Anatomical and pathological findings in hearts
from fetuses and infants with cardiac
manifestations of neonatal lupus
Carolina Llanos1,2, Deborah M. Friedman3, Amit Saxena1, Peter M. Izmirly1,
Chung-E. Tseng1, Renata Dische4,y, Rosanna G. Abellar5, Marc Halushka6,
Robert M. Clancy1and Jill P. Buyon1
Objective. The autopsy and clinical information on children dying with anti-SSA/Ro-associated cardiac
manifestations of neonatal lupus (cardiac NL) were examined to identify patterns of disease, gain insight
into pathogenesis and enhance the search for biomarkers and preventive therapies.
Methods. A retrospective analysis evaluating reports from 18 autopsies of cardiac NL cases and clinical
data from the Research Registry for Neonatal Lupus was performed.
Results. Of the 18 cases with autopsies, 15 had advanced heart block, including 3 who died in the
second trimester, 9 in the third trimester and 3 post-natally. Three others died of cardiomyopathy without
advanced block, including two dying pre-natally and one after birth. Pathological findings included fibro-
sis/calcification of the atrioventricular (AV) node, sinoatrial (SA) node and bundle of His, endocardial
fibroelastosis (EFE), papillary muscle fibrosis, valvular disease, calcification of the atrial septum and mono-
nuclear pancarditis. There was no association of pathology with the timing of death except that in the
third-trimester deaths more valvular disease and/or extensive conduction system abnormalities were
observed. Clinical rhythm did not always correlate with pathology of the conduction system, and the
pre-mortem echocardiograms did not consistently detect the extent of pathology.
Conclusion. Fibrosis of the AV node/distal conduction system is the most characteristic histopathological
finding. Fibrosis of the SA node and bundle of His, EFE and valve damage are also part of the anti-Ro
spectrum of injury. Discordance between echocardiograms and pathology findings should prompt the
search for more sensitive methods to accurately study the phenotype of antibody damage.
Key words: neonatal lupus, anti-SSA/Ro antibodies, autoimmune congenital heart block.
Neonatal lupus (NL) is a pathological read-out of maternal
anti-SSA/Ro-SSB/La autoantibodies (Abs) affecting 2% of
offspring exposed in utero [1, 2]. The target organs of NL
comprise the heart, skin, liver and haematological system.
The cardiac manifestations associated with NL (cardiac
NL) are the most serious, 17.5% being fatal and >60%
requiring lifelong pacemakers [3?5]. Moreover, the risk of
cardiac NL recurrence in a subsequent pregnancy has
been reported to be 17.4% . To date, preventive stra-
tegies such as maternal steroids, low-dose IVIG and
plasmapheresis have not decreased the incidence [7, 8].
Although recent data from a case?control study suggests
that maternal exposure to HCQ may decrease the risk of
1Department of Medicine, Division of Rheumatology, New York
University School of Medicine, New York, NY, USA,2Departamento de
Inmunologı ´a Clı ´nica y Reumatologı ´a, Facultad de Medicina, Pontificia
Universidad Cato ´lica de Chile and Millenium Institute for Immunology
and Immunotherapy, Santiago, Chile,3Department of Pediatrics,
Division of Pediatric Cardiology, New York Medical College, Valhalla,
4Department of Pediatrics, Columbia Presbyterian Hospital,
5Department of Pathology, Columbia University Medical Center, New
York, NY and6Department of Pathology, Johns Hopkins Medical
Institutions, Baltimore, MD, USA.
Correspondence to: Carolina Llanos, Departamento de Inmunologia
Clinica y Reumatologia, Pontificia Universidad Catolica de Chile,
Marcoleta 350, Santiago, Chile.
E-mail: email@example.com; firstname.lastname@example.org
Submitted 2 August 2011; revised version accepted
15 December 2011.
! The Author 2012. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: email@example.com
Advance Access publication 3 February 2012
cardiac NL, prospective controlled studies are warranted
to confirm these results . Therapeutic approaches
using maternal dexamethasone have not revealed sus-
tained reversibility of third-degree block and have had in-
consistent effects on the reversal of incomplete heart
blocks [8, 9]. Attempts at early detection via markers
such as fetal Doppler mechanical PR interval have been
disappointing . Maternal antibodies to amino acids
200?239 (p200) of the Ro52 protein hold promise as an
indicator for an increased risk of having a child with car-
diac NL; however, its value as a biomarker has not yet
been established due to variations in assays and different
cohorts studied [10, 11].
