ORIGINAL ARTICLE
Fetal Interventions for Congenital Heart Disease in Brazil
Simone Rolim Fernandes Fontes Pedra • Cleisson Fabio Andrioli Peralta •
Luciana Crema • Ieda Bosisio Jatene • Rodrigo Nieckel da Costa •
Carlos Augusto Cardoso Pedra
Received: 14 May 2013 / Accepted: 28 August 2013 / Published online: 13 September 2013
� Springer Science+Business Media New York 2013
Abstract Fetal interventions have been performed for
some congenital heart diseases. However, these procedures
have not gained wide acceptance due to concerns about
their efficacy and safety. The aim of this study was to
report on a preliminary experience with fetal cardiac
interventions in Brazil. Twenty-two cardiac interventions
were performed in 21 fetuses. Thirteen fetuses had critical
aortic stenosis (CAS), 4 had hypoplastic left heart syn-
drome (HLHS) and intact interatrial septum or small patent
foramen ovale, 1 had pulmonary atresia with intact ven-
tricular septum (IVS), and 3 had critical pulmonary ste-
nosis (CPS). The main outcome variables evaluated were
technical success and procedural complications as well as
pregnancy and postnatal outcomes. Success was achieved
in 20 of 22 procedures (91 %) with 1 failed aortic and 1
failed pulmonary valvuloplasties. There was 1 fetal death.
No maternal complications occurred. One patient with
CAS, severe mitral regurgitation, and hydrops died post-
natally within 5 months of age. All patients with HLHS
and restrictive atrial septum died after interventional or
surgical procedures and prolonged hospitalizations. All
patients with CPS/IVS survived and achieved a biventric-
ular (BV) circulation after neonatal valvuloplasty and
ductal stenting. A BV circulation was achieved in 4 of 8
patients with CAS and evolving HLHS (one still in utero),
including 2 with initial borderline left ventricles (LV) in
whom surgical LV overhaul was performed at 9 months of
age. In this preliminary experience, the feasibility of fetal
cardiac interventions and their outcomes were similar to
those previously reported.
Keywords Congenital heart disease � Fetal
intervention � Fetal surgery � Fetal therapy
Introduction
Since first reported by Maxwell et al. [10] in 1991, fetal
interventions have been performed for some congenital
heart diseases, such as critical aortic stenosis (CAS),
hypoplastic left heart syndrome (HLHS), and pulmonary
atresia (PA) or critical pulmonary stenosis (CPS) with
hypoplastic right heart syndrome (HRHS) [1, 6–9, 11–13,
15–18]. The rationale behind these procedures is the pos-
sibility of improvement of cardiac morphology and func-
tion, which may help to change the natural intrauterine
history of these diseases. However, these interventions
have not gained wide acceptance due to concerns about
their efficacy and safety [4, 5].
The aim of this study was to describe our preliminary
experience with fetal cardiac intervention in the context of
an established cardiology program at a referral institution
in Brazil.
Materials and Methods
Case Selection
Records of all patients who underwent fetal cardiac inter-
ventions from July 2007 through December 2012 per-
formed by a multidisciplinary team were reviewed. The
parents provided written consent after they were informed
S. R. F. F. Pedra � C. F. A. Peralta (&) � L. Crema �I. B. Jatene � R. N. da Costa � C. A. C. Pedra
Fetal Cardiology Unit, Heart Hospital, Rua Desembargador
Eliseu Guilherme, 123, Sao Paulo, SP CEP 05675-120, Brazil
e-mail: [email protected]
123
Pediatr Cardiol (2014) 35:399–405
DOI 10.1007/s00246-013-0792-3
about the risks and potential benefits of these procedures.
The Ethics Committee for Clinical Investigation approved
this study.
The inclusion criteria for fetal intervention consisted of
isolated cardiac defects (i.e., absence of any other struc-
tural abnormality or marker for chromosomal aberration)
with the following echocardiographic findings:
1. CAS and evolving HLHS: The presence of thickened,
immobile aortic valve with turbulent or decreased
color Doppler flow; left-ventricular (LV) diastolic
length above the lower limit of normal (z-score[-2);
reversed blood flow in the transverse aortic arch; left-
to-right flow across the interatrial septum (IAS);
monophasic mitral valve inflow; and severe LV
dysfunction. In cases with smaller left ventricles (LV
diastolic length z-score \-2), valvuloplasty was
performed in an effort to ameliorate LV function [1,
6, 8, 11, 12].
