no relationships relevant to the contents of this paper to disclose. Manuscript received November 11, 2013; revised manuscript received February 5, 2014, accepted February 25, 2014.
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Fetal Cardiomyopathies
ABBREVIATIONS
The hypertrophic phenotype was predomi-
performance index (MPI) >0.48, ventricular end-
AND ACRONYMS
nantly (76%) related to maternal diabetes
diastolic
and twin-twin transfusion syndrome. Cardiac
area ratio (CTR) >35%, and more than mild valvar
pathology secondary to these conditions is
regurgitation (11–14). For fetuses with normal sinus
CI = confidence interval CM = cardiomyopathy CTR = cardiothoracic area ratio CVPS = cardiovascular profile score
HCM = hypertrophic cardiomyopathy
HR = hazard ratio LV = left ventricular
index
NHCM = nonhypertrophic cardiomyopathy
>2
z-scores,
cardiothoracic
often reversible (9,10), with a substantially
rhythm, the severity of heart failure was quantified
better long-term prognosis compared with
using
primary CM. Accordingly, the purpose of
(Table 1) with 2 modifications to the original scoring
the
cardiovascular
profile
score
(CVPS)
this single-center cohort study was to assess
system (replacement of “skin edema” with “fetal
the disease pattern and outcome of disorders
hydrops” and elimination of “tricuspid valve dP/dt,”
in which the primary pathology is the fetal
which had not been routinely measured, as 2-point
myocardium and to determine epidemiolog-
criteria) (12).
ical and hemodynamic markers associated
MPI = myocardial performance
dimensions
with adverse outcomes.
Interrater agreement was assessed on 10 randomly selected fetal studies for the following variables: CVPS, CTR, systolic and diastolic ventricular di-
METHODS
ameters,
ventricular
septal
wall
thickness,
iso-
volumic relaxation time, and MPI. Interrater bias was The Research Ethics Board of the Hospital for Sick
nonstatistically significant for all parameters. Inter-
Children approved this retrospective study.
rater correlation was statistically significant (r > 0.8,
PATIENTS. The Hospital for Sick Children is the
exclusive tertiary perinatal cardiac care provider for a population with 80,000 live births per year. Of 8,506 pregnancy referrals to the Fetal Cardiac Program between January 2000 and June 2012, 2,426 were affected by fetal heart disease. These included 61 fetuses (2.5%) with myocardial disease unrelated to structural heart disease, tachyarrhythmia, abnormal cardiac loading, ischemia, or maternal diabetes. After echocardiographic diagnosis of fetal CM, a comprehensive evaluation by the High-Risk Pregnancy Program and, after birth, by the Heart Failure Program was arranged. The diagnostic workup included genetic counseling, virology (polymerase chain reaction, TORCH [toxoplasmosis, other infections, rubella, cytomegalovirus, and herpes simplex virus] serology), metabolic screening, karyotype, pan-cardiomyopathy gene-panel screening, microarray, and, if applicable, invasive or post-mortem specialized testing. Echocardiograms were offered to first-degree relatives in whom familial CM was a possibility. MEASUREMENTS. Patient information was system-
p < 0.01) for all parameters with the exception of LV MPI (r ¼ 0.55, p > 0.05). These data confirm that interrater reproducibility was excellent for most parameters. DEFINITIONS. CM was divided into 2 anatomic phe-
notypes, depending on the presence or absence of myocardial hypertrophy at final assessment. This approach was selected to allow for phenotypic crossover that can occur during fetal life. Hypertrophic cardiomyopathy (HCM) demonstrated inappropriate ventricular hypertrophy and was defined by diastolic ventricular wall thickness >2 z-scores at the last echocardiogram or at autopsy (15,16). Nonhypertrophic cardiomyopathy (NHCM) was defined by cardiac dysfunction in the absence of myocardial hypertrophy at any stage and included dilated and nondilated phenotypes (17,18). Dilated NHCM was defined by ventricular enlargement >2 z-scores of 1 or both ventricles. LV noncompaction was diagnosed on the basis of prominent trabeculations and multiple deep recesses at the ventricular apex (19,20). Fibrosis and calcification were identified as areas of persistently echogenic endomyocardium (8,16,21). Fetal hydrops
atically reviewed including demographic factors,
was defined by $2 sites of fluid collections. Diastolic
tests, and outcomes to December 2012. All patients
dysfunction was defined by $3 of 5 abnormal echo-
underwent detailed 2-dimensional, M-mode, and
cardiographic markers: monophasic tricuspid flow;
Doppler echocardiography to determine cardiovas-
monophasic mitral flow; pulmonary venous flow
cular anatomy and function. Ventricular dimensions
reversal during atrial systole; absent/reversed ductus
were obtained in the cardiac 4-chamber view from
venosus flow during atrial systole; and umbilical
M-mode and 2-dimensional recordings. Offline mea-
vein pulsations. Umbilical vein pulsation was the
surements were made by a single investigator (E.J.)
only variable used to diagnose diastolic dysfunction
and the mean of 3 consecutive measurements were
in cases of nonsinus rhythm (8).
compared with institutional reference data (11).
Each condition was also classified by etiology as
Findings considered abnormal included ventricular
follows: 1) genetic-metabolic related to chromosomal
shortening fraction <28%, left ventricular (LV) iso-
disorder, inborn error of metabolism, or first-degree
volumic relaxation time >43 ms, LV myocardial
family members with CM; 2) inflammatory secondary
Weber et al.
JACC: HEART FAILURE VOL. 2, NO. 4, 2014 AUGUST 2014:403–11
to post-infectious or antibody-mediated myocardial damage; and 3) idiopathic if no etiology was
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Fetal Cardiomyopathies
T A B L E 1 The Modified Cardiovascular Profile Score Combines the Results
of 5 Echocardiographic Variables to Assess the Severity of Heart Failure
established. Normal (2 Points)
STATISTICAL ANALYSIS. Descriptive statistics for
and frequencies for categorical variables. When
Abdominal or pleural or pericardial effusion or skin edema
Fetal hydrops
Cardiothoracic area ratio
<0.35
0.35–0.50
>0.50
Cardiac function indexes
Biphasic and no or mild and SF $28%
Holosystolic TR or SF <28%
Monophasic or holosystolic MR
available, anatomic measures were converted to
TV/MV inflow pattern
gestational age or body surface area–based z-score.
TV/MV regurgitation
Statistical significance of the difference in patient characteristics and baseline echocardiographic findings between NHCM and HCM (Table 2) and between survivors and nonsurvivors (Table 3) was assessed using the Fisher exact test and Student t test assuming unequal variance between groups. In addition, in assessing differences between survivors
Minus 2 Points
No
both the entire cohort and specific subgroups are expressed as mean SD for continuous variables
Minus 1 Point
Effusions, skin edema
LV and RV shortening DV and UV flow
Normal
DV flow reversal
UV pulsations
End-diastolic UA flow
Antegrade
Absent
Reversed
Points were deducted for abnormalities of each component marker, and the degree of heart failure was graded as being absent (10 points), mild (8 or 9 points), moderate (6 or 7 points), or severe (#5 points). DV ¼ ductus venosus; LV ¼ left ventricular; MR ¼ mitral regurgitation; MV ¼ mitral valve; RV ¼ right ventricular; SF ¼ shortening fraction; TR ¼ tricuspid regurgitation; TV ¼ tricuspid valve; UA ¼ umbilical artery; UV ¼ umbilical vein.
and nonsurvivors (Table 3), freedom from the composite endpoints of death or transplantation after birth was modeled using Kaplan-Meier analysis with
shortening fractions and larger end-diastolic RV di-
Cox proportional regression analysis to determine
mensions compared with those with HCM. In 17 of
the significance of the between-group differences
21 (81%) HCM cases, myocardial hypertrophy was
(PROC PHREG on the SAS system). Findings from
present on the first echocardiogram. Exceptions
this analysis are reported as hazard ratio (HR) with
included 1 fetus each with Noonan syndrome, Hurler
95% confidence interval (CI). From the univariable regression models described, multivariable models were created. In an initial step, all potentially associated factors were assessed individually. Those
T A B L E 2 Characteristics of NHCM Versus HCM Cohorts of the
First Fetal Echocardiogram
associations with a univariable p value <0.20 were then entered into a multivariable regression analysis
Gestational age, weeks
NHCM (n ¼ 40)
HCM (n ¼ 21)
24.9 6.3
24.3 5.1
p Value
0.72
with backward selection of variables to obtain a final
Fetal hydrops
model. This was repeated for the subgroup of patients
Cardiothoracic ratio, %
39.0 9.2
40.1 12.1
0.69
in sinus rhythm separately. Underlying assumptions
IVS (z-score)
0.05 1.4
3.83 3.6
<0.001
14/40 (35)
8/21 (38)
0.95
of all Cox proportional hazard regression models were
>2
0/40 (0)
17/21 (81)
<0.001
checked and satisfactory. All statistical analyses were
>3
0/40 (0)
10/21 (48)
<0.001
performed using SAS version 9.2 (SAS Institute, Cary,
LV SF
26.0 10.3
36.6 13.4
0.001
North Carolina).
