J. Perinat. Med.
2021; 49(5): 529–538
Review
Julia Marta Derdulska, Lidia Rudnicka*, Agata Szykut-Badaczewska, Dorota Mehrholz,
Roman J. Nowicki, Wioletta Barańska-Rybak and Aleksandra Wilkowska
Neonatal lupus erythematosus – practical
guidelines
https://doi.org/10.1515/jpm-2020-0543
Received July 24, 2020; accepted December 11, 2020;
published online January 18, 2021
Abstract
Background: Neonatal lupus erythematosus is an auto-
immune disease acquired during fetal life as a result of
transplacental passage of maternal anti-Sjögren’s-syn-
drome-related antigen A (anti-SSA/Ro), anti-Sjögren’s-
syndrome-related antigen B (anti-SSB/La) or anti-U1 ribo-
nucleoprotein (anti-U1-RNP) antinuclear autoantibodies.
Contents: Clinical manifestations include skin lesions,
congenital heart block, hepatobiliary involvement and
cytopenias. Most of the disorders disappear spontaneously
after clearance of maternal antibodies. Cardiac symptoms,
however, are not self-resolving and often pacemaker
implantation is required. Diagnosis is based on clinical
presentation and the presence of typical antibodies in the
mother’s or infant’s serum.
Outlook: Neonatal lupus erythematosus may develop in
children born to anti-SSA/Ro or anti-SSB/La women with
various systemic connective tissue diseases. However, in
half of the cases, the mother is asymptomatic, which may
delay the diagnosis and have negative impact on the
child’s prognosis. Testing for antinuclear antibodies
should be considered in every pregnant woman since
*Corresponding author: Professor Lidia Rudnicka, MD, PhD,
Department of Dermatology, Medical University of Warsaw,
Koszykowa 82A 02-008 Warsaw, Poland, Phone: +48 22 502 13 24,
E-mail: lidia.rudnicka@dermatolodzy.com.pl. https://orcid.org/
0000-0002-8308-1023
Julia Marta Derdulska and Agata Szykut-Badaczewska, Department of
Dermatology, Medical University of Warsaw, Warsaw, Poland.
https://orcid.org/0000-0002-9624-1540 (J.M. Derdulska). https://
orcid.org/0000-0001-6158-8993 (A. Szykut-Badaczewska)
Dorota Mehrholz, Roman J. Nowicki, Wioletta Barańska-Rybak
and Aleksandra Wilkowska, Department of Dermatology, Medical
University of Gdańsk, Gdańsk, Poland. https://orcid.org/0000-0001-
6411-9172 (D. Mehrholz). https://orcid.org/0000-0003-4768-1387
(R.J. Nowicki). https://orcid.org/0000-0002-4018-6706
(W. Barańska-Rybak). https://orcid.org/0000-0001-6316-983X
(A. Wilkowska)
early treatment with hydroxychloroquine or intravenous
immunoglobulin (IVIG) has proven to be effective in pre-
venting congenital heart block.
Keywords: antinuclear antibodies; congenital heart block;
neonatal lupus erythematosus; newborn; pediatric
dermatology.
Introduction
Neonatal lupus erythematosus (NLE) is an acquired con-
genital autoimmune disease, which occurs in fetuses and
infants of women with anti-Sjögren’s-syndrome-related
antigen A (anti-SSA/Ro) and/or anti-Sjögren’s-syndrome-
related antigen B (anti-SSB/La) antinuclear antibodies that
are transmitted across the placenta during pregnancy [1, 2].
Less frequently, NLE is associated with anti-U1 ribonu-
cleoprotein (anti-U1-RNP) antibodies [1, 2]. Mothers may be
affected by various rheumatic conditions such as systemic
lupus erythematous (SLE), Sjögren’s disease, rheumatoid
arthritis, mixed connective tissue disease, or an undiffer-
entiated autoimmune syndrome but, in 25–60% of cases,
they are asymptomatic and unaware of their ailment [3].