2. CAS, massive mitral regurgitation (MR), giant left
atrium (GLA), and hydrops: Presence of dilated LV
and reversed flow in the transverse aortic arch [18].
3. HLHS and intact IAS or small patent foramen ovale
(PFO): The presence of unequivocal HLHS with either
an intact IAS or a small (B1 mm) PFO, dilated left
atrium, and pulmonary veins. The pulmonary vein flow
Doppler tracing was bidirectional with the systolic
component having the same velocity as the ‘‘a’’ wave
reversal and tiny or no forward flow in early diastole
[7, 9].
4. PA with intact ventricular septum (PA/IVS) or CPS
with impending HRHS: The presence of membranous
PA with identifiable pulmonary valve (PV) leaflets or
membrane; no/minimal systolic PV opening; no/min-
imal color Doppler ultrasound flow across the PV;
reversed flow in a patent ductus arteriosus; and right
heart hypoplasia with a tricuspid valve (TV) annulus
z-score \2 and an identifiable but qualitatively small
right ventricle (RV) [2, 15, 17].
Technique
Table 1 lists the standard technique used for the proce-
dures, which were all monitored solely by fetal echocar-
diography. A technically successful aortic or pulmonary
valvuloplasty was defined as a case where antegrade flow
and/or new aortic/pulmonary regurgitation were detected
by color Doppler. A technically successful atrial septo-
plasty was defined as a case where there was evidence of a
newly created atrial septal defect (ASD) with significant
improvement on the left-to-right shunt, which was associ-
ated with a decrease in LA size and improvement in the
pulmonary vein Doppler pattern.
Follow-up and Postnatal Management
Follow-up and delivery occurred at our center or at the
referring institution. Mothers had elective cesarean sections
(C-section), and the neonates were transferred to the
intensive care unit to receive prostaglandin.
Postnatal management varied according to the cardiac
defect and the institution providing care and consisted of
percutaneous aortic valvuloplasty through the carotid
artery; branch pulmonary artery banding and ductal stent-
ing through a median sternotomy (hybrid approach); atrial
septostomy; surgical aortic valvuloplasty; surgical mitral
replacement; surgical resection of endocardial fibroelasto-
sis (LV overhaul); and percutaneous pulmonary valvulo-
plasty plus ductal stenting.
Main Outcome Variables
The main outcome variables evaluated in this study were
technical success and procedural complications as well as
pregnancy and postnatal outcomes. Among the surviving
neonates, postnatal outcomes were characterized as (1)
having biventricular (BV) circulation from birth, (2) having
BV circulation (at the time of cross-sectional follow-up)
after an initial staging procedure, or (3) having univen-
tricular (UV) circulation (i.e., a definitive UV circulation
from birth or at the time of cross-sectional follow-up) or (4)
a temporary intermediate (mixed) circulation in which one
or both ventricles contributed to the systemic and pul-
monary output. Z-scores were calculated according to GA
on the basis of unpublished fetal norms derived from data
collected at The Children’s Hospital of Boston and used in
their previous publications [6–9, 11, 12, 17].
Results
Twenty-one fetuses with a median GA of 29 weeks (range
23–34) and a median estimated weight of 1,200 g (range
500–2,500) underwent cardiac interventions. Thirteen
fetuses had CAS (9 had evolving HLHS, of whom 3 had
LV diastolic length z-score \-2 and 4 had dilated LVs,
severe MR, GLA, and hydrops, respectively); 4 had HLHS
and intact IAS or small PFO; 1 had PA/IVS; and 3 had
CPS.
Technical Success and Procedural Complications
(Table 2)
Twenty of 22 interventions (91 %) were performed suc-
cessfully (case no. 17 underwent atrial septostomy and aortic
valvuloplasty). Significant pericardial effusion requiring
drainage (1–3 ml) for recovery and hemodynamic instability
400 Pediatr Cardiol (2014) 35:399–405
123
requiring epinephrine administration to resume the heart rate
were observed in 9 (45 %) and 8 (40 %) of the 20 technically
successful cases, respectively. No maternal complications
occurred.