RESULTS
<28% LV EDD (z-score)*
22/40 (55) 0.63 2.3
8/21 (38)
0.28
0.33 1.60
0.10 0.24
>2
6/34 (18)
1/21 (5)
>3
3/34 (9)
1/21 (5)
1.00
LV MPI*
0.70 0.31
0.50 0.67
0.60
Over a period of 12 years, we diagnosed 61 fetuses
LV IVRT, ms*
63.4 24.7
58.8 21.7
0.50
with CM as the primary abnormality, suggesting an
Mitral regurgitation
incidence of 6.2 (95% CI: 3.8 to 8.5) per 100,000.
RV SF, %
Referral indications at a median of 23 (range, 15 to 41) gestational weeks included suspected cardiac (n ¼ 35) or noncardiac (n ¼ 21) anomalies on the basis of
<28% RV EDD (z-score)*
of fetal hydrops, diastolic function indexes, and CVPS. Fetuses with NHCM had lower ventricular
0.01 0.009
0/20 (0)
0.02
5/34 (15)
0/20 (0)
0.15
MCVPS (points)
(n ¼ 40) groups included age at diagnosis, prevalence
4/21 (19) 0.28 1.30
0.54 <0.001
9/34 (26)
first-degree family members with CM (n ¼ 5).
Similar findings between HCM (n ¼ 21) and NHCM
26/40 (65) 0.97 1.80
35.4 10.7
>3 Tricuspid regurgitation
fetal cardiac examination are summarized in Table 2.
24.0 9.5
4/21 (19)
>2
abnormal obstetrical ultrasound examinations or
FETAL PRESENTATION. The results of the baseline
11/40 (28)
#6
26/40 (65) 5.9 2.2 23/40 (58)
7/21 (33) 6.0 2.1 11/21 (52)
0.03 0.83 0.79
Values are mean SD or n/N (%) of cases with an abnormal finding. *Excluded are the findings of 6 cases with fetal bradycardia. EDD ¼ end-diastolic dimension; HCM ¼ hypertrophic cardiomyopathy; IVRT ¼ isovolumetric relaxation time; IVS ¼ intraventricular septum; MCVPS ¼ modified cardiovascular profile score; MPI ¼ myocardial performance index; NHCM ¼ nonhypertrophic cardiomyopathy; other abbreviations as in Table 1.
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Fetal Cardiomyopathies
T A B L E 3 Comparison of Baseline Echocardiographic Characteristics Among Neonatal Survivors (n ¼ 24) Versus Nonsurvivors (n ¼ 24)
With Cardiomyopathy Survivors
Nonsurvivors
p Value
HR for Death (95% CI)
NHCM
18
13
0.23
0.59 (0.26–1.33)
HCM
6
11
27.0 5.8
24.6 5.7
0.13
0.95 (0.87–1.02)
0.15
2/24 (8)
15/24 (63)
<0.001
3.90 (1.67–9.07)
0.002
Gestational age, weeks Fetal hydrops Fetal bradycardia Cardiothoracic ratio, %
HR p Value
0.20
2/24 (8)
3/24 (13)
1.00
1.17 (0.35–3.94)
0.80
38.1 6.5
42.6 12.8
0.13
1.03 (0.99–1.06)
0.19
0.24 1.7
3.26 3.6
<0.001
1.13 (1.04–1.22)
0.004
LV SF, %
27.7 9.2
33.7 14.6
0.10
1.02 (0.99–1.06)
0.18
RV SF, %
27.3 10.8
30.4 11.8
0.35
1.01 (0.98–1.05)
0.49
LV EDD (z-score)*
0.21 2.0
0.36 2.5
0.84
1.03 (0.85–1.24)
0.78
IVS (z-score)
0.77 1.9
0.17 1.8
0.29
0.91 (0.72–1.15)
0.43
LV MPI*
0.62 0.27
0.76 0.33
0.15
2.22 (0.59–8.31)
0.23
RV MPI*
RV EDD (z-score)*
0.66 0.28
0.77 0.64
0.56
1.45 (0.50–4.18)
0.50
Diastolic dysfunction ($3)
7/24 (29)
18/24 (75)
0.004
3.36 (1.32–8.56)
0.01
Monophasic TV flow*
11/22 (50)
18/21 (86)
0.02
3.35 (0.98–11.5)
0.053
Monophasic MV flow*
3/22 (14)
10/21 (48)
0.02
2.48 (1.04–5.91)
0.04
Reversed PV flow*
9/22 (41)
10/21 (48)
0.76
1.19 (0.50–2.81)
0.69
Abnormal DV flow*
10/22 (45)
14/21 (67)
0.22
1.66 (0.67–4.12)
0.27
Pulsatile UV flow*
4/24 (17)
14/24 (58)
0.007
2.80 (1.23–6.38)
0.01
$2 valvar regurgitation
1/22 (5)
10/21 (48)
0.005
3.57 (1.52–8.42)
0.004
LV IVRT >43 ms
15/19 (79)
17/20 (85)
0.70
1.24 (0.36–4.25)
0.73
CVPS (points)*
7.0 1.4
4.4 2.0
<0.001
0.69 (0.56–0.86)
0.001
8/22 (36)
18/21 (86)
0.002
4.60 (1.34–15.8)
0.02
#6*
Values are the number of cases, mean SD, or n (%) of cases with an abnormal finding. *Cases with normal cardiac rhythm. CI ¼ confidence interval; CVPS ¼ modified cardiovascular profile score; HR ¼ hazard ratio; PV ¼ pulmonary vein; other abbreviations as in Tables 1 and 2.
syndrome, congenital glycosylation disorder, and fa-
echocardiogram. Functional abnormalities included
milial HCM, all of whom initially presented with
reduced shortening fraction of 1 (n ¼ 5) or both
marked isolated diastolic dysfunction followed by
(n ¼ 22) ventricles, $1 diastolic abnormality (n ¼ 27),
development of myocardial hypertrophy before (n ¼
and more than mild tricuspid regurgitation (n ¼ 17),
2) or early after (n ¼ 2) birth. Etiologies, spectrum of abnormalities, and out-
mitral (n ¼ 1) regurgitation, or both (n ¼ 9). Other cardiac diagnoses included endocardial fibroelastosis
come of NHCM and HCM are shown in Tables 4 and 5,
(n ¼ 12), myocardial calcifications (n ¼ 2), first- (n ¼ 2)
respectively. In 27 of 61 (44%) cases, no disease
or third- (n ¼ 5) degree heart block, and LV non-
mechanism was established. Lack of a disease etiol-
compaction (n ¼ 8). Etiologies were highly variable
ogy was associated with increased odds of in
and included rare genetic-metabolic, familial, and
utero demise (n ¼ 17) or pregnancy termination
inflammatory disorders (Table 4).
(n ¼ 13) (18 of 27 [67%] mortality in patients with no
The atrial myocardium was the primary disease site
CM etiology vs. 12 of 34 (35%) mortality with CM
in 2 (5%) fetuses. The first fetus had atrial standstill,
etiology; OR: 3.7; CI: 1.1 to 12.4; p ¼ 0.02). Genetic-
bradycardia, and fetal hydrops at 26 weeks’ gestation.
metabolic, post-infectious, and idiopathic disorders
Post-mortem examination at 30 weeks’ gestation
were often associated with noncardiac abnormalities,
revealed complete loss of atrial myocytes secondary
most commonly of the brain (e.g., global develop-
to a novel sarcolipin mutation (22). The second fetus
mental delay, autism, sensory-neural hearing loss,
had massive right atrial enlargement in the absence of
brain calcifications).