While the presence of the autoantibodies is necessary for
the offspring to develop NLE, only 1–2% of children of sero-
positive mothers present symptoms [1, 4].
Most frequent manifestations of NLE are skin lesions and
congenital heart block (CHB), while signs from the central
nervous system or hepatobiliary and hematological abnor-
malities are less common. Cardiac are the only permanent
symptoms that do not resolve with the disappearance of the
maternal antibodies from the infant’s system [2, 5].
Epidemiology
Autoimmune diseases are fairly uncommon conditions
with the prevalence in the general population being 3–5%.
Most of them appear up to 10 times more frequently in
women than men. The female-to-male ratio in Sjogren’s
disease and SLE is 9:1 and in rheumatoid arthritis 2:1 [6].
530 Derdulska et al.: Neonatal lupus erythematosus
NLE is a disease that occurs annually in 1 of 20,000 live
births in The USA and in 0.6 of 100,000 births overall [2]. It
affects offspring of women with anti-SSA/Ro or anti-SSB/
La antibodies. These antibodies are most likely to be found
in patients with Sjögren’s disease and SLE. Patients with
rheumatoid arthritis should also be tested for Sjögren’s
syndrome antibodies as their newborns may also develop
NLE. These antibodies are also present in 0.1–1.5% of
healthy women. Mothers of the children affected by NLE
may have an active autoimmune disease but 25–60% of
women are asymptomatic [1, 3]. 50% of them may develop
symptoms of SLE or Sjögren’s disease within the next 3–5
years from delivery [1, 7]. Only 1–2% of women with anti-
SSA/Ro and/or anti-SSB/La antibodies are going to give
birth to a child with NLE. Nevertheless, the risk increases
up to 17–20% if any symptoms occurred in previous preg-
nancies [1, 2, 4].
Initial studies suggested female infants are two to three-
fold more prone to developing cardiac and dermatological
symptoms of NLE [3]. However, recent studies refute that
thesis proving this condition affects both sexes with similar
frequency and the male–female ratio is 1:1.05 [1, 8].
Pathogenesis
Antigens and autoantibodies
There are three types of antibodies in the pathogenesis of
NLE – anti-SSA/Ro, anti-SSB/La and anti-U1-RNP [2]. Anti-
SSA/Ro antibodies are directed against two cellular pro-
teins with different molecular masses – 52 kD (Ro52) and
60 kD (Ro60). The Ro52 antigen is present in the nucleus
and the cytoplasm whereas Ro60 in the nucleus and
nucleolus. Anti-SSB/La antibodies target a 48 kD protein
localized in the nucleus [1]. As a result of the process of cell
apoptosis during fetal development, these antigens are
displayed on the surface of the cells. In the second tri-
mester, maternal autoantibodies (immunoglobulin G [IgG])
start to cross the placenta and form complexes with the
antigens in fetal organs. These complexes are then
opsonized and phagocytosed which triggers proin-
flammatory process and subsequent tissue damage [2].
The type of antibodies and serum concentration corre-
lates with clinical presentation of NLE. Most studies point to
anti-Ro52 antibodies as the main agents in the pathogenesis,
rather than anti-Ro60, as they were found in 85% of mothers
of children with CHB [1, 9]. It has also been suggested that
anti-Ro52-p200 antibodies to a specific fragment in the Ro52
peptide (amino acids 200 through 239, p200–239) play a
fundamental role in developing cardiac neonatal lupus [10].
While these antibodies were also observed in mothers of
healthy infants, women who gave birth to children with CHB
presented with significantly higher levels of anti-Ro60, anti-
Ro52 or anti-Ro52-p200 antibodies [10]. Anti-SSB/La anti-
bodies are believed to have stronger association with NLE
since they have only been detected in mothers of affected
and never healthy children [9]. In mothers with both, anti-
SSA/Ro and anti-SSB/La antibodies, the risk of developing
cutaneous symptoms by the infant is higher compared to
only anti-SSA/Ro [2]. Children of women who have exclu-
sively anti-U1-RNP antibodies are prone to dermatological
but not cardiac manifestations [2], but one case of a woman
with only anti-U1-RNP giving birth to infant with CHB has
also been reported [11]. Thus, women with all three types of
antibodies should be regularly monitored for fetal
bradycardia.