Cardiac NL has been classically confined to the atrio-
ventricular (AV) node, and the fibrosis of this structure has
been considered as the histological hallmark. This finding
has driven research efforts to link the putative maternal
autoantibody to cardiac scarring. It has been reported that
in an in vitro culturing system, maternal anti-SSA/Ro-SSB/
La antibodies bind apoptotic cardiocytes, blocking the
normal physiological removal of these cells [12, 13].
Co-culture of macrophages with opsonized apoptotic car-
diocytes results in the release of pro-inflammatory and
pro-fibrosing cytokines, which transdifferentiate cardiac
fibroblasts to a scarring phenotype [12, 14]. This model
supports inflammation as a key initiating event in the
pathogenesis of cardiac NL and, if correct, would predict
that fibrosis might extend beyond the conduction tissue
per se. In recent years, fatal cardiomyopathy, including
endocardial fibroelastosis (EFE), with or without conduc-
tion abnormalities has also been acknowledged as part of
the clinical spectrum of cardiac NL [15, 16]. Interestingly,
sinoatrial (SA) and infra-Hisian conduction system disease
in fetuses exposed to anti-SSA/Ro-SSB/La antibodies
have each been described as well . Atrial flutter and
valve aberrations were reported among the cardiac mani-
festations found in these patients . Furthermore, it
has been shown that maternal sera containing antibodies
Ca-channel currents in isolated cardiac myocytes and
induce sinus bradycardia in a murine model of congenital
heart block (CHB), implying that the SA node could also
be affected . However, low atrial rates are only rarely
documented in the affected fetuses, an observation best
explained by the presence of subsidiary atrial pacemakers
. Most recently, Cuneo et al.  reported two cases of
AV valve insufficiency due to chordal rupture from the
papillary muscles in a 34-week gestation fetus and a
6-month-old infant born to mothers that tested positive
for anti-Ro 52 antibodies.
Accordingly, this study was initiated to provide critical
clues toward elucidating not only the spectrum of cardiac
pathology, but the potential temporal sequence of injury.
This was approached by studying the autopsy reports
of hearts from 18 fetuses/infants with cardiac NL enrolled
in the Research Registry for Neonatal Lupus (RRNL).
abstracted to determine maternal and fetal demographic
and health status, with emphasis on the pathological
findings and timing of death relative to initial diagnosis
of cardiac NL and echocardiographic findings.
Patients and methods
As previously described, mothers enrolled in the RRNL
satisfy two requirements: (i) antibodies to SSA/Ro or
SSB/La RNPs and (ii) a child with any manifestation of
NL , verified by review of medical records. The RRNL
and its informed consent documents were approved by
the New York University School of Medicine Institutional
Review Board. This covers ethical approval for all studies
involving retrospective analysis of autopsy or clinical
materials submitted by the families at our request.
The enrolment period for this study extended from
September 1994 to March 2010; however, a mother
could enter the RRNL if the child was born before 1994.
Inclusion criteria for the present study were: (i) enrol-
ment in the RRNL and (ii) available autopsy studies on a
fetus/infant with cardiac NL defined herein as the pres-
ence of heart block (first-, second- or third-degree) docu-
mented by electrocardiogram, echocardiogram, history of
pacemaker or statement in the medical record; and/or
presence of cardiac injury, which specifically included
histological evidence of a mononuclear infiltrate or fibrosis
in the endocardium, myocardium and pericardium; and/or
EFE or dilated cardiac chambers with evidence of
decreased cardiac output on echocardiogram. Maternal
health status, ethnicity and medications were based on
phone interviews and information obtained from medical
records as well as from enrolment and follow-up question-
naires available in the RRNL. For the purposes of this
study, the maternal health status at the time of the
affected pregnancy is reported.
Detection of antibodies to SSA/Ro and SSB/La
Determination of maternal antibodies to SSA/Ro and SSB/
La was done by the clinical immunology laboratory at the
Hospital for Joint Diseases using a commercial ELISA kit
(Diamedix, Miami, FL, USA). In this commercial test, the
cut-off for normal has been established at 19 EU for both
SSA/Ro and SSB/La. Titres of antibodies to Ro52 were
evaluated by ELISA using recombinant Ro52, as previous-
ly described [10, 21].
Eighteen autopsy reports were included in this study. The
autopsies were performed between March 1982 and
March 2010 in different centres across the USA by the
patients’ health-care providers. Fourteen of the deaths
occurred before the mother’s enrolment in the RRNL
and four deaths occurred at the time of or subsequent
to enrolment. Three additional autopsy reports were ob-
tained (all from fetuses with third-degree block) but were
excluded because the microscopic evaluation of conduc-
tion system was not available or was not adequate due to
Cardiac NL autopsy findings
severe autolysis of the heart tissue. Four of the cases
included have been previously published [22, 23, 28].