other structural cardiovascular abnormalities. The
NONHYPERTROPHIC CM. Among the 40 fetuses with
perinatal outcome was complicated by pericardial
the nonhypertrophic phenotype, 13 of 34 (38%)
effusion, atrial flutter, and respiratory distress due to
without a rhythm disorder and 2 of 6 (33%) with
mechanical airway obstruction from the enlarged
persistent fetal bradycardia due to complete heart
atrium. The right atrial wall was partially excised in
block (n ¼ 5) or atrial standstill (n ¼ 1), respectively,
the neonatal period. Atrial histology showed focal
had increased ventricular dimensions on the baseline
complete loss of atrial myocytes. This now 4-year-old
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JACC: HEART FAILURE VOL. 2, NO. 4, 2014 AUGUST 2014:403–11
407
Fetal Cardiomyopathies
T A B L E 4 Causes, Associated Anomalies, and Outcomes of NHCM (n ¼ 40)
Etiology
Cases
Genetic or metabolic
Phenotype*
Other Anomalies
Demise
13/40 (33%) Del 1 p 36
Nondilated NC
Dupl 6 p 23-25
Dilated
Multiple
Dupl 15
Dilated
MYH7 mutation
Dilated
Sarcolipin mutation
Biatrial EFE
Toriello-Carey syndrome
Dilated
CNS
TOP
Hemochromatosis (n ¼ 2)
Nondilated
Liver
IUD (n ¼ 2)
MC 1 mutation
Dilated NC
Liver
HTX
Gene not known (n ¼ 4)
Nondilated
Multiple
TOP
Dilated þ EFE
CNS (n ¼ 1)
IUD (n ¼ 1)
IUD (n ¼ 1); NND (n ¼ 1)
CNS NND
Familial forms (n ¼ 7)
Dilated NC (n ¼ 2) Inflammatory
9/40 (22%)
Idiopathic
Anti-Ro (n ¼ 6)
Dilated þ EFE (n ¼ 4) Focal EFE (n ¼ 2)
CAVB (n ¼ 4) AVB I (n ¼ 1)
Cytomegalovirus (n ¼ 2)
Dilated þ calcifications
CNS; bowel
Focal EFE
CNS
Coxsackie B virus
Dilated
CNS
TOP
18/40 (45%)
Nondilated (n ¼ 3)
Multiple (n ¼ 1)
TOP (n ¼ 2); NND (n ¼ 1)
þ calcifications
Arteries
IUD
Dilated (n ¼ 4)
Multiple (n ¼ 2)
IUD (n ¼ 3); NND (n ¼ 1)
TOP
þ EFE (n ¼ 3)
CNS (n ¼ 2)
IUD (n ¼ 1)
þ NC (n ¼ 4)
Multiple (n ¼ 1)
TOP (n ¼ 1)
þ IVS aneurysm (n ¼ 2)
CAVB (n ¼ 1)
TOP (n ¼ 2)
Giant right atrium
AVB I (n ¼ 1) Atrial flutter
*Phenotypes at last fetal, post-mortem, or post-natal examination are shown. AVB ¼ atrio-ventricular block; CAVB ¼ complete atrio-ventricular block; CNS ¼ central nervous system; Dupl ¼ duplication anomaly; EFE ¼ endocardial fibroelastosis; HTX ¼ heart transplantation; IUD ¼ intrauterine demise; MC ¼ mitochondrial complex; MYH7 mutation ¼ myosin storage myopathy; NC ¼ ventricular noncompaction; NND ¼ neonatal demise; TOP ¼ termination of pregnancy; other abbreviations as in Table 2.
child is clinically well without signs of ventricular
alpha-thalassemia (n ¼ 5) and Noonan syndrome
involvement.
(n ¼ 2). Other conditions were observed in isolation
The ventricular myocardium was predominantly
(Table 5). Four pregnancies (19%) were terminated,
affected in 38 fetuses (95%). In 18, the pregnancy was
whereas 8 fetuses (38%) died in utero. Repeated fetal
terminated (n ¼ 9; 23%) or ended with fetal demise (n ¼ 9; 23%). Of the 20 live births, 14 (70%) had significant dilation of 1 (n ¼ 12) or both (n ¼ 2) ventricles at the most recent echocardiogram. Moreover, 4 of 17 (24%) with >1 year of post-natal follow-up have
T A B L E 5 Causes, Associated Anomalies, and Outcomes of HCM (n ¼ 21)
Etiology
Genetic or metabolic
neurocognitive abnormalities in association with metabolic or syndromic disorders. Transplacental dexamethasone and immunoglob-
Cases
Phenotype*
Other Anomalies
Demise
Alpha-thalassemia (n ¼ 5)
Hypertrophic
Hypospadia (n ¼ 1)
IUD (n ¼ 3), NND (n ¼ 1)
Noonan syndrome (n ¼ 2)
HOCM Hypertrophic
Lymphangiectasia
NND HTX TOP
12/21 (57)
ulin were routinely used to treat antibody-mediated
Hurler syndrome
Hypertrophic
endocardial fibroelastosis (n ¼ 6) (23,24). Post-natal
Trisomy 13
Hypertrophic
Multiple
surgery was required in 6 cases, including a permanent pacemaker for bradycardia (n ¼ 3), right atrial reduction surgery (n ¼ 1), infant heart transplantation for biventricular noncompaction (n ¼ 1), and repair of
Idiopathic
Infancy
ATPase deficiency
Hypertrophic
CNS
CDG 1L
Hypertrophic
CNS
Familial, gene not known
Hypertrophic
9/21 (43)
Hypertrophic
Infancy Multiple (n ¼ 2)
ruptured tricuspid valve secondary to antibodymediated fibroelastosis (n ¼ 1) (25). HYPERTROPHIC CM. In all 21 cases, myocardial hypertrophy eventually affected both ventricles. The
main
associations
were
with
homozygous
2 yrs
TOP (n ¼ 3), IUD (n ¼ 5), NND (n ¼ 1)
*Phenotypes at last fetal, postmortem, or postnatal examination are shown. CDG ¼ congenital disorder of glycosylation; HOCM ¼ hypertrophic obstructive cardiomyopathy; other abbreviations as in Table 4.
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Fetal Cardiomyopathies
transfusions were used to treat alpha-thalassemia, but
compares characteristics among survivors and non-
ultimately only 1 of 5 (20%) survived. Of 9 pregnancy
survivors from fetal diagnosis to infancy. Figure 2 il-
survivors, 2 had post-natal interventions. The first
lustrates the distribution of CVPS at the time of a fetal
fetus
heart
baseline echocardiogram and outcome at 1 month and
transplantation in infancy because of progressive
1 year of life. Multivariable analysis including all
with
Noonan
syndrome
underwent
The
actively managed CM patients demonstrates signifi-
second with Hurler syndrome died of complications of
cant associations between mortality and ventricular
bone marrow transplantation. Finally, a child of
septal thickness (HR: 1.21 per z-score increment; 95%
consanguineous parents with a previously affected
CI: 1.07 to 1.36; p ¼ 0.002), CTR (HR: 1.06 per percent
sibling died of heart failure while awaiting heart
increment; 95% CI: 1.02 to 1.1; p ¼ 0.006), diastolic
transplantation.
dysfunction (HR: 1.44; 95% CI: 1.07 to 1.95; p ¼ 0.02),
ventricular
hypertrophy
and
heart
failure.
CLINICAL OUTCOMES. Figure 1 shows Kaplan-Meier
and gestational age at CM diagnosis (HR per week
trans-
increment: 0.91; 95% CI: 0.83 to 0.99; p ¼ 0.03). If pa-
plantation. When compared with NHCM, HCM was
tients not in sinus rhythm are removed from the
associated with significantly worse odds of fetal sur-
model, the only factor associated with increased haz-
vival (OR: 2.3; 95% CI: 1.4 to 8.4; p ¼ 0.007) and a
ard of mortality is a lower CVPS score (HR: 1.45 per
estimates
of
freedom
from
death
and
significantly worse survival rate from birth (HR: 4.5;
point decrease; 95% CI: 1.16 to 1.79; p ¼ 0.001). Multi-
95% CI: 1.9 to 27.9; p ¼ 0.004), respectively. Table 3
variate subgroup analysis for fetal NHCM also shows similar association between death and lower CVPS (1.81 per point decrease; 95% CI: 1.09 to 3.00; p ¼ 0.02).
DISCUSSION This study documents the disease pattern of fetal CM in a well-defined population, the largest published to date. Echocardiography, by providing an accurate demonstration of cardiac morphology and function, was shown to be an important tool to predict fetal CM outcomes. The CVPS was demonstrated here for the first time to have a strong prognostic value. A CVPS #6 was associated with the highest risk of death or need for heart transplantation of any of the tested variables. The incidence of prenatally diagnosed CM (6.2 of 100,000) in our population is comparable to that reported in children younger than 1 year of age in Finland (4.1 of 100,000), Australia (7.8 of 100,000), and the United States (8.34 of 100,000) and higher than among older children and adults (2–4). Similar to the post-natal experience (6), we found that prenatally diagnosed CM represents a heterogeneous group of predominantly rare disorders. Moreover, diseases with similar phenotypes have different etiologies and commonly involve other organs. Moreover, conditions with similar etiology may present and evolve differently, which makes parental counseling very challenging. F I G U R E 1 Kaplan-Meier Estimates of Freedom From Death and
Transplantation
Illustrations of the probability of transplantation-free survival from the time of fetal diagnosis (A) and from birth (B) of fetuses with hypertrophic
The diagnostic workup for CM is relatively invasive and not readily obtainable during pregnancy. In many cases, the etiology remains unknown despite comprehensive workups. In this series, a causal
cardiomyopathy (HCM) versus nonhypertrophic cardiomyopathy (NHCM).
