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1. October 3, 2017 Circulation. 2017;136:1346–1349. DOI: 10.1161/CIRCULATIONAHA.116.0258731346
I
nfants with hypoplastic left heart syndrome and an intact or highly restrictive
atrial septum (HLHS-IAS) represent a high-risk subset. Fetal cardiac intervention
(FCI) for fetuses with HLHS-IAS has been reported in single-institution series as
a therapy that may improve outcomes. This study uses the International Fetal Car-
diac Intervention Registry (IFCIR) to examine fetal and maternal characteristics and
pregnancy and neonatal outcome data for FCI in this population.
For this descriptive analysis, the IFCIR was queried for fetuses with HLHS-IAS
evaluated between 2001 and March 2015 for possible FCI and felt to be candi-
dates at the referral center by a variety of published criteria including foramen
ovale (FO) size, shunt flow direction across the FO, and pulmonary venous Dop-
pler flow patterns. It includes those who were determined not to be candidates
because of other fetal noncardiac conditions, maternal conditions, or maternal
preferences, or because FCI was not performed at the participating institution.
Further details on the methodology of the IFCIR registry are found in the initial
report.1
Participating IFCIR member sites obtained local institutional review board and
ethics board approval or a waiver, as governed by applicable local standards. Forty-
eight previously published patients (15 non-FCI, 33 FCI including 17 septoplasties
and 16 stents) from the 2015 initial IFCIR report were included, of whom 18 FCI
patients had also been reported in single-center publications.1–5
The results are summarized in Tables 1 and 2. Data from 13 institutions were
submitted; 89 maternal–fetal dyads with fetal HLHS-IAS were identified. We ex-
cluded 17 non-FCI patients who terminated the pregnancy. Of the remaining 72
cases of HLHS-IAS, 47 dyads from 8 sites underwent FCI: 27 with atrial septoplas-
ty alone (atrial perforation/ balloon dilation) and 20 with atrial septal stent place-
ment. There were 36 (77%) procedural successes with a higher proportion of
septoplasties being successful, although this did not reach statistical significance
(13/20=65% stent versus 23/27=85% septoplasty, Fisher exact P=0.16). Although
there were no maternal complications, fetal complications were common, and
procedure-related fetal demise occurred in 6 (13%). Cesarean delivery, planned
immediate postnatal intervention, restrictive FO, and neonatal resuscitation were
less common in those who underwent procedurally successful FCI in comparison
with those with unsuccessful FCI or no FCI. Only 18/41=45% of all FCI livebirths
had a clinically nonrestrictive FO at delivery. One successful stent terminated preg-
nancy. There was a trend toward stents performing better than septoplasties in
maintaining a nonrestrictive FO at delivery after procedural success (9/12=75%
versus 9/23=39%, Fisher exact P=0.075), and discharge survival was 7/12=58%
with successful stents. However, overall discharge survival was poor (35%), and
there was no difference between groups, either overall (34% FCI versus 36%
no FCI) or with procedural success (44% successful FCI versus 33% unsuccess-
ful or no FCI). Postdischarge follow-up data were available in 18/24=75% of the
David W. Jantzen, MD
Anita J. Moon-Grady, MD
Shaine A. Morris, MD,
MPH
Aimee K. Armstrong, MD
Christoph Berg, MD
Joanna Dangel, MD, PhD
Carlen G. Fifer, MD
Michele Frommelt, MD
Ulrich Gembruch, MD
Ulrike Herberg, MD
Edgar Jaeggi, MD
Eftichia V. Kontopoulos,
MD, PhD
Audrey C. Marshall, MD
Owen Miller
Renate Oberhoffer, MD,
PhD
Dick Oepkes, MD, PhD
Carlos A. Pedra, MD, PhD
Simone R. Pedra, MD, PhD
Fabio Peralta, MD
Ruben A. Quintero, MD
Greg Ryan, MB
Sarah K. Gelehrter, MD
© 2017 American Heart
Association, Inc.
Correspondence to: David W.
