This article reviews fetal aortic valvuloplasty (FAV) to prevent progression to hypoplastic left heart syndrome (HLHS) in utero. The article discusses the rationale for FAV intervention in fetuses with severe aortic stenosis that is progressing to HLHS. FAV aims to improve fetal heart function and allow for a biventricular circulation after birth rather than requiring single ventricle palliation. The article reviews patient selection criteria, procedural technique, outcomes of FAV including rates of biventricular outcome and survival, and the importance of a multidisciplinary team in performing fetal cardiac interventions.

1. R E V I E W A R T I C L E
Fetal aortic valvuloplasty to prevent progression to hypoplastic
left heart syndrome in utero
Matthew A. Crystal | Lindsay R. Freud
Department of Pediatrics, Division of Pediatric
Cardiology, Columbia University Medical Center,
Morgan Stanley Children's Hospital of NewYork-
Presbyterian, New York, New York
Correspondence
Lindsay R. Freud, MD, Department of Pediatrics,
Division of Pediatric Cardiology, Columbia
University Medical Center, Morgan Stanley
Children's Hospital of NewYork-Presbyterian,
3959 Broadway, Children's Hospital North, 2nd
Floor, New York, NY 10032.
Email: lrf2136@columbia.edu
Advances in fetal echocardiography have allowed for the prenatal diagnosis of con-
genital heart disease and an understanding of its natural history in utero. This
insight has led to the development of fetal cardiac intervention (FCI) for select
defects to prevent significant morbidity or mortality postnatally. Fetal aortic valvu-
loplasty (FAV) may be performed to prevent progression to hypoplastic left heart
syndrome, a severe form of congenital heart disease, in utero. The current review
focuses on this type of FCI and discusses the history of FAV, the rationale for
intervention, candidate selection, procedural technique, and outcomes to date.
Finally, the importance of building a multidisciplinary team to perform FCI is
addressed.
KEYWORDS
congenital heart disease, fetal cardiac intervention, fetal echocardiography,
hypoplastic left heart syndrome, prenatal diagnosis
1 | INTRODUCTION
Fetal echocardiography allows for the early detection of con-
genital heart defects. A small subset of defects may progress
in severity before birth. Percutaneous fetal cardiac interven-
tion (FCI) was developed in an attempt to modify the natural
history of these lesions.
One of the most well-described defects is severe, mid-
gestation aortic stenosis (AS), which may progress to hypo-
plastic left heart syndrome (HLHS) by the time of birth.
Staged univentricular surgical palliation has allowed chil-
dren with HLHS to survive with the right ventricle acting as
the systemic ventricle, but significant issues related to peri-
operative mortality, long-term morbidity, and neurodevelop-
mental disability remain (Ghanayem et al., 2012; Mitchell
et al., 2006; Williams et al., 2009). Fetal aortic valvuloplasty
(FAV) is performed to prevent evolution to HLHS and, ide-
ally, to allow children to have a biventricular circulation.
Maxwell, Allan, and Tynan first performed FAV in
1991. Although technical success was achieved in one of the
two fetuses in their report, there were challenges regarding
optimal patient selection and procedural technique (Maxwell,
Allan, & Tynan, 1991). After another decade, the global expe-
rience of FAV reached only 12 reported cases (Kohl, Sharland
et al., 2000). Greater success was ultimately achieved in the
2000's due to a better understanding of the natural history,
which allowed for refinement of patient selection, and techni-
cal modifications. Over the past decade, FAV has become
more widespread; however, it is still largely performed at
major academic medical centers with expertise in fetal cardi-
ology, catheterization, and high-risk obstetrics.
2 | RATIONALE FOR INTERVENTION AND
PATIENT SELECTION
Multiple natural history studies have demonstrated that
fetuses with severe AS at mid-gestation commonly evolve to
HLHS by the time of birth (Allan, Sharland, & Tynan, 1989;
Danford & Cronican, 1992; McCaffrey & Sherman, 1997;
Simpson & Sharland, 1997). In the presence of severe AS,
left ventricular (LV) dilation and dysfunction occur. As the
LV becomes less capable of supporting the circulation, sev-
eral additional pathophysiologic features develop, including
monophasic mitral inflow, left to right flow at the foramenThe authors have no financial disclosures to report.
Received: 29 January 2019 Accepted: 30 January 2019
DOI: 10.1002/bdr2.1478
Birth Defects Research. 2019;1–6. wileyonlinelibrary.com/journal/bdr2 © 2019 Wiley Periodicals, Inc. 1