diagnosis was ascertained in 40% of fetal non-
Excluded are cases with pregnancy termination.
survivors but in 71% of live births. In pediatric series, only 33% to 43% had a known cause of CM
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JACC: HEART FAILURE VOL. 2, NO. 4, 2014 AUGUST 2014:403–11
Fetal Cardiomyopathies
(3,4,6). With the increasing use of microarray and whole-exome sequencing techniques, this percentage is likely to increase. An important finding of this study is that despite its etiological heterogeneity, fetal CM prognosis is closely associated with the phenotypic and functional presentation. However, we found that conventional distinctions between hypertrophic, dilated, restrictive, and unclassified CM subtypes, frequently used in postnatal CM (15), were difficult to apply to the fetus. In infancy, ventricles are typically either hypertrophic or dilated,
with
the
left
ventricle
predominantly
affected. In fetal life, typically both ventricles were either hypertrophied or had normal wall thickness, whereas significant ventricular dilation was uncommon early in the disease. Restrictive diastolic filling occurred with all CM phenotypes. Therefore, we elected to simplify classification to hypertrophic or nonhypertrophic phenotypes. Although others have defined dilated CM to include restrictive and unclassified forms of fetal NHCM (8,17,18), we believe that our classification into 1 of 2 mutually exclusive phenotypes on the basis of myocardial wall thickness is phenotypically more precise, easily applied, reproducible, and of prognostic relevance. Moreover, it appears to have reasonable fidelity because the phenotypic case classification changed in only 4 patients (6%) over time, these being fetuses presenting with isolated diastolic dysfunction and in whom later phenotypic HCM developed.
F I G U R E 2 Cardiovascular Profile Scores and Outcomes
There are few previous reports on fetal “dilated”
The distribution of cardiovascular profile score at the time of the
CM. The largest by Sivasankaran et al. (26) included
fetal baseline echocardiogram and outcome at 1 month (A) and 1
36 of 50 fetuses with ventricular dilation secondary to
year (B) of life is shown. Excluded are all cases of elective
genetic-metabolic disorders (n ¼ 11), viral infections
termination of pregnancy. Model C-statistic was 0.82.
(n ¼ 11), LV noncompaction (n ¼ 1), and idiopathic (n ¼ 13; 36%) causes. Two-thirds had fetal hydrops. Excluding the remaining 14 fetuses with cardiac dysfunction secondary to vascular obstruction, renal
fetuses by NHCM may explain the better survival
disease, or anemia, the overall survival rate was 15%
rates compared with previous studies. Freedom from
with an undefined follow-up period. Pedra et al. (8)
death or transplantation of fetal survivors with NHCM
documented 22 fetal NHCM cases related to CMV
was 85% and 75% at 1 and 5 years, respectively,
infection (n ¼ 2), maternal autoantibodies (n ¼ 6),
comparing also more favorably with outcomes of
familial CM (n ¼ 5), or unknown etiology (n ¼ 9). Only
children with dilated CM with transplantation-free
18% in which the pregnancy was continued survived
survival rates of 75% and 63% at 1 and 5 years,
to infancy. Similarly, only 1 of 6 fetuses with NHCM
respectively (28).
survived to childhood in the Yinon et al. series (18). A
In
contrast
to
NHCM,
we
found
that
fetal
common feature of previous fetal CM reports has
HCM was associated with a dismal rate (12%) of
been the extremely poor outcome. However, this
transplantation-free
may not be true for patients in whom an identifiable
school age, making this an even worse condition in
cause is demonstrated. We reported improved out-
terms of survival than any other form of severe
comes of antibody-mediated CM with perinatal anti-
congenital heart disease (29). Importantly, none
inflammatory steroid and immunoglobulin therapy
of the survivors beyond the first year of life
compared with untreated patients (24,27). This and
had myocardial wall thickness z-scores >2.5 at the
the increased detection of less severely affected
baseline examination, suggesting that restrictive
survival
from
diagnosis
to
409
410
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JACC: HEART FAILURE VOL. 2, NO. 4, 2014 AUGUST 2014:403–11
Fetal Cardiomyopathies
diastolic filling is not tolerated by the fetus and in-
demise. Finally, fetal CM represents a mixed group of
fant with more severe HCM. Data regarding pre-natal
rare disorders, and the relatively small number of
diagnosis and postnatal outcome of HCM are scarce:
fetuses with each condition precluded an etiology-
of 8 earlier fetal cases with nonpregnancy-related
specific statistical analysis.
HCM, Pedra et al. (8) encountered a single survivor beyond the neonatal period. As in the current study,
CONCLUSIONS
most of these cases were attributed to alphathalassemia, Noonan syndrome, or an unidentified
Fetal CM is an etiologically highly diverse disease
etiology. Similarly, several pediatric publications
with cardiac function and morphometry-specific
have indicated that HCM presenting in infancy
outcomes. We propose a simple classification on
carries a worse prognosis than in older children due
the basis of a hypertrophic phenotype that seems
to its frequent association with intractable heart
to correlate well with prognosis. Ventricular septal
failure (30–32).
thickness, CTR, diastolic dysfunction, gestational
Ventricular noncompaction has been recognized as
age, and CVPS are independently associated with
a pre-natally detectable entity, especially in the past
mortality. Fetuses with HCM had a very high
decade, typically in association with structural heart
risk of perinatal demise. In contrast, those fetuses
disease, fetal hydrops, and demise (19,26,33,34). In
with a fetal diagnosis of NHCM had better out-
our series, 5 of 8 patients with isolated ventricular
comes than previously reported. Involvement of
noncompaction are currently alive, 1 of whom un-
other organs was common in fetuses with genetic,
derwent heart transplantation in infancy. In 1 patient,
metabolic, post-infectious, or syndromic disorders
severe fetal hydrops resolved spontaneously in late
and may substantially affect the clinical outcome of
gestation. Two of the mothers in this subgroup were
survivors.
also affected by CM, suggesting a dominant inheritance pattern in some families.
REPRINT REQUESTS AND CORRESPONDENCE: Dr.
STUDY LIMITATIONS. This was a retrospective re-
Edgar Jaeggi, Fetal Cardiac Program, Labatt Family
view, and some eligible cases of primary CM may not
Heart Centre, The Hospital for Sick Children, 555
have been documented. A complete diagnostic
University Avenue,
workup was not always possible in cases of pre-natal
Canada. E-mail: [email protected].
Toronto,
Ontario
M5G
1X8,
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tensor apparatus as late manifestation of antiRo/SSA antibody-mediated cardiac disease. Am J Cardiol 2011;107:761–6. 26. Sivasankaran S, Sharland GK, Simpson JM. Dilated cardiomyopathy presenting during fetal life. Cardiol Young 2005;15:409–16. 27. Nield LE, Silverman ED, Taylor GP, et al. Maternal anti-Ro and anti-La antibody-associated endocardial fibroelastosis. Circulation 2002;105: 843–8. 28. Daubeney PE, Nugent AW, Chondros P, et al. Clinical features and outcomes of childhood dilated cardiomyopathy: results from a national populationbased study. Circulation 2006;114:2671–8.
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KEY WORDS cardiomyopathy, echocardiography, fetal, noncompaction, outcome
411
VOL. 2, NO. 4, 2014
ª 2014 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
ISSN 2213-1779/$36.00
PUBLISHED BY ELSEVIER INC.
http://dx.doi.org/10.1016/j.jchf.2014.02.010
Spectrum and Outcome of Primary Cardiomyopathies Diagnosed During Fetal Life Roland Weber, MD,* Paul Kantor, MD,y David Chitayat, MD,z Mark K. Friedberg, MD,* Fraser Golding, MD,* Luc Mertens, MD, PHD,* Lynne E. Nield, MD,* Greg Ryan, MB,x Mike Seed, MD,* Shi-Joon Yoo, MD,* Cedric Manlhiot, BSC,* Edgar Jaeggi, MD*
ABSTRACT OBJECTIVES The purpose of this study was to determine the phenotypic presentation, causes, and outcome of fetal cardiomyopathy (CM) and to identify early predictors of outcome. BACKGROUND Although prenatal diagnosis is possible, there is a paucity of information about fetal CM. METHODS This was a retrospective review of 61 consecutive fetal cases with a diagnosis of CM at a single center between 2000 and 2012. RESULTS Nonhypertrophic CM (NHCM) was diagnosed in 40 and hypertrophic CM (HCM) in 21 fetuses at 24.7 5.7 gestational weeks. Etiologies included familial (13%), inflammatory (15%), and genetic-metabolic (28%) disorders, whereas 44% were idiopathic. The pregnancy was terminated in 13 of 61 cases (21%). Transplantation-free survival from diagnosis to 1 month and 1 year of life for actively managed patients was better in those with NHCM (n ¼ 31; 58% and 58%, respectively) compared with those with HCM (n ¼ 17; 35% and 18%, respectively; hazard ratio [HR]: 0.44; 95% confidence interval [CI]: 0.12 to 0.72; p ¼ 0.007). Baseline echocardiographic variables associated with mortality in actively managed patients included ventricular septal thickness (HR: 1.21 per z-score increment; 95% CI: 1.07 to 1.36; p ¼ 0.002), cardiothoracic area ratio (HR: 1.06 per percent increment; 95% CI: 1.02 to 1.10; p ¼ 0.006), $3 abnormal diastolic Doppler flow indexes (HR: 1.44; 95% CI: 1.07 to 1.95; p ¼ 0.02), gestational age at CM diagnosis (HR: 0.91 per week increment; 95% CI: 0.83 to 0.99; p ¼ 0.03), and, for fetuses in sinus rhythm, a lower cardiovascular profile score (HR: 1.45 per point decrease; 95% CI: 1.16 to 1.79; p ¼ 0.001). CONCLUSIONS Fetal CM originates from a broad spectrum of etiologies and is associated with substantial mortality. Early echocardiographic findings appear useful in predicting adverse perinatal outcomes. (J Am Coll Cardiol HF 2014;2:403–11) © 2014 by the American College of Cardiology Foundation.