Demographics and clinical findings
Seventeen women enrolled in the RRNL and pathology
findings on their 18 offspring with cardiac NL were stu-
died. The demographic characteristics of the mothers,
including medications, health and antibody status at the
time of the affected pregnancy are summarized in Table 1.
Maternal ethnicity was as follows: 10 women were
Caucasian (59%), 3 (18%) were African-American, 2
Asian (12%), 1 Hispanic (6%) and 1 (6%) Indian. The ma-
jority (59%) of the mothers at the time of the studied preg-
nancy were classified as having a defined rheumatological
disease, five (29%) had SLE, three (18%) had SS and two
(12%) met criteria for both diseases. The remainder (41%)
had either an undifferentiated autoimmune syndrome
(UAS) or were completely asymptomatic at the time of
pregnancy . The majority of mothers (71%) had anti-
bodies against both SSA/Ro and SSB/La, with 29%
having only antibodies reactive with SSA/Ro. Fifteen of
the 17 (88%) mothers had antibodies to Ro52.
The clinical information on the reported cases, including
degree of heart block and clinical manifestations, age of
detection and age of death, is summarized in Table 2.
Overall, 14 (78%) of the 18 deceased cardiac NL children
had third-degree block and 1 (6%) had second-degree
block. In three cases (17%), two fetuses and one
3-month-old infant, advanced conduction disease was
not demonstrated. One woman had two dead offspring;
both fetuses had third-degree block and died during the
third trimester of gestation.
TABLE 2 Summary of clinical information on the reported cases
20 weeks of gestation
26 weeks of gestation
Third-trimester deaths (n=9)
23.3 weeks of gestation
32.4 weeks of gestation
Post-natal deaths (n=3)
19 weeks of gestationa
16 weeks of gestation
17 weeks of gestation
Third-trimester deaths (n=1)
33 weeks of gestation
34 weeks of gestation
Post-natal deaths (n=1)
Values are provided as n (%).aExcluding one baby who was detected at 3 months of age and is not included in the mean.bCardiomyopathy+first-degree heart block.cMultiple foci of
fibrosis and calcification surrounding the area of the AV node while the conduction system itself appeared intact.
TABLE 1 Maternal demographics and clinical information
Maternal antibody status
Anti SSA/Ro only
Carolina Llanos et al.
Second-trimester deaths with advanced conduction
Of the total cases studied, there were three second-tri-
mester deaths associated with advanced conduction dis-
ease. The mean time of detection for this group was
20 weeks and the mean time of death was 26 weeks. All
three cases had third-degree heart block, with ventricular
rates ranging from 44 to 55 beats per minute (b.p.m.)
on available echocardiograms performed within 6 days
before death. Despite the clinical finding of complete
block, the histological evaluation revealed fibrosis with
collagen deposition and calcification of the AV node in
only two of the cases. In the third case, dilated ventricles,
EFE, and fibrosis and calcification of the papillary muscles
was described. No abnormalities in the SA were reported
in any of these fetuses. Two of the autopsies reported
EFE, but in only one of these cases was this mentioned
in an earlier echocardiogram. In addition, a mononuclear
inflammatory infiltrate with giant cells in the myocardium
was also noted in one of the cases studied.
Third-trimester deaths with advanced conduction
Nine deaths associated with advanced conduction dis-
ease occurred in the third trimester. The respective
means for time of detection and death were 23.3 and
32.4 weeks of gestation. Seven of nine (78%) autopsies
showed fibrosis of the AV node. In two of nine (22%)
cases, fibrosis of the SA node was reported; in one of
these cases, inflammatory infiltrates were identified in
the SA node. However, no decrease in atrial rates was
recorded; the lowest atrial rates ranged from 128 to
130b.p.m. In four (44.4%) fetuses, fibrosis of the conduc-
tion system included the bundle of His, broadening the
extension of damage. The two cases without reported
fibrosis of the AV node had clinical advanced block, with
one of them showing an alternating second- to third-
degree block. In this fetus with alternating block, the
bundle of His was fibrotic and calcified and the AV node
and right and left bundle branches appeared unremark-
able. This fetal heart also demonstrated evidence of pan-
carditis in the context of biventricular hypertrophy with
dilated atria and ventricles. In the other case, microcalci-
fications surrounding soft tissue adjacent to the AV node
and fatty replacement adjacent to the AV were noted. No
inflammatory infiltrate was described on autopsy report.