Pregnancy and Postnatal Outcomes
CAS and Evolving HLHS (Fig. 1; Tables 2, 3)
Median GA at the procedure was 28 weeks (range 23–30).
One patient is still in utero (case no. 21), and one patient
(case no. 9) was born prematurely (34 weeks of gestation)
due to maternal pre-eclampsia.
Among those who had successful AV dilation and who
were born at term (n = 6), the survival rate was 50 %.
Three of four patients (75 %) who were delivered at our
center survived: one child (case no. 8) had a BV circulation
from birth, underwent a successful aortic valvuloplasty at
3 weeks of age, is doing well, and has normal LV size and
function. The other two patients (cases no. 13 and 14) had
borderline LVs at birth, underwent hybrid procedures, and,
at age 9 months, were changed to BV circulation after LV
rehabilitation and aortic valvotomy. One fetus (case no. 15)
had a severely dilated, dysfunctional thin-walled LV and
hydrops. No improvement in the size and function of the
left heart structures was observed. Because he was deemed
to have a functionally UV heart, the parents opted for
supportive care after delivery.
Both patients born at other centers had borderline LVs at
birth. One patient (case no. 5) died after bidirectional
cavopulmonary anastomosis at age 6 months. The other
patient (case no. 7) died after a hybrid procedure due to
complications related to central venous line insertion.
CAS, MR, GLA, and Hydrops (Tables 2, 3)
Four fetuses presented with this condition and underwent
successful aortic valvuloplasty at 25, 30 (two cases), and
34 weeks’ gestation. Postnatal survival rate was 25 %.
Two patients (cases no. 2 and 10) were born prematurely
(at 33 and 35 weeks of gestation, respectively) in other
institutions while still severely hydropic, and each died a
couple of hours after birth. The third patient (case no. 12)
was born at our institution and underwent aortic valvulo-
plasty with no improvement of mitral valve regurgitation.
She underwent surgical replacement of the mitral valve and
aortic valvuloplasty. At 5 months of age, she had severe
prosthesis stenosis, which was treated percutaneously, with
immediate severe MR followed by death. The fourth fetus
(case no. 19) had a successful valvuloplasty followed by
complete in utero resolution of the hydrops. After birth at
our institution, she underwent balloon septostomy and
aortic valvuloplasty, which resulted in a significant
improvement of her hemodynamic status. Due to mild LV
hypoplasia, a hybrid procedure was performed, and she was
discharge home at age 4 months.
HLHS and Intact IAS or Small PFO (Tables 2, 3)
There was no postnatal survival in this group. Our first
patient (case no. 1) had successful creation of a 3-mm ASD
at 32 weeks’ gestation. Delivery was at term at another
institution. The neonate underwent a successful hybrid
procedure on the day of life 4 followed by atrial stenting on
the postoperative day 14. She subsequently underwent
Norwood–Glenn surgery at age 5 months and died on the
operating room probably due to pulmonary hypertension.
The second patient (case no. 3) underwent a hybrid pro-
cedure and died from sepsis after a prolonged period under
Table 1 Technique for fetal cardiac intervention
Uterine contraction prevention
Nifedipine 20 mg PO TID starting 8 h before and 2 more doses
afterward
Maternal anesthesia
Conscious sedation and spinal blockade
Polydramnious evacuation (if needed)
Fetal external version (if needed) to obtain optimal angle of needle
entry
Fetal anesthesia (chordal or muscular)
Fentanyl ? pancuronium ? atropine (usual anesthetic doses)
Maternal access
Percutaneous transabdominal and transuterine
Fetal access
Transthoracic or subcostal
Valvuloplasties, apical access
Septostomy, right atrial wall access
Needles
Chiba 15 mm long, 17G, 18G, and 19G
Balloons
Coronary balloons premounted on 0.01400 guidewire (floppy tip)
3.0–4.0 mm diameter, 6–10 mm length
System marked and secured with sterile tapes
Septostomy
4.0 mm diameter balloons inflated B 4.7 mm
Aortic and pulmonary valvuloplasties
10–30 % greater than valve annulus
System (wire ? balloon ? needle) withdrawn as a unit
Pericardial effusion drainage
20G Chiba needle
Fetal resuscitation if needed
Epinephrine and/or atropine in pericardial space (small doses)
Pediatr Cardiol (2014) 35:399–405 401
123
difficult mechanical ventilation. One fetal death (case no.