C
ardiomyopathies (CMs) encompass a spec-
cardiac transplantation in infants (1,7). The condition
trum of heart muscle disorders that affect
is rarely diagnosed prenatally, and there is little
cardiac filling, contraction, or both, in the
knowledge of the disease spectrum and outcome
absence of correctible anatomic and/or hemodynamic
when detected prenatally. In a study that predated
abnormalities (1). Most children present with a
this research, Pedra et al. (8) reported 55 fetuses
dilated or hypertrophic phenotype (2–4) without an
with a hypertrophic (n ¼ 33) or dilated (n ¼ 22) pheno-
identifiable genetic, familial, infectious, or metabolic
type, diagnosed at The Hospital for Sick Children in
cause (5,6). CM is the most common indication for
Toronto, Ontario, Canada between 1990 and 1999.
From the *Fetal Cardiac Program, Labatt Family Heart Center, The Hospital for Sick Children, Toronto, Ontario, Canada; yHeart Failure Program, Labatt Family Heart Center, The Hospital for Sick Children, Toronto, Ontario, Canada; zPrenatal Diagnosis and Medical Genetics Programs, Mount Sinai Hospital; University of Toronto, Toronto, Ontario, Canada; and the xFetal Medicine Unit, Mount Sinai Hospital; University of Toronto, Toronto, Ontario, Canada. The authors have reported that they have no relationships relevant to the contents of this paper to disclose. Manuscript received November 11, 2013; revised manuscript received February 5, 2014, accepted February 25, 2014.
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Fetal Cardiomyopathies
ABBREVIATIONS
The hypertrophic phenotype was predomi-
performance index (MPI) >0.48, ventricular end-
AND ACRONYMS
nantly (76%) related to maternal diabetes
diastolic
and twin-twin transfusion syndrome. Cardiac
area ratio (CTR) >35%, and more than mild valvar
pathology secondary to these conditions is
regurgitation (11–14). For fetuses with normal sinus
CI = confidence interval CM = cardiomyopathy CTR = cardiothoracic area ratio CVPS = cardiovascular profile score
HCM = hypertrophic cardiomyopathy
HR = hazard ratio LV = left ventricular
index
NHCM = nonhypertrophic cardiomyopathy
>2
z-scores,
cardiothoracic
often reversible (9,10), with a substantially
rhythm, the severity of heart failure was quantified
better long-term prognosis compared with
using
primary CM. Accordingly, the purpose of
(Table 1) with 2 modifications to the original scoring
the
cardiovascular
profile
score
(CVPS)
this single-center cohort study was to assess
system (replacement of “skin edema” with “fetal
the disease pattern and outcome of disorders
hydrops” and elimination of “tricuspid valve dP/dt,”
in which the primary pathology is the fetal
which had not been routinely measured, as 2-point
myocardium and to determine epidemiolog-
criteria) (12).
ical and hemodynamic markers associated
MPI = myocardial performance
dimensions
with adverse outcomes.
Interrater agreement was assessed on 10 randomly selected fetal studies for the following variables: CVPS, CTR, systolic and diastolic ventricular di-
METHODS
ameters,
ventricular
septal
wall
thickness,
iso-
volumic relaxation time, and MPI. Interrater bias was The Research Ethics Board of the Hospital for Sick
nonstatistically significant for all parameters. Inter-
Children approved this retrospective study.
rater correlation was statistically significant (r > 0.8,
PATIENTS. The Hospital for Sick Children is the
exclusive tertiary perinatal cardiac care provider for a population with 80,000 live births per year. Of 8,506 pregnancy referrals to the Fetal Cardiac Program between January 2000 and June 2012, 2,426 were affected by fetal heart disease. These included 61 fetuses (2.5%) with myocardial disease unrelated to structural heart disease, tachyarrhythmia, abnormal cardiac loading, ischemia, or maternal diabetes. After echocardiographic diagnosis of fetal CM, a comprehensive evaluation by the High-Risk Pregnancy Program and, after birth, by the Heart Failure Program was arranged. The diagnostic workup included genetic counseling, virology (polymerase chain reaction, TORCH [toxoplasmosis, other infections, rubella, cytomegalovirus, and herpes simplex virus] serology), metabolic screening, karyotype, pan-cardiomyopathy gene-panel screening, microarray, and, if applicable, invasive or post-mortem specialized testing. Echocardiograms were offered to first-degree relatives in whom familial CM was a possibility. MEASUREMENTS. Patient information was system-
p < 0.01) for all parameters with the exception of LV MPI (r ¼ 0.55, p > 0.05). These data confirm that interrater reproducibility was excellent for most parameters. DEFINITIONS. CM was divided into 2 anatomic phe-
notypes, depending on the presence or absence of myocardial hypertrophy at final assessment. This approach was selected to allow for phenotypic crossover that can occur during fetal life. Hypertrophic cardiomyopathy (HCM) demonstrated inappropriate ventricular hypertrophy and was defined by diastolic ventricular wall thickness >2 z-scores at the last echocardiogram or at autopsy (15,16). Nonhypertrophic cardiomyopathy (NHCM) was defined by cardiac dysfunction in the absence of myocardial hypertrophy at any stage and included dilated and nondilated phenotypes (17,18). Dilated NHCM was defined by ventricular enlargement >2 z-scores of 1 or both ventricles. LV noncompaction was diagnosed on the basis of prominent trabeculations and multiple deep recesses at the ventricular apex (19,20). Fibrosis and calcification were identified as areas of persistently echogenic endomyocardium (8,16,21). Fetal hydrops
atically reviewed including demographic factors,
was defined by $2 sites of fluid collections. Diastolic
tests, and outcomes to December 2012. All patients
dysfunction was defined by $3 of 5 abnormal echo-
underwent detailed 2-dimensional, M-mode, and
cardiographic markers: monophasic tricuspid flow;
Doppler echocardiography to determine cardiovas-
monophasic mitral flow; pulmonary venous flow
cular anatomy and function. Ventricular dimensions
reversal during atrial systole; absent/reversed ductus
were obtained in the cardiac 4-chamber view from
venosus flow during atrial systole; and umbilical
M-mode and 2-dimensional recordings. Offline mea-
vein pulsations. Umbilical vein pulsation was the
surements were made by a single investigator (E.J.)
only variable used to diagnose diastolic dysfunction
and the mean of 3 consecutive measurements were
in cases of nonsinus rhythm (8).
compared with institutional reference data (11).
Each condition was also classified by etiology as
Findings considered abnormal included ventricular
follows: 1) genetic-metabolic related to chromosomal
shortening fraction <28%, left ventricular (LV) iso-
disorder, inborn error of metabolism, or first-degree
volumic relaxation time >43 ms, LV myocardial
family members with CM; 2) inflammatory secondary
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to post-infectious or antibody-mediated myocardial damage; and 3) idiopathic if no etiology was
405
Fetal Cardiomyopathies
T A B L E 1 The Modified Cardiovascular Profile Score Combines the Results
of 5 Echocardiographic Variables to Assess the Severity of Heart Failure
established. Normal (2 Points)
STATISTICAL ANALYSIS. Descriptive statistics for
and frequencies for categorical variables. When
Abdominal or pleural or pericardial effusion or skin edema
Fetal hydrops
Cardiothoracic area ratio
<0.35
0.35–0.50
>0.50
Cardiac function indexes
Biphasic and no or mild and SF $28%
Holosystolic TR or SF <28%
Monophasic or holosystolic MR
available, anatomic measures were converted to
TV/MV inflow pattern
gestational age or body surface area–based z-score.