Jantzen, MD, Congenital Heart
Center, Children’s Hospital of
Illinois, 420 NE Glen Oak Avenue,
Suite 301, Peoria, IL 61603. E-mail
jantzen@uic.edu
Key Words: atrial septostomy
◼ echocardiography ◼ fetal
therapies ◼ heart defects,
congenital ◼ hypoplastic left heart
syndrome
Hypoplastic Left Heart Syndrome With
Intact or Restrictive Atrial Septum
A Report From the International Fetal Cardiac Intervention Registry
RESEARCH LETTER
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2. Fetal Intervention HLHS With Intact Atrial Septum
Circulation. 2017;136:1346–1349. DOI: 10.1161/CIRCULATIONAHA.116.025873 October 3, 2017 1347
CORRESPONDENCE
Table 1. Procedural and Outcome Registry* Data for Hypoplastic Left Heart Syndrome
with Restrictive or Intact Atrial Septum, Fetal Cardiac Intervention and Non-Intervention
All Patients
(N=72) No FCI† (N=25) FCI (N=47) P Value
Pregnancy Outcome, n (%)
Procedural death+TOP 7 (10) 0 6+1 (15) 0.57
(livebirths) Preterm (37wks) 16 (22) 5 (20) 11 (23)
Term 49 (68) 20 (80) 29 (62)
Pregnancy complication reported, n (%) 9 (13) 3 (12) 6 (13) 1.00
Type of delivery‡, livebirths§, n (%)
Cesarean‖ 31/44 (70) 18/21 (86) 13/23 (57) 0.049
IMPACT or EXIT 17/44 (39) 14/21 (67) 3/23 (13) 0.01
Gestational age§, wk, median (IQR) 38.4 (36.9–39.0) 38.4 (37.3–39.0) 38.4 (36.9–39.0) 0.95
Birth weight,§ g, median (IQR) 2953 (2589–3408) 3100 (2805–
3536)
2863 (2468–
3068)
0.09
Neonatal resuscitation,§ n (%) 24/50 (48) 15/23 (65) 9/27 (33) 0.046
Mechanical ventilation,§ n (%) 33/44 (75) 17/21 (81) 16/23 (70) 0.49
ECMO before surgery,§ n (%) 3/45 (7) 1/21 (5) 2/24 (8) 1.00
Clinically nonrestrictive FO at delivery,§¶
n (%)
23 (38) 6 (22) 17 (50) 0.03
First procedure,§ n (%)
Atrial decompression 21 (34) 13 (48) 8 (24) 0.13
Hybrid 10 (16) 2 (7) 8 (24)
Norwood 19 (31) 7 (26) 12 (35)
None 10 (16) 5 (19) 5 (15)
Unknown 1 (2) 0 (0) 1 (3)
Neonatal outcome,§ n (%)
Alive at 30 d 32 (52) 12 (44) 20 (59) 0.31
Alive at discharge 24 (39) 9 (33) 15 (44) 0.44
ECMO indicates extracorporeal membrane oxygenation; EXIT, ex utero intrapartum treatment; FCI, fetal cardiac
intervention; FO, foramen ovale; g, grams; IMPACT, Immediate Postnatal Access to Cardiac Therapy; IQR, interquartile
range; IUFD, in utero fetal demise; SD, standard deviation; and TOP, termination of pregnancy. Data were described using
standard summary statistics and compared using nonparametric testing (Fisher’s exact test and Mann-Whitney test) as
appropriate. Patients with missing data were excluded from analyses involving that variable but were included in the
overall reporting as appropriate.
*Registry is maintained within a Research Electronic Data Capture (REDCap) Database. REDCap is a secure, web-based
application designed to support data capture for research studies, with more details at https://www.project-redcap.org.
†The most common reason for not having FCI performed was that the patient did not meet criteria for intervention at
the reporting institution (44%), followed by patient refusal (24%), procedure not offered at reporting institution (16%),
and FCI offered but not able to be performed, either due to position of the fetus or atrial size (16%); for livebirth data,
unsuccessful FCI patients are included in this category for purposes of comparison.
‡For remaining data, for patients in the FCI category only procedurally successful outcomes are reported. “Procedural
success” was defined as successful completion of the intervention, as coded in the registry by the performing institution
and without periprocedural (48 hours) fetal demise.
§Live births with planned postnatal intervention only (excluded comfort care): total N=61, unsuccessful or no FCI N=27,
FCI N=34 unless noted.
‖Cesarean section numbers include surgical delivery for planned postnatal intervention including IMPACT and EXIT.
¶“Clinically nonrestrictive FO” was defined by a FO that does not require urgent intervention within the first 24 hours
after delivery.
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3. Jantzen et al
October 3, 2017 Circulation. 2017;136:1346–1349. DOI: 10.1161/CIRCULATIONAHA.116.0258731348
survivor cohort, with 59% 1-year actuarial survival in
the FCI fetuses with a nonrestrictive FO at birth versus
19% in non FCI fetuses (log rank P=0.03).