Mechanisms
There are no data explaining the mechanism leading to
development of clinical features of NLE. However, studies
suggest two possible mechanisms resulting in atrioven-
tricular heart block. One possible theory highlights the role
of cellular apoptosis and translocation of the fetal auto-
antigens SSA/Ro and/or SSB/La to the surface of car-
diomyocytes with the subsequent formation of complexes
with maternal autoantibodies. These opsonized car-
diomyocytes are phagocytosed by macrophages that
release pro-inflammatory cytokines (with the major role of
tumor necrosis factor α [TNF-α] and transforming growth
factor β [TGF-β]) leading inflammation-induced injuries to
atrioventricular node and its surrounding tissue. The sec-
ond approach advocates the role of molecular mimicry. It
suggests that autoantibodies cross-react with cardiac
L-type calcium channels inhibiting their essential role in
process of potential propagation leading to arrhythmias. It
is possible that both of these mechanisms may occur
simultaneously [1, 2, 10].
A report published in Pediatrics International in 2015
focused on the cytokine profile in two siblings with NLE of
which one developed CHB and the other typical skin rash.
Although clinical and laboratory findings were very dif-
ferent, the authors emphasize that both infants had ele-
vated interleukin 6 (IL-6), IL-8, interferon gamma (INF-γ)
and monocyte chemoattractant protein-1 (MCP-1). Other
cytokines, such as IL-12, IL-13 and IL-17, showed increased
serum levels only in newborn with skin lesions. The
authors indicate that clinical manifestations, especially the
presence or absence of cutaneous abnormalities may can
depend on the cytokine profile [12].

It has been postulated that in a mother with active
systemic lupus erythematosus the development of NLE
may occur in the mechanism of the loss of immune toler-
ance to the fetus [13].
Risk factors
While the interaction between maternal autoantibodies and
fetal antigens is crucial, 98% of children exposed to those
antibodies are healthy. This observation suggests that other
co-factors are necessary in the pathogenesis (Table 1).
Some studies point to a genetic susceptibility. It was
observed that infants with dermatological manifestations
carry all three human leukocyte antigen (HLA) alleles
DQB1*02, DRB1*03 and a polymorphism in the promoter
region of the gene encoding TNF-α two times more fre-
quently than unaffected children. Mothers with HLA-B8
and HLA-DR3 are at a higher risk of giving birth to children
with atrioventricular heart block [2]. Another study points
to HLA-B*15, HLA-C*02, HLA-DQ5 and HLA-DR10 antigens
as they were present in the mother and both of her children
[14]. Another significant factor is the concentration of
maternal autoantibodies – high titers of anti-SSA/Ro and/
or anti-SSB/La antibodies predispose infants to atrioven-
tricular heart block [1]. Duration of mother’s disease or
activity of SLE during pregnancy does not increase sus-
ceptibility to developing NLE [15]. Hyperthyroidism seems
to be another risk factor as women with both hyper-
thyroidism and anti-SSA/Ro have given birth to children
with CHB 9-fold more frequently than women with only
anti-SSA/Ro [2]. Some studies point that younger age, first
pregnancy and no exposure to steroids also may be con-
sidered risk factors [15].
Some reports suggest that the interaction between
genetic predisposition, in utero environment and circulating
maternal antibodies is more complex than currently
Table : Risk factors of neonatal lupus erythematosus (NLE).