TV/MV regurgitation
Statistical significance of the difference in patient characteristics and baseline echocardiographic findings between NHCM and HCM (Table 2) and between survivors and nonsurvivors (Table 3) was assessed using the Fisher exact test and Student t test assuming unequal variance between groups. In addition, in assessing differences between survivors
Minus 2 Points
No
both the entire cohort and specific subgroups are expressed as mean SD for continuous variables
Minus 1 Point
Effusions, skin edema
LV and RV shortening DV and UV flow
Normal
DV flow reversal
UV pulsations
End-diastolic UA flow
Antegrade
Absent
Reversed
Points were deducted for abnormalities of each component marker, and the degree of heart failure was graded as being absent (10 points), mild (8 or 9 points), moderate (6 or 7 points), or severe (#5 points). DV ¼ ductus venosus; LV ¼ left ventricular; MR ¼ mitral regurgitation; MV ¼ mitral valve; RV ¼ right ventricular; SF ¼ shortening fraction; TR ¼ tricuspid regurgitation; TV ¼ tricuspid valve; UA ¼ umbilical artery; UV ¼ umbilical vein.
and nonsurvivors (Table 3), freedom from the composite endpoints of death or transplantation after birth was modeled using Kaplan-Meier analysis with
shortening fractions and larger end-diastolic RV di-
Cox proportional regression analysis to determine
mensions compared with those with HCM. In 17 of
the significance of the between-group differences
21 (81%) HCM cases, myocardial hypertrophy was
(PROC PHREG on the SAS system). Findings from
present on the first echocardiogram. Exceptions
this analysis are reported as hazard ratio (HR) with
included 1 fetus each with Noonan syndrome, Hurler
95% confidence interval (CI). From the univariable regression models described, multivariable models were created. In an initial step, all potentially associated factors were assessed individually. Those
T A B L E 2 Characteristics of NHCM Versus HCM Cohorts of the
First Fetal Echocardiogram
associations with a univariable p value <0.20 were then entered into a multivariable regression analysis
Gestational age, weeks
NHCM (n ¼ 40)
HCM (n ¼ 21)
24.9 6.3
24.3 5.1
p Value
0.72
with backward selection of variables to obtain a final
Fetal hydrops
model. This was repeated for the subgroup of patients
Cardiothoracic ratio, %
39.0 9.2
40.1 12.1
0.69
in sinus rhythm separately. Underlying assumptions
IVS (z-score)
0.05 1.4
3.83 3.6
<0.001
14/40 (35)
8/21 (38)
0.95
of all Cox proportional hazard regression models were
>2
0/40 (0)
17/21 (81)
<0.001
checked and satisfactory. All statistical analyses were
>3
0/40 (0)
10/21 (48)
<0.001
performed using SAS version 9.2 (SAS Institute, Cary,
LV SF
26.0 10.3
36.6 13.4
0.001
North Carolina).
RESULTS
<28% LV EDD (z-score)*
22/40 (55) 0.63 2.3
8/21 (38)
0.28
0.33 1.60
0.10 0.24
>2
6/34 (18)
1/21 (5)
>3
3/34 (9)
1/21 (5)
1.00
LV MPI*
0.70 0.31
0.50 0.67
0.60
Over a period of 12 years, we diagnosed 61 fetuses
LV IVRT, ms*
63.4 24.7
58.8 21.7
0.50
with CM as the primary abnormality, suggesting an
Mitral regurgitation
incidence of 6.2 (95% CI: 3.8 to 8.5) per 100,000.
RV SF, %
Referral indications at a median of 23 (range, 15 to 41) gestational weeks included suspected cardiac (n ¼ 35) or noncardiac (n ¼ 21) anomalies on the basis of
<28% RV EDD (z-score)*
of fetal hydrops, diastolic function indexes, and CVPS. Fetuses with NHCM had lower ventricular
0.01 0.009
0/20 (0)
0.02
5/34 (15)
0/20 (0)
0.15
MCVPS (points)
(n ¼ 40) groups included age at diagnosis, prevalence
4/21 (19) 0.28 1.30
0.54 <0.001
9/34 (26)
first-degree family members with CM (n ¼ 5).
Similar findings between HCM (n ¼ 21) and NHCM
26/40 (65) 0.97 1.80
35.4 10.7
>3 Tricuspid regurgitation
fetal cardiac examination are summarized in Table 2.
24.0 9.5
4/21 (19)
>2
abnormal obstetrical ultrasound examinations or
FETAL PRESENTATION. The results of the baseline
11/40 (28)
#6
26/40 (65) 5.9 2.2 23/40 (58)
7/21 (33) 6.0 2.1 11/21 (52)
0.03 0.83 0.79
Values are mean SD or n/N (%) of cases with an abnormal finding. *Excluded are the findings of 6 cases with fetal bradycardia. EDD ¼ end-diastolic dimension; HCM ¼ hypertrophic cardiomyopathy; IVRT ¼ isovolumetric relaxation time; IVS ¼ intraventricular septum; MCVPS ¼ modified cardiovascular profile score; MPI ¼ myocardial performance index; NHCM ¼ nonhypertrophic cardiomyopathy; other abbreviations as in Table 1.
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Fetal Cardiomyopathies
T A B L E 3 Comparison of Baseline Echocardiographic Characteristics Among Neonatal Survivors (n ¼ 24) Versus Nonsurvivors (n ¼ 24)
With Cardiomyopathy Survivors
Nonsurvivors
p Value
HR for Death (95% CI)
NHCM
18
13
0.23
0.59 (0.26–1.33)
HCM
6
11
27.0 5.8
24.6 5.7
0.13
0.95 (0.87–1.02)
0.15
2/24 (8)
15/24 (63)
<0.001
3.90 (1.67–9.07)
0.002
Gestational age, weeks Fetal hydrops Fetal bradycardia Cardiothoracic ratio, %
HR p Value
0.20
2/24 (8)
3/24 (13)
1.00
1.17 (0.35–3.94)
0.80
38.1 6.5
42.6 12.8
0.13
1.03 (0.99–1.06)
0.19
0.24 1.7
3.26 3.6
<0.001
1.13 (1.04–1.22)
0.004
LV SF, %
27.7 9.2
33.7 14.6
0.10
1.02 (0.99–1.06)
0.18
RV SF, %
27.3 10.8
30.4 11.8
0.35
1.01 (0.98–1.05)
0.49
LV EDD (z-score)*
0.21 2.0
0.36 2.5
0.84
1.03 (0.85–1.24)
0.78
IVS (z-score)
0.77 1.9
0.17 1.8
0.29
0.91 (0.72–1.15)
0.43
LV MPI*
0.62 0.27
0.76 0.33
0.15
2.22 (0.59–8.31)
0.23
RV MPI*
RV EDD (z-score)*
0.66 0.28
0.77 0.64
0.56
1.45 (0.50–4.18)
0.50
Diastolic dysfunction ($3)
7/24 (29)
18/24 (75)
0.004
3.36 (1.32–8.56)
0.01
Monophasic TV flow*
11/22 (50)
18/21 (86)
0.02
3.35 (0.98–11.5)
0.053
Monophasic MV flow*
3/22 (14)
10/21 (48)
0.02
2.48 (1.04–5.91)
0.04
Reversed PV flow*
9/22 (41)
10/21 (48)
0.76
1.19 (0.50–2.81)
0.69
Abnormal DV flow*
10/22 (45)
14/21 (67)
0.22
1.66 (0.67–4.12)
0.27
Pulsatile UV flow*
4/24 (17)
14/24 (58)
0.007
2.80 (1.23–6.38)
0.01
$2 valvar regurgitation
1/22 (5)
10/21 (48)
0.005
3.57 (1.52–8.42)
0.004
LV IVRT >43 ms
15/19 (79)
17/20 (85)
0.70
1.24 (0.36–4.25)
0.73
CVPS (points)*
7.0 1.4
4.4 2.0
<0.001
0.69 (0.56–0.86)
0.001
8/22 (36)
18/21 (86)
0.002
4.60 (1.34–15.8)
0.02
#6*
Values are the number of cases, mean SD, or n (%) of cases with an abnormal finding. *Cases with normal cardiac rhythm. CI ¼ confidence interval; CVPS ¼ modified cardiovascular profile score; HR ¼ hazard ratio; PV ¼ pulmonary vein; other abbreviations as in Tables 1 and 2.
syndrome, congenital glycosylation disorder, and fa-
echocardiogram. Functional abnormalities included
milial HCM, all of whom initially presented with
reduced shortening fraction of 1 (n ¼ 5) or both
marked isolated diastolic dysfunction followed by
(n ¼ 22) ventricles, $1 diastolic abnormality (n ¼ 27),
development of myocardial hypertrophy before (n ¼
and more than mild tricuspid regurgitation (n ¼ 17),
2) or early after (n ¼ 2) birth. Etiologies, spectrum of abnormalities, and out-
mitral (n ¼ 1) regurgitation, or both (n ¼ 9). Other cardiac diagnoses included endocardial fibroelastosis
come of NHCM and HCM are shown in Tables 4 and 5,
(n ¼ 12), myocardial calcifications (n ¼ 2), first- (n ¼ 2)
respectively. In 27 of 61 (44%) cases, no disease
or third- (n ¼ 5) degree heart block, and LV non-
mechanism was established. Lack of a disease etiol-
compaction (n ¼ 8). Etiologies were highly variable
ogy was associated with increased odds of in
and included rare genetic-metabolic, familial, and
utero demise (n ¼ 17) or pregnancy termination
inflammatory disorders (Table 4).