4) occurred the day after successful and uneventful atrial
septoplasty (transplacental approach).
In our last case (no. 17), atrial septostomy was performed
successfully and was followed by aortic valvuloplasty with
significant improvement of antegrade aortic flow. The
neonate underwent an atrial septostomy immediately after
birth followed by a hybrid procedure. A complicated post-
operative course ensued, and the patient died at age
4 months.
Table 2 Indications and results of 22 interventions for congenital heart disease performed in 21 fetuses
Case no. GA (weeks) Disease/indication Procedure Result
1 32 HLHS ? small PFO AS Successful
2 30 CAS ? MR ? GLA ? hydrops AoV Successful
3 29 HLHS ? intact IAS AS Successful
4 32 HLHS ? small PFO AS Successful
5 29 CAS ? evolving HLHS AoV Successful
6 28 PA/IVS PuV Unsuccessful
7 27 CAS ? evolving HLHS AoV Successful
8 30 CAS ? evolving HLHS AoV Successful
9 23 CAS ? evolving HLHS AoV Successful
10 34 CAS ? MR ? GLA ? hydrops AoV Successful
11 29 4/7 CPS PuV Successful
12 30 CAS ? MR ? GLA ? hydrops AoV Successful
13 28 CAS ? evolving HLHS AoV Successful
14 27 5/7 CAS ? evolving HLHSa AoV Successful
15 25 4/7 CAS ? evolving HLHS ? hydrops AoV Successful
16 23 CAS ? evolving HLHSa AoV Unsuccessful
17 26 HLHS ? small PFO AS ? AoV Successful
18 29 CPS PuV Successful
19 25 CAS ? MR ? GLA ? hydrops AoV Successful
20 27 CPS PuV Successful
21 29 CAS ? evolving HLHSa AoV Successful
GA gestational age, HLHS hypoplastic left heart syndrome, PFO patent foramen ovale, AS atrial septostomy, CAS critical aortic stenosis, MR
mitral regurgitation, GLA giant left atrium, AoV aortic valvuloplasty, IAS inter-atrial septum, PA/IVS pulmonary atresia and intact ventricular
septum, PuV pulmonary valvuloplasty, CPS critical pulmonary stenosisa Small LV = diastolic length Z-score \-2
Fig. 1 Serial echocardiograms of a fetus who underwent aortic
valvuloplasty (case no. 13, Tables 1 and 2). a Four-chamber view at
27 weeks of gestation before fetal intervention. The LV is dysfunc-
tional and small (long-axis z-value -4). There are patchy areas of
endocardial fibroelastosis and hypertrophic papillary muscle. The
mitral valve annulus is smaller than normal (z-value -3). b At birth,
the LV showed important growth (long-axis z-value -2.5) and
normal function. This neonate underwent a hybrid procedure as a
bridge to definitive repair. c At the age of 9 months, the LV was of
normal size (long-axis z-value -0.1). Patchy areas of endocardial
fibroelastosis are seen on the septum. The infant underwent successful
LV overhaul and surgical aortic valvuloplasty after the ductal stent
and pulmonary artery bands were removed
402 Pediatr Cardiol (2014) 35:399–405
123
PA/IVS and CPS with Impending HRHS (Fig. 2; Tables 2,
3)
Our first valvuloplasty attempt (case 6) was unsuccessful
due to a high point of needle entry in the infundibulum.
This child died from sepsis at age 8 weeks after successful
radiofrequency-assisted PV dilation and ductal stenting.
The second fetus (case no. 11) was born at term with PV
stenosis. The neonate underwent successful pulmonary
valvuloplasty on day of life 2 followed by ductal stenting.
The child is now 5 months old and doing well.
The third and fourth fetuses, each with moderate to
severe RV hypoplasia (cases no. 18 and 20), had significant
increase in their RV sizes after pulmonary valvuloplasty.