In five (56%) of the third-trimester deaths, EFE was
noted. This finding was only described in one case on
the echocardiogram; in the other four cases, EFE was
not reported by echocardiographic evaluation. One aut-
opsy study showed a lympho-histiocytic infiltrate with
giant cells in the interventricular septum and another
showed apoptotic debris between myofibres. Represen-
tative findings are shown in Fig. 1.
Four (44%) had pathology findings of the valves/valve
apparatus, including the tricuspid, mitral, aortic and
FIG. 1 Neonatal heart at 29 weeks of gestation. (A) At low power, loss of normal AV nodal architecture is clear.
(B and C) At higher power, calcified remnants of cells are noted. (D) Multinucleated giant cells are part of the scattered
inflammatory cell infiltrate (haematoxylin?eosin staining).
Cardiac NL autopsy findings
pulmonary valves. One of these fetuses had aortic valve
insufficiency and stenosis together with severe pulmonary
valve stenosis and mild hypoplasia of the mitral and tri-
cuspid valve leaflets. In only one case were these valvular
abnormalities reported on the echocardiogram performed
Post-natal deaths with advanced conduction disease
Three post-natal deaths associated with advanced con-
duction disease were included, with a mean time of de-
tection of 19 gestational weeks and a mean time of death
of 13.3 months of age. All three had third-degree block as
detected by pre-natal echocardiograms. Two (67%) of the
post-natal autopsy studies showed fibrosis of the conduc-
tion system; one showed fibrosis and calcification of the
AV node and the other reported fibrosis of the bundle of
His. In the third case, a few foci of microscopic calcifica-
tion were reported in the atrial septum in proximity to
the AV node, but not involving the node. No pathology of
the SA node was identified in any of the three cases. In
addition, two (67%) autopsy studies showed EFE, both of
which were not described in any of the pre-mortem echo-
cardiograms. One study showed hypoplasia of the tricus-
pidvalve papillary muscle.The echocardiogram performed
2 days before death did not describe any abnormalities
(functional or anatomical) of the tricuspid valve.
Cardiomyopathy without advanced conduction
In addition to the cases with advanced conduction dis-
ease, there were three cases of cardiomyopathy without
associated advanced conduction abnormalities. One of
these fetuses was diagnosed with first-degree block at
19 weeks of gestation with a mechanical PR interval of
150ms; the echocardiogram done 1 week before death
revealed echodensities of both atrial walls and interatrial
septum with virtually no motion of the atria, a normal heart
rate of 160b.p.m. and no structural abnormalities. A week
later, the fetus developed pleural and pericardial effusions
and no heartbeat was detected. The autopsy findings of
this fetus included pancarditis and a predominant mono-
nuclear inflammatory infiltrate with few neutrophils. A fetus
that died in the third trimester showed pancarditis with a
mononuclear infiltrate in the endocardium, pericardium
and myocardium with cells that stained for CD68 and
CD45 and T/B lymphocytes as well. Patchy calcification
of the ventricles and extensive calcification of the atria
were noted; a normal heartbeat was recorded at Week
33 by US. Finally, the autopsy on a neonate that died at
3 months old revealed multiple foci of fibrosis and calcifi-
cation surrounding the area of the AV node, whereas the
conduction system itself appeared intact. No anomalies
were noted on an echocardiogram at Day 9 of life and
EKGs done up to 3h before death.
Damage to the AV node, including calcification and
collagen deposition, was the main finding in the autopsy
reports studied. Disease also extended to other areas of
the conduction system, including the SA node and the
bundle of His. In addition, damage to the valves and
valve apparatus, which included fibrosis and calcification
of the papillary muscles, was noted in a considerable pro-
portion of cases. These valvular abnormalities were most
frequently reported in the third-trimester deaths. Signs of
cardiomyopathy were seen in a large proportion of the
fetal and post-natal autopsies and not invariably asso-
ciated with conduction disease. Although most of these
histological changes were consistent with EFE, which
has been previously described as part of the spectrum
of cardiac NL [15, 25, 26], a mononuclear inflammatory
infiltrate involving endocardium, myocardium and pericar-
dium was seen in several cases, as well as apoptotic
debris in one case.