(n ¼ 13) (18 of 27 [67%] mortality in patients with no
The atrial myocardium was the primary disease site
CM etiology vs. 12 of 34 (35%) mortality with CM
in 2 (5%) fetuses. The first fetus had atrial standstill,
etiology; OR: 3.7; CI: 1.1 to 12.4; p ¼ 0.02). Genetic-
bradycardia, and fetal hydrops at 26 weeks’ gestation.
metabolic, post-infectious, and idiopathic disorders
Post-mortem examination at 30 weeks’ gestation
were often associated with noncardiac abnormalities,
revealed complete loss of atrial myocytes secondary
most commonly of the brain (e.g., global develop-
to a novel sarcolipin mutation (22). The second fetus
mental delay, autism, sensory-neural hearing loss,
had massive right atrial enlargement in the absence of
brain calcifications).
other structural cardiovascular abnormalities. The
NONHYPERTROPHIC CM. Among the 40 fetuses with
perinatal outcome was complicated by pericardial
the nonhypertrophic phenotype, 13 of 34 (38%)
effusion, atrial flutter, and respiratory distress due to
without a rhythm disorder and 2 of 6 (33%) with
mechanical airway obstruction from the enlarged
persistent fetal bradycardia due to complete heart
atrium. The right atrial wall was partially excised in
block (n ¼ 5) or atrial standstill (n ¼ 1), respectively,
the neonatal period. Atrial histology showed focal
had increased ventricular dimensions on the baseline
complete loss of atrial myocytes. This now 4-year-old
Weber et al.
JACC: HEART FAILURE VOL. 2, NO. 4, 2014 AUGUST 2014:403–11
407
Fetal Cardiomyopathies
T A B L E 4 Causes, Associated Anomalies, and Outcomes of NHCM (n ¼ 40)
Etiology
Cases
Genetic or metabolic
Phenotype*
Other Anomalies
Demise
13/40 (33%) Del 1 p 36
Nondilated NC
Dupl 6 p 23-25
Dilated
Multiple
Dupl 15
Dilated
MYH7 mutation
Dilated
Sarcolipin mutation
Biatrial EFE
Toriello-Carey syndrome
Dilated
CNS
TOP
Hemochromatosis (n ¼ 2)
Nondilated
Liver
IUD (n ¼ 2)
MC 1 mutation
Dilated NC
Liver
HTX
Gene not known (n ¼ 4)
Nondilated
Multiple
TOP
Dilated þ EFE
CNS (n ¼ 1)
IUD (n ¼ 1)
IUD (n ¼ 1); NND (n ¼ 1)
CNS NND
Familial forms (n ¼ 7)
Dilated NC (n ¼ 2) Inflammatory
9/40 (22%)
Idiopathic
Anti-Ro (n ¼ 6)
Dilated þ EFE (n ¼ 4) Focal EFE (n ¼ 2)
CAVB (n ¼ 4) AVB I (n ¼ 1)
Cytomegalovirus (n ¼ 2)
Dilated þ calcifications
CNS; bowel
Focal EFE
CNS
Coxsackie B virus
Dilated
CNS
TOP
18/40 (45%)
Nondilated (n ¼ 3)
Multiple (n ¼ 1)
TOP (n ¼ 2); NND (n ¼ 1)
þ calcifications
Arteries
IUD
Dilated (n ¼ 4)
Multiple (n ¼ 2)
IUD (n ¼ 3); NND (n ¼ 1)
TOP
þ EFE (n ¼ 3)
CNS (n ¼ 2)
IUD (n ¼ 1)
þ NC (n ¼ 4)
Multiple (n ¼ 1)
TOP (n ¼ 1)
þ IVS aneurysm (n ¼ 2)
CAVB (n ¼ 1)
TOP (n ¼ 2)
Giant right atrium
AVB I (n ¼ 1) Atrial flutter
*Phenotypes at last fetal, post-mortem, or post-natal examination are shown. AVB ¼ atrio-ventricular block; CAVB ¼ complete atrio-ventricular block; CNS ¼ central nervous system; Dupl ¼ duplication anomaly; EFE ¼ endocardial fibroelastosis; HTX ¼ heart transplantation; IUD ¼ intrauterine demise; MC ¼ mitochondrial complex; MYH7 mutation ¼ myosin storage myopathy; NC ¼ ventricular noncompaction; NND ¼ neonatal demise; TOP ¼ termination of pregnancy; other abbreviations as in Table 2.
child is clinically well without signs of ventricular
alpha-thalassemia (n ¼ 5) and Noonan syndrome
involvement.
(n ¼ 2). Other conditions were observed in isolation
The ventricular myocardium was predominantly
(Table 5). Four pregnancies (19%) were terminated,
affected in 38 fetuses (95%). In 18, the pregnancy was
whereas 8 fetuses (38%) died in utero. Repeated fetal
terminated (n ¼ 9; 23%) or ended with fetal demise (n ¼ 9; 23%). Of the 20 live births, 14 (70%) had significant dilation of 1 (n ¼ 12) or both (n ¼ 2) ventricles at the most recent echocardiogram. Moreover, 4 of 17 (24%) with >1 year of post-natal follow-up have
T A B L E 5 Causes, Associated Anomalies, and Outcomes of HCM (n ¼ 21)
Etiology
Genetic or metabolic
neurocognitive abnormalities in association with metabolic or syndromic disorders. Transplacental dexamethasone and immunoglob-
Cases
Phenotype*
Other Anomalies
Demise
Alpha-thalassemia (n ¼ 5)
Hypertrophic
Hypospadia (n ¼ 1)
IUD (n ¼ 3), NND (n ¼ 1)
Noonan syndrome (n ¼ 2)
HOCM Hypertrophic
Lymphangiectasia
NND HTX TOP
12/21 (57)
ulin were routinely used to treat antibody-mediated
Hurler syndrome
Hypertrophic
endocardial fibroelastosis (n ¼ 6) (23,24). Post-natal
Trisomy 13
Hypertrophic
Multiple
surgery was required in 6 cases, including a permanent pacemaker for bradycardia (n ¼ 3), right atrial reduction surgery (n ¼ 1), infant heart transplantation for biventricular noncompaction (n ¼ 1), and repair of
Idiopathic
Infancy
ATPase deficiency
Hypertrophic
CNS
CDG 1L
Hypertrophic
CNS
Familial, gene not known
Hypertrophic
9/21 (43)
Hypertrophic
Infancy Multiple (n ¼ 2)
ruptured tricuspid valve secondary to antibodymediated fibroelastosis (n ¼ 1) (25). HYPERTROPHIC CM. In all 21 cases, myocardial hypertrophy eventually affected both ventricles. The
main
associations
were
with
homozygous
2 yrs
TOP (n ¼ 3), IUD (n ¼ 5), NND (n ¼ 1)
*Phenotypes at last fetal, postmortem, or postnatal examination are shown. CDG ¼ congenital disorder of glycosylation; HOCM ¼ hypertrophic obstructive cardiomyopathy; other abbreviations as in Table 4.
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Fetal Cardiomyopathies
transfusions were used to treat alpha-thalassemia, but
compares characteristics among survivors and non-
ultimately only 1 of 5 (20%) survived. Of 9 pregnancy
survivors from fetal diagnosis to infancy. Figure 2 il-
survivors, 2 had post-natal interventions. The first
lustrates the distribution of CVPS at the time of a fetal
fetus
heart
baseline echocardiogram and outcome at 1 month and
transplantation in infancy because of progressive
1 year of life. Multivariable analysis including all
with
Noonan
syndrome
underwent
The
actively managed CM patients demonstrates signifi-
second with Hurler syndrome died of complications of
cant associations between mortality and ventricular
bone marrow transplantation. Finally, a child of
septal thickness (HR: 1.21 per z-score increment; 95%
consanguineous parents with a previously affected
CI: 1.07 to 1.36; p ¼ 0.002), CTR (HR: 1.06 per percent
sibling died of heart failure while awaiting heart
increment; 95% CI: 1.02 to 1.1; p ¼ 0.006), diastolic
transplantation.
dysfunction (HR: 1.44; 95% CI: 1.07 to 1.95; p ¼ 0.02),
ventricular
hypertrophy
and
heart
failure.