This exploratory analysis confirmed the poor survival
in this population. However, successful FCI was asso-
ciated with secondary outcomes of reduced Cesarean
deliveries and improved neonatal stability at delivery, as
evidenced by decreased planned immediate postnatal
interventions and neonatal resuscitation. These poten-
tial benefits of lessening maternal risk and resource use
that accompanies coordinated deliveries have not been
examined previously. Future studies could address the
effect of timing on the success of fetal intervention. It is
reasonable for this procedure to be performed as early
in gestation as possible; however, the benefits of early
intervention on pulmonary vascular changes need to be
Table 2. Fetal Cardiac Intervention Procedural Details and
Outcomes
Atrial
Septoplasty
(N=27)
Atrial Stent
(N=20) P Value
Gestational age at FCI, wk, mean (SD) 29.0 (2.7) 29.3 (3.8) 0.76
Routine periprocedural tocolysis, n (%) 18 (67) 15 (75) 0.75
Maternal anesthesia types used, n (%)
General 11 (41) 4 (20) 0.21
Regional 10 (37) 11 (55) 0.25
IV Sedation 4 (15) 6 (30) 0.29
Local 4 (15) 3 (15) 1.00
Largest balloon diameter, mm, median
(range)
4.0 (2.5–4.7) 3.2 (2.5–4.7) 0.003
1 Balloon used, n (%) 3 (11) 4 (20) 0.44
Laser, n (%) 1 (4) 1 (5) 1.00
1 Cardiac puncture, n (%) 6 (22) 6 (30) 1.00
Procedural complications, n (%)
Any complication 17 (63) 13 (65) 1.00
Fetal bradycardia 7 (26) 4 (20) 0.74
Pericardial effusion 13 (38) 11 (55) 0.77
Hemothorax 3 (11) 3 (15) 1.00
Balloon rupture 1 (4) 4 (20) 0.15
Stent embolization n/a 5 (25) n/a
Fetal demise 1 (4) 1 (5) 1.00
Fetal resuscitation medication given, n
(%)
6 (22) 5 (25) 1.0
Fetal complication within 48 h (excludes intraprocedural), n (%)
None 14 (52) 15 (75) 0.14
Pericardial effusion 1 (4) 0 (0) 1.00
Hemothorax 0 (0) 2 (10) 0.17
Fetal demise 2 (7) 2 (10) 1.00
Procedural success,* n (%) 23 (85) 13 (65) 0.16
FCI indicates fetal cardiac intervention; and SD, standard deviation. Data were described
using standard summary statistics and compared using nonparametric testing (Fisher’s exact
test and Mann-Whitney test) as appropriate. Patients with missing data were excluded from
analyses involving that variable but were included in the overall reporting as appropriate.
*“Procedural success” was defined as successful completion of the intervention, as coded in
the registry by the performing institution and without periprocedural (48 hours) fetal demise.
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4. Fetal Intervention HLHS With Intact Atrial Septum
Circulation. 2017;136:1346–1349. DOI: 10.1161/CIRCULATIONAHA.116.025873 October 3, 2017 1349
CORRESPONDENCE
weighed with the technical challenges of manipulating
relatively large needles in extremely premature hearts.
Atrial morphology, optimal sized balloon/stent, or the
ratio of stent diameter to septum were not studied and
may have an effect on the success of FCI. The effect of
variation in postnatal care was not able to be studied,
because the IFCIR does not contain detailed postnatal
procedural information. Last, given limited case num-
bers, we did not evaluate the effect of procedural vol-
ume or experience on success rates, which may be a
topic for further research.
This multicenter registry report demonstrated that
procedural success for HLHS-IAS can be achieved in a
significant proportion of fetuses, although this did not
always translate to a patent septum at delivery and
survival to discharge did not differ between FCI and
non-FCI patients. We showed that FCI has the poten-
tial to improve maternal pregnancy outcomes and neo-
natal stability, and there may be longer-term benefits
in the course of single-ventricle palliation by affecting
pulmonary vascular changes that we could not assess.
Our study reflects areas of both promise and improve-
ment for this very high-risk patient group, suggesting
continuation of FCI at select institutions to concentrate
experience and further standardize the interventional
approach and postnatal care to the greatest extent pos-
sible.
ACKNOWLEDGMENTS
The authors acknowledge the expert assistance of Ray Lowery
and Katie Archbold in support of this project and the article.
DISCLOSURES
Dr Armstrong: Medtronic, Inc. (modest, research grant), Ed-
wards Lifesciences (modest, research grant), St. Jude Medical
(modest, consultant/advisory board), Siemens Healthcare AX
(modest, consultant/advisory board), and B. Braun Interven-
tional Systems Inc. (modest, consultant/advisory board).
AFFILIATIONS
From C.S. Mott Children’s Hospital, University of Michigan,
Ann Arbor (D.W.J., C.G.F., S.K.G.); University of California–
San Francisco (A.J.M.-G.); Baylor College of Medicine, Hous-
ton, TX (S.A.M.); Nationwide Children’s Hospital, Columbus,
OH (A.K.A.); University of Bonn, Germany (C.B., U.H.); Peri-
natal Cardiology Clinic, Medical University of Warsaw, Poland
(J.D.); Children’s Hospital of Wisconsin, Milwaukee (M.F.);
University Hospital Bonn, Germany (U.G.); Hospital for Sick
Children, Toronto, Ontario, Canada (E.J.); Florida International
University, Miami (E.V.K., R.A.Q.); Boston Children’s Hospital,
MA (A.C.M.); Evelina London Children’s Hospital, United
Kingdom (O.M.); Technische Universität München, Germany
(R.O.); Leiden University Medical Center, Netherlands (D.O.);
Hospital do Coração, São Paolo, Brazil (C.A.P., S.R.P., F.P.); and
Mount Sinai Hospital, Toronto, Ontario, Canada (G.R.).
FOOTNOTES
The online-only Data Supplement is available with this ar-
ticle at http://circ.ahajournals.org/lookup/suppl/doi:10.1161/
CIRCULATIONAHA.116.025873/-/DC1.
Oral abstract presentation at American Heart Association
Scientific Sessions 2015, Orlando, FL, November 2015.
Circulation is available at http://circ.ahajournals.org.
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