2. ovale, and flow reversal in the transverse aortic arch. These
features may be used to select fetuses that are likely to
evolve to HLHS by the time of birth and are, therefore,
potential candidates for FAV (Makikallio et al., 2006). Tech-
nically successful interventions may reverse these patho-
physiologic features in utero (Selamet Tierney et al., 2007),
and such changes are more likely to yield a biventricular cir-
culation at birth (Prosnitz et al., 2018).
An additional consideration with regard to patient selec-
tion for FAV is whether the LV is salvageable. In other
words, will the LV be able to recover its function and effec-
tively support the systemic circulation postnatally? In 2009,
McElhinney et al. published revised criteria to ensure that
the LV and mitral valve are not too hypoplastic, that is,
z-score >−2, and that the LV is capable of generating
adequate pressure (McElhinney et al., 2009). In 2018, Fried-
man et al. updated these criteria to additionally evaluate the
dimension of the ascending aorta and the mitral inflow time,
the latter as a marker of diastolic dysfunction (Figure 1). The
authors found that fetuses with LV pressure >47 mmHg and
ascending aortic z-score >0.57 had a 92% chance of having
a biventricular circulation following a technically successful
intervention (Friedman et al., 2018).
3 | PROCEDURAL TECHNIQUE AND
RESULTS
One of the most important features of a technically success-
ful FCI is the positioning of the fetus at the onset of the pro-
cedure. In order to obtain access across the aortic valve for
FIGURE 1 This diagram depicts the classification and regression tree analysis to predict fetal candidates that will have a biventricular (Biv) circulation at
birth. AscAo = ascending aorta, MV = mitral valve, LV = left ventricle
Adapted from Friedman et al., 2018. Improved technical success, postnatal outcome and refined predictors of outcome for fetal aortic valvuloplasty.
Ultrasound in Obstetrics & Gynecology, 52(2), 212–220
2 CRYSTAL AND FREUD

3. balloon dilation, direct alignment needs to be visualized from
the maternal abdomen through the fetal LV apex and across
the outflow tract by ultrasound (Figure 2). Once the fetus has
been adequately positioned, a small spinal needle is used for
intramuscular delivery of paralysis and analgesia to the fetus.
The angioplasty balloon/wire unit is prepared with the
coronary wire through the balloon catheter with a Y-adapter
attached to the end of the balloon. A coronary balloon/wire
is used to accommodate the small size of the fetal aortic
valve. After the needle introducer is opened, the balloon/
wire unit is advanced beyond the tip until it is fully exposed
to allow unimpeded dilation. At this point, a marker is
affixed to the balloon catheter. The balloon is drawn back
into the needle and once fully covered, the distance between
the needle hub and the marker on the catheter is noted. As
such, the length of the needle is evident from landmarks
external to the mother and fetus.
An 18G or 19G needle introducer is placed into the mater-
nal abdomen and advanced through the uterine wall until at
the fetal thorax. Alignment is re-confirmed, and the introducer
is passed through the fetal thorax and LV apex to the outflow
tract. Once positioned, the stylet is removed, and the pre-
prepared coronary balloon/wire unit is advanced to the tip of
the needle based on the external markers. The coronary wire
FIGURE 2 These line drawings depict the ideal alignment of the needle through the maternal abdomen to the fetus (left) and in the left ventricular outflow
tract (right)
Adapted from Tworetzky et al., 2004. Balloon dilation of severe aortic stenosis in the fetus. Circulation, 110, 2125–2131
FIGURE 3 Ultrasound images of (a) the needle traversing the maternal abdomen and fetal thorax to terminate in the left ventricle (LV), directed at the
outflow tract; and (b) the balloon/wire unit advanced and positioned across the aortic valve (AV) for dilation
Images courtesy of Boston Children's Hospital
CRYSTAL AND FREUD 3