CLINICAL OUTCOMES. Figure 1 shows Kaplan-Meier
and gestational age at CM diagnosis (HR per week
trans-
increment: 0.91; 95% CI: 0.83 to 0.99; p ¼ 0.03). If pa-
plantation. When compared with NHCM, HCM was
tients not in sinus rhythm are removed from the
associated with significantly worse odds of fetal sur-
model, the only factor associated with increased haz-
vival (OR: 2.3; 95% CI: 1.4 to 8.4; p ¼ 0.007) and a
ard of mortality is a lower CVPS score (HR: 1.45 per
estimates
of
freedom
from
death
and
significantly worse survival rate from birth (HR: 4.5;
point decrease; 95% CI: 1.16 to 1.79; p ¼ 0.001). Multi-
95% CI: 1.9 to 27.9; p ¼ 0.004), respectively. Table 3
variate subgroup analysis for fetal NHCM also shows similar association between death and lower CVPS (1.81 per point decrease; 95% CI: 1.09 to 3.00; p ¼ 0.02).
DISCUSSION This study documents the disease pattern of fetal CM in a well-defined population, the largest published to date. Echocardiography, by providing an accurate demonstration of cardiac morphology and function, was shown to be an important tool to predict fetal CM outcomes. The CVPS was demonstrated here for the first time to have a strong prognostic value. A CVPS #6 was associated with the highest risk of death or need for heart transplantation of any of the tested variables. The incidence of prenatally diagnosed CM (6.2 of 100,000) in our population is comparable to that reported in children younger than 1 year of age in Finland (4.1 of 100,000), Australia (7.8 of 100,000), and the United States (8.34 of 100,000) and higher than among older children and adults (2–4). Similar to the post-natal experience (6), we found that prenatally diagnosed CM represents a heterogeneous group of predominantly rare disorders. Moreover, diseases with similar phenotypes have different etiologies and commonly involve other organs. Moreover, conditions with similar etiology may present and evolve differently, which makes parental counseling very challenging. F I G U R E 1 Kaplan-Meier Estimates of Freedom From Death and
Transplantation
Illustrations of the probability of transplantation-free survival from the time of fetal diagnosis (A) and from birth (B) of fetuses with hypertrophic
The diagnostic workup for CM is relatively invasive and not readily obtainable during pregnancy. In many cases, the etiology remains unknown despite comprehensive workups. In this series, a causal
cardiomyopathy (HCM) versus nonhypertrophic cardiomyopathy (NHCM).
diagnosis was ascertained in 40% of fetal non-
Excluded are cases with pregnancy termination.
survivors but in 71% of live births. In pediatric series, only 33% to 43% had a known cause of CM
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JACC: HEART FAILURE VOL. 2, NO. 4, 2014 AUGUST 2014:403–11
Fetal Cardiomyopathies
(3,4,6). With the increasing use of microarray and whole-exome sequencing techniques, this percentage is likely to increase. An important finding of this study is that despite its etiological heterogeneity, fetal CM prognosis is closely associated with the phenotypic and functional presentation. However, we found that conventional distinctions between hypertrophic, dilated, restrictive, and unclassified CM subtypes, frequently used in postnatal CM (15), were difficult to apply to the fetus. In infancy, ventricles are typically either hypertrophic or dilated,
with
the
left
ventricle
predominantly
affected. In fetal life, typically both ventricles were either hypertrophied or had normal wall thickness, whereas significant ventricular dilation was uncommon early in the disease. Restrictive diastolic filling occurred with all CM phenotypes. Therefore, we elected to simplify classification to hypertrophic or nonhypertrophic phenotypes. Although others have defined dilated CM to include restrictive and unclassified forms of fetal NHCM (8,17,18), we believe that our classification into 1 of 2 mutually exclusive phenotypes on the basis of myocardial wall thickness is phenotypically more precise, easily applied, reproducible, and of prognostic relevance. Moreover, it appears to have reasonable fidelity because the phenotypic case classification changed in only 4 patients (6%) over time, these being fetuses presenting with isolated diastolic dysfunction and in whom later phenotypic HCM developed.
F I G U R E 2 Cardiovascular Profile Scores and Outcomes
There are few previous reports on fetal “dilated”
The distribution of cardiovascular profile score at the time of the
CM. The largest by Sivasankaran et al. (26) included
fetal baseline echocardiogram and outcome at 1 month (A) and 1
36 of 50 fetuses with ventricular dilation secondary to
year (B) of life is shown. Excluded are all cases of elective
genetic-metabolic disorders (n ¼ 11), viral infections
termination of pregnancy. Model C-statistic was 0.82.
(n ¼ 11), LV noncompaction (n ¼ 1), and idiopathic (n ¼ 13; 36%) causes. Two-thirds had fetal hydrops. Excluding the remaining 14 fetuses with cardiac dysfunction secondary to vascular obstruction, renal
fetuses by NHCM may explain the better survival
disease, or anemia, the overall survival rate was 15%
rates compared with previous studies. Freedom from
with an undefined follow-up period. Pedra et al. (8)
death or transplantation of fetal survivors with NHCM
documented 22 fetal NHCM cases related to CMV
was 85% and 75% at 1 and 5 years, respectively,
infection (n ¼ 2), maternal autoantibodies (n ¼ 6),
comparing also more favorably with outcomes of
familial CM (n ¼ 5), or unknown etiology (n ¼ 9). Only
children with dilated CM with transplantation-free
18% in which the pregnancy was continued survived
survival rates of 75% and 63% at 1 and 5 years,
to infancy. Similarly, only 1 of 6 fetuses with NHCM
respectively (28).
survived to childhood in the Yinon et al. series (18). A
In
contrast
to
NHCM,
we
found
that
fetal
common feature of previous fetal CM reports has
HCM was associated with a dismal rate (12%) of
been the extremely poor outcome. However, this
transplantation-free
may not be true for patients in whom an identifiable
school age, making this an even worse condition in
cause is demonstrated. We reported improved out-
terms of survival than any other form of severe
comes of antibody-mediated CM with perinatal anti-
congenital heart disease (29). Importantly, none
inflammatory steroid and immunoglobulin therapy
of the survivors beyond the first year of life
compared with untreated patients (24,27). This and
had myocardial wall thickness z-scores >2.5 at the
the increased detection of less severely affected
baseline examination, suggesting that restrictive
survival
from
diagnosis
to
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410
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Fetal Cardiomyopathies
diastolic filling is not tolerated by the fetus and in-
demise. Finally, fetal CM represents a mixed group of
fant with more severe HCM. Data regarding pre-natal
rare disorders, and the relatively small number of
diagnosis and postnatal outcome of HCM are scarce:
fetuses with each condition precluded an etiology-
of 8 earlier fetal cases with nonpregnancy-related
specific statistical analysis.
HCM, Pedra et al. (8) encountered a single survivor beyond the neonatal period. As in the current study,
CONCLUSIONS
most of these cases were attributed to alphathalassemia, Noonan syndrome, or an unidentified
Fetal CM is an etiologically highly diverse disease
etiology. Similarly, several pediatric publications
with cardiac function and morphometry-specific
have indicated that HCM presenting in infancy
outcomes. We propose a simple classification on
carries a worse prognosis than in older children due
the basis of a hypertrophic phenotype that seems
to its frequent association with intractable heart
to correlate well with prognosis. Ventricular septal
failure (30–32).
thickness, CTR, diastolic dysfunction, gestational
Ventricular noncompaction has been recognized as
age, and CVPS are independently associated with
a pre-natally detectable entity, especially in the past
mortality. Fetuses with HCM had a very high
decade, typically in association with structural heart
risk of perinatal demise. In contrast, those fetuses
disease, fetal hydrops, and demise (19,26,33,34). In
with a fetal diagnosis of NHCM had better out-
our series, 5 of 8 patients with isolated ventricular
comes than previously reported. Involvement of
noncompaction are currently alive, 1 of whom un-
other organs was common in fetuses with genetic,
derwent heart transplantation in infancy. In 1 patient,
metabolic, post-infectious, or syndromic disorders
severe fetal hydrops resolved spontaneously in late
and may substantially affect the clinical outcome of
gestation. Two of the mothers in this subgroup were
survivors.
also affected by CM, suggesting a dominant inheritance pattern in some families.
REPRINT REQUESTS AND CORRESPONDENCE: Dr.
STUDY LIMITATIONS. This was a retrospective re-
Edgar Jaeggi, Fetal Cardiac Program, Labatt Family
view, and some eligible cases of primary CM may not
Heart Centre, The Hospital for Sick Children, 555
have been documented. A complete diagnostic
University Avenue,
workup was not always possible in cases of pre-natal
Canada. E-mail: [email protected].
Toronto,
Ontario
M5G
1X8,
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KEY WORDS cardiomyopathy, echocardiography, fetal, noncompaction, outcome
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