Both were born at our institution and underwent percuta-
neous pulmonary valvuloplasties and ductal stenting.
Discussion
In this preliminary experience, we have shown that fetal
cardiac interventions were feasible in our hands and that
the outcomes were comparable with those of other insti-
tutions. Several aspects of these interventions merit
discussion.
Older GA at intervention was observed in our series
when compared with those seen in previous reports, par-
ticularly for aortic and pulmonary valvuloplasties [7, 16,
17]. This probably results from late prenatal diagnosis and
referrals in our environment and perhaps some reluctance
to accept fetal cardiac intervention as a feasible treatment
modality.
The indications for fetal interventions were similar to
those encountered in previously published experiences,
with the exception of intervening in fetuses with CAS and
smaller LVs (z-value -2 to -3). Acknowledging that fetal
CAS with evolving HLHS is intrinsically a disease of the
LV myocardium, we agree that only a subset of patients
would eventually achieve BV circulation [11, 12]. In our
series, BV circulation was observed in 50 % of patients
with CAS and evolving HLHS who underwent successful
AV dilation and who were born at term. However, we still
believe that there are other reasons to intervene in fetuses
with smaller and borderline LVs. This group may theo-
retically benefit from the procedure due to improved cor-
onary flow and preservation of myocardial function, which
may have a positive impact on neonatal outcomes regard-
less of the initial strategy (Norwood vs. hybrid). Because
the classic and modified neonatal Norwood procedures are
associated with disappointing outcomes in our institution,
the so-called hybrid approach has been widely adopted
with improved results in the last 5 years (unpublished
data). In such palliated patients, it is our impression that
antegrade aortic flow results in a more stable and predict-
able postoperative course. In addition, promoting forward
flow across the aortic valve in utero may theoretically help
minimize the neurodevelopmental abnormalities secondary
to retrograde transverse aortic arch perfusion observed in
Table 3 Postnatal procedures
and outcomes of 20 fetuses who
underwent prenatal
interventions for congenital
heart disease
HLHS hypoplastic left heart
syndrome, CAS critical aortic
stenosis, GLA giant left atrium,
PA/IVS pulmonary atresia and
intact ventricular septum, PuV
pulmonary valvuloplasty, AoV
aortic valvuloplasty, BV
biventricular, MV mitral valve,
LVRH left-ventricle
rehabilitation, UV
univentricular, BAS balloon
atrial septostomy
Case no. Disease Postnatal procedure Outcome
1 HLHS Hybrid–Norwood/Glenn Death at stage II
2 CAS ? GLA None Death soon after birth
3 HLHS Hybrid Death after hybrid procedure
4 HLHS None Death after fetal intervention
5 CAS Norwood I and II Death at stage II
6 PA/IVS PuV ? stent Death at 8 weeks of sepsis
7 CAS Hybrid Death after hybrid procedure
8 CAS AoV BV; survived
9 CAS AoV BV; prematurity; died
10 CAS ? GLA None Death soon after birth
11 CPS PuV ? stent BV; survived
12 CAS ? GLA MV replacement ? AoV BV; died at 5 months
13 CAS AoV ? hybrid ? LVRH BV; survived
14 CAS Hybrid ? LVRH BV; survived
15 CAS None Supportive care provided
16 CAS Hybrid UV; interstage death
17 HLHS BAS ? hybrid UV; interstage death
18 CPS PuV ? stent BV; survived
19 CAS ? GLA AoV ? hybrid Probable BV; survived
20 CPS PuV ? stent BV; survived
Pediatr Cardiol (2014) 35:399–405 403
123
fetuses with established HLHS. Moreover, progressive
growth of the left heart structures during fetal life and
during infancy, resulting in an eventual BV repair, was
observed in two patients in this study.
Indications for interventions in fetuses with HLHS and
intact IAS or small PFO and PA/IVS were the same as
those found in the literature [7, 9]. Fetuses with CAS and
severe MR associated with hydrops have dismal outcomes
no matter what strategy employed was employed [18].
Perhaps in those patients, ASD creation, or enlargement of
PFO to decompress the GLA, should be assigned the same
importance as aortic valvuloplasty [18].