4. is advanced beyond the needle under direct ultrasound visuali-
zation and maneuvered across the aortic valve into the ascend-
ing aorta. The coronary balloon is subsequently advanced and
positioned across the aortic valve until it is exposed according
to the external marker on the catheter (Figure 3). The balloon
is dilated to maximal inflation with a goal balloon: annulus
ratio of 1.1–1.2 as reported previously (Marshall et al., 2005).
Typically, several inflations are performed until ultrasound
confirms either a broader jet of antegrade flow across the aortic
valve or the presence of aortic regurgitation.
Once the valvuloplasty has been performed, the entire
coronary balloon/wire unit and needle are removed simulta-
neously. Postprocedural monitoring is essential. Compli-
cations include pericardial effusion/tamponade and/or
bradycardia that may require acute intervention with pericar-
diocentesis or administration of intracardiac epinephrine
(Mizrahi-Arnaud et al., 2007).
Technical success has been reported to range from 77 to
94% (Friedman et al., 2018; Galindo et al., 2017; Kovacevic
et al., 2018), with higher success rates at centers with greater
experience. Similarly, although fetal demise rates of ~10%
were previously described (Freud et al., 2014; Kovacevic
et al., 2018; Moon-Grady et al., 2015), a large center
recently reported that their rate has decreased to <5%
(Friedman et al., 2018). Importantly, no significant maternal
complications have been reported (Wohlmuth, Tulzer, Arzt,
Gitter, & Wertaschnigg, 2014).
4 | OUTCOMES
Technically successful FAV may result in improved hemo-
dynamics and size of left heart structures throughout the
remainder of gestation, permitting a biventricular circulation
at the time of birth (Figure 4). Of the first 100 patients to
undergo FAV at a large center, Freud et al. reported that
38 of the 88 live-born patients were managed with a biven-
tricular circulation from birth (43%). Importantly, after a
median postnatal follow-up of 5.4 years, cardiac survival
was better in the biventricular group as compared to the
HLHS cohort (Figure 5) (Freud et al., 2014). In a report from
the multicenter International Fetal Cardiac Intervention Reg-
istry in 2015, 26% (23 of 90) of fetuses that did not undergo
FAV were alive postnatally (22% with a biventricular circu-
lation). In contrast, 80% (69 of 86) that underwent FAV
were alive postnatally with 40% achieving a biventricular
circulation (Moon-Grady et al., 2015). Most recently,
improved survival at 10 years was noted among patients
who underwent FAV in Europe (Kovacevic et al., 2018).
FIGURE 4 (a) and (b) Fetal and neonatal echocardiograms of a patient with evolving hypoplastic left heart syndrome (HLHS) in utero who underwent a
technically unsuccessful fetal aortic valvuloplasty; the left ventricle (LV) was inadequate at birth, and the patient was managed as HLHS. (c) and (d) Fetal and
neonatal echocardiograms of a patient with evolving HLHS who had a technically successful intervention; the LV was able to support the circulation after
birth, and the patient was managed as biventricular
Adapted from Freud et al., 2014. Fetal aortic valvuloplasty for evolving hypoplastic left heart syndrome: Postnatal outcomes of the first 100 patients.
Circulation, 130(8), 638–645
4 CRYSTAL AND FREUD

5. While this survival advantage seemed to be independent of
the final circulation, the numbers were quite limited.
The achievement of a biventricular circulation and
improved survival are notable outcomes following FAV.
However, such patients are not free from morbidity. In a
series from a large center, nearly all patients with a biventri-
cular circulation required postnatal intervention, which often
consisted of aortic and mitral valve procedures. Valve
replacements, in particular, were not uncommon with 39%
requiring replacement of the aortic valve and 21% of the
mitral valve (Freud et al., 2014). LV diastolic dysfunction
and abnormal remodeling pose additional issues (Friedman
et al., 2011, 2015).
With regard to noncardiac outcomes, there has been no
reported difference in somatic growth or neurodevelopmen-
tal measures between patients managed as biventricular or
HLHS (Freud et al., 2014; Laraja et al., 2017). Long-term
follow-up of these patients is essential.
5 | BUILDING A TEAM
The success of FCI requires the collaboration of an experi-
enced, multidisciplinary team, including high-risk obstetrics,
fetal and interventional cardiology, and anesthesia. Postna-
tally, commitment to a biventricular strategy is also critical.
At our center, we recently created a FCI team. We began
by performing site visits to centers with experience and
expertise and then proceeded with hands-on simulation in
order to optimize communication and coordination. First, we
developed inanimate molds to practice needle placement
under ultrasound guidance. Subsequently, as initially reported
by Kohl et al. in 2000 and more recently studied by Emery
et al. in 2010, our team moved to an animal model to hasten
our learning curve (Kohl, Strumper et al., 2000). In this envi-
ronment with a fetal sheep, we were able to successfully per-
form multiple procedures, including FAV, fetal pulmonary
valvuloplasty, and atrial septal stent implantation. We believe
this process will improve our workflow and ultimately lead to
greater technical success.
6 | SUMMARY
Fetal echocardiography allows for the early detection of con-
genital heart defects that may progress in utero, such as
severe, mid-gestation AS with evolving HLHS. Despite
early struggles, technical success of FAV for this disease has
improved, and a biventricular outcome with improved sur-
vival may be achieved in select patients. Many challenges
remain to determine the best candidates with salvageable
LV's and to develop better technology to allow for greater,
and perhaps earlier, procedural success. Critical evaluation
of both local institutional practices in the process of FCI
team building, as well as pooled long-term outcomes from
multiple centers, is essential as this field evolves.
ACKNOWLEDGMENTS
None.
ORCID
Lindsay R. Freud https://orcid.org/0000-0002-1221-081X
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How to cite this article: Crystal MA, Freud LR. Fetal
aortic valvuloplasty to prevent progression to hypoplas-
tic left heart syndrome in utero. Birth Defects Research.
2019;1–6. https://doi.org/10.1002/bdr2.1478
6 CRYSTAL AND FREUD