The clinical and serological features of NL syndromes
have been extensively described; however, publications
detailing the anatomical pathology findings in the heart
are limited [15, 20]. The majority of the initially reported
cases demonstrated fibrosis and or calcification of the AV
node, and in several cases SA nodal scarring was
described [17, 23, 27?30]. EFE has been previously
demonstrated in pathological
Ro-SSB/La-exposed fetuses with and without the pres-
ence of heart block, and it is currently acknowledged as
part of the spectrum of cardiac NL [9, 15, 25, 26]. Valvular
abnormalities have been only rarely reported. Nield et al.
 described dystrophic and calcified mitral valve
papillary muscles in the post-mortem study of an
anti-SSB/La-positive but anti-SSA/Ro-negative female
fetus with diffuse EFE, as well as calcification of the SA
and AV nodes. Litsey et al.  has previously reported
one of the cases herein with tricuspid valve dysplasia and
Cuneo et al.  described chordal avulsion of the mitral
valve and tricuspid valve in one case. These findings,
taken together with the other valvular abnormalities
depicted in our cohort, support evaluation of anti-SSA/
Ro-SSB/La antibodies in the mothers of children with
more diffuse but unexplained valvular defects.
With the exception of valvular disease, overall, the
histological findings appear similar across all ages of
death. These data do not support the hypothesis that
there is an orderly progression over time of anti-SSA/
Ro-SSB/La-mediated damage with initial injury manifest
as first-degree block, followed by advanced block, cardio-
myopathy and culminating in EFE. The absence of AV
nodal pathology in one case of first-degree block sug-
gests that this early finding may be functional and transi-
ent rather than part of a continuum of the inflammatory/
fibrotic cascade. Although the data are limited, it is pos-
sible that severe valvular disease is a late third-trimester
In this series there were several notable discordances
findings at the SA node, the AV node and endomyocar-
dium. In several cases, abnormal SA nodal tissue
was observed, yet abnormally slow atrial rates had not
been clinically recorded. This observation raises the
Carolina Llanos et al.
question of whether the SA node has an escape mechan-
ism via atrial subsidiary pacemakers, which are used
at times of SA node dysfunction . There were two
cases of advanced block observed on the echocardio-
gram but with no reported pathology of the AV node or
surrounding tissue. Although speculative, this could be ex-
plained by an exit block mechanism or similarly related
functional, rather than anatomical, disorder. This may in-
clude transient dysfunction of L-type calcium channels
 or damage to the surrounding tissues. In several in-
stances, EFE that was clearly demonstrated by histo-
logical evaluation was not observed on the pre-mortem
echocardiograms. Finally, there were several cases in
which the valvular abnormalities were only noted on aut-
opsy. Thus the fetal echocardiogram may not be a sensi-
tive enough tool to detect changes that may be of clinical
Although the largest series of autopsies reported to
date, several limitations of this study should be noted.
Data were retrospectively collected and the autopsies
were done at different centres and read by different path-
ologists. Due to the small size of the conducting system in
fetal and neonatal hearts, it may not have been possible to
fully assess this system in all autopsies, artificially redu-
cing the incidence of immunohistological support for clin-
ical disease in this population.
In summary, NL is a rare condition with a substantial
mortality and morbidity. Considering the few reports
available in the literature, information on any autopsies
is invaluable since it provides the blueprint to patho-
search for reliable biomarkers and novel preventive
therapies (our suggested autopsy protocol can be
found as supplementary data available at Rheumatology
Online). Currently available techniques, such as echocar-
diography and magnetocardiography, and the extensive
research efforts in recent years have allowed us to better
identify the clinical phenotype of anti-SSA/Ro-SSB/La car-
diac disease. Increasing evidence suggests that AV node
fibrosis and complete heart block are only the tip of the
iceberg. There is clinical precedent in the literature for an
expanded spectrum of cardiac NL, and although our find-
ings support the concept of AV node fibrosis as the most
clinically obvious manifestation, several other disease
manifestations in the conductive and non-conductive
tissues have been identified. The apparent discordance
in several cases between echocardiographic and histo-
logical findings suggests that more sensitive methods
should be utilized to adequately evaluate these fetuses
and anticipate perinatal complications.
will surely enhancethe
Rheumatology key messages
. Although the hallmark of cardiac NL is AV node
. Valvular disease is part of the spectrum of cardiac
NL and seems to be more frequent in the third
We thank all the mothers enrolled in the RRNL.
Funding: This work was funded by National Institutes of
Health, Contract NO1-AR-4-2220 (RRNL) and NIAMS
(grant RO1 AR42455-01) (maternal Abs: pathogenesis of
NL) to J.P.B.; S.L.E. Foundation NY Inc. grants (to C.L.
and P.M.I.); American Heart Association Founders Affiliate
Clinical Research Program Award #11CRP7950008 and
the 2011-2012/2013 Pfizer Fellowships in Rheumatology/
Partnerships programme to A.S.
Disclosure statement: The authors have declared no
conflicts of interest.
Supplementary data are available at Rheumatology
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