In this series, we employed techniques that had been
described before and which helped to optimize our learning
curve. Avoiding maternal general anesthesia most likely
facilitated fetal positioning and minimized the need for
laparotomy, which is eschewed in our practice.
Fetal hemodynamic instability due to bradycardia and
hemopericardium were common complications in this and
other series [8, 13, 15–17]. Therefore, prophylactic atro-
pine administration during fetal anesthesia, occasional
intracardiac or pericardial injection of epinephrine and
atropine, and prompt pericardial drainage should be con-
sidered as part of the standard of care in such interventions.
Although any fetal intervention may incite premature
labor, this complication was not observed in this series.
Nonetheless, three of our neonates were born preterm: two
had CAS, severe MR, and hydrops, and one had CAS and
evolving HLHS (prematurity was associated with maternal
pre-eclampsia). The observation that three of the remaining
six fetuses with CAS and evolving HLHS who were born
near term in this series achieved a BV circulation is
encouraging and in line with previously reported experi-
ences [1, 16].
It remains unclear whether our three patients with CPS
really benefited from fetal pulmonary valvuloplasty.
According to a previously published scoring system with
morphological and functional predictors of eventual BV
circulation, their PV and TV/MV ratio were already greater
than the cut-off values for UV circulation at 29–30 weeks
of gestation [2]. However, despite being more challenging
from a technical standpoint, procedural feasibility was
confirmed and thus may be useful for future cases.
Although we were able to create ASDs in fetuses with
HLHS and intact IAS or small PFO, postnatal outcomes
were disappointing. In two fetuses, the IAS was highly
restrictive at birth. In the other patient, despite an initially
favorable clinical course, death occurred due to pulmonary
hypertension. This raises the question of procedural effi-
cacy in late gestation in terms of preventing the develop-
ment of secondary pulmonary vascular and parenchymal
changes.
Although a fetal intervention may place the mother at
risk, previous experiences with cardiac and noncardiac
fetal interventions performed by our group and other
groups have shown excellent safety profile with limited
morbidity and no mortality to the mother [1, 3, 6–18].
Although we acknowledge that an elective C-section may
theoretically add some more risk to this equation and that
most centers advocate vaginal delivery for fetuses with
congenital heart disease, we believe that this delivery route
poses much less cardiovascular stress to such fragile
patients, especially those with CAS and ventricular dys-
function as well as those with HLHS and near-intact IAS.
In addition, an elective C-section facilitates postnatal care
and planning for subsequent invasive procedures. Finally,
assessment and perception of maternal and fetal risks
should take into consideration each individual’s value
system. What is a tolerable risk for some parents may differ
from others with a different culture, socioeconomic class,
religious background, or personal family situation. Proper
parental counseling with more than one individual and
Fig. 2 Serial echocardiograms of a fetus who underwent pulmonary
valvuloplasty (case no. 11, Tables 1 and 2). a Four-chamber view at
29 weeks of gestation before fetal intervention. The RV (long-axis
z-value -4.1) and the TV (z-value -2.7) are small. b The balloon is
inflated at the PV level. The neonate underwent pulmonary
valvuloplasty and ductal stenting. c Four-chamber view at age
5 months. The RV is of normal size (z-value TV -1.3). There is
predominant left-to-right shunting across a PFO. The ductal stent
closed spontaneously, and the RV outflow tract is unobstructed
404 Pediatr Cardiol (2014) 35:399–405
123
institutional surveillance are crucial to ensure that parents
are aware of the current state of knowledge and possible
alternatives to fetal catheter intervention. This highlights
the importance of establishing a complete fetal cardiac
program with its own peculiarities from diagnostic to
prenatal and postnatal cardiologic and neonatal treatment
capabilities and parental support [4, 5].
This study has obvious limitations, including its
descriptive nature, small number of patients, and nonuni-
form postnatal care. However, we believe that none of
these limitations affects the take-home message of this
report.
The feasibility of fetal cardiac interventions and their
outcomes in this preliminary experience were similar to
those previously reported. Although we believe that the
data presented herein justify expanding the availability of
fetal catheter intervention as a treatment option to centers
with the infrastructure and commitment to perform these
procedures, they should still be restricted to referral centers
that can amass a critical volume of experience to ensure
clinical competence.
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