Risk factors Probable risk
factors
. Genetic susceptibility . Younger age
a) Infant’s: HLA alleles DQB*, DRB* and . First pregnancy
a TNF-alpha gene polymorphism
b) Mother’s: Antigens HLA-B and HLA-DR . No exposure to
steroids
c) Both: HLA-B*, HLA-C*, HLA-DQ and
HLA-DR antigens
. High titers of motherly anti-SSA/Ro and/or
anti-SSB/La antibodies
. Hyperthyroidism
Derdulska et al.: Neonatal lupus erythematosus 531
understood [16]. Cases of monozygotic and dizygotic twins in
which only one of the pair developed NLE have been
reported [12, 17]. In 2016, there was a 4-week-old female
infant presenting typical cutaneous and hepatic manifes-
tations of NLE [16]. The baby was conceived through in vitro
fertilization, an unrelated oocyte donor showed no clinical or
laboratory signs of autoimmune diseases. Gestational
mother, however, was affected by Sjogren syndrome and
tested positive for anti-SSA/Ro and anti-SSB/La antibodies.
Clinical presentation
The clinical features of NLE include both reversible and
irreversible conditions. In the first group, the most com-
mon are cutaneous symptoms whereas hepatobiliary,
hematological or neurological findings are observed less
frequently. Cardiac manifestations such as atrioventricular
heart block are not only irreversible but also uniquely can
be detected before birth.
If an infant (or in case of cardiac manifestation a fetus)
presents at least one of the above symptoms (Table 2) and it
or its mother is positive for NLE-specific antinuclear anti-
bodies, the diagnosis of neonatal lupus erythematosus can
be established [1, 2].
Cutaneous manifestations
Cutaneous manifestations are present in 40% of cases;
however, 80% of children with NLE are born without any
dermatological symptoms [1]. These may develop in the
first 3 months after birth, mostly following exposure to the
sunlight. Ultraviolet (UV) light increases expression of
antigens on the keratinocytes’ plasma membrane, there-
fore, escalates interaction with the antibodies, resulting in
triggering or exacerbating skin lesions [7]. In about 20% of
cases lesions are present at birth, indicating that UV light
exposure is not essential for the development of cutaneous
lesions. This may be confirmed by the presence of cuta-
neous lesions in areas not exposed to the sunlight such as
the diaper area or plantar surfaces [4, 7].
Some of the observed skin abnormalities are secondary
to other afflictions. Jaundice is a manifestation of an
NLE-related liver disorder whereas petechiae may indicate
thrombocytopenia [7].
Common lesions
Typical cutaneous lesions resemble these observed in
subacute cutaneous lupus erythematosus (SCLE). They
532 Derdulska et al.: Neonatal lupus erythematosus

Table : Clinical manifestations. present as pink to red macular elliptic or annular eryth-
ematosus lesions or plaques with fine scaling. Targetoid
System Main clinical manifestations lesions with central clearing may be present as well as
Skin . Transient lesions discoid lesions.
a) SCLE-like erythematosus lesions NLE usually affects areas exposed to the sunlight with
b) Targetoid lesions
most common localization of the rash being the face,
c) Discoid lesions
especially the periocular area (inducing the characteristic
d) Cutis marmorata telangiectatica congenita-like
lesions “eye mask” or “raccoon-like” appearance) but also perio-
d) Malar rash ral, zygomatic and temporal area. It may occur on the scalp
e) Blueberry muffin rash or neck, less frequently on the trunk or extremities (Fig-
. Residual lesions ures 1–3) [1–3, 7]. Erythematous lesions or erosions in the
a) Telangiectasias
ano-genital area or the oral cavity may be present [18].
b) Dyspigmentation
c) Pitting The lesions are often clinically misdiagnosed as fungal
d) Scarring infection, eczema or trauma. The differential should
e) Atrophy include seborrheic dermatitis, tinea capitis, eyelid telan-
Hepatobiliary . Asymptomatic elevation of aminotransferases giectasias and erythema multiforme, erythema margin-
. Cholestasis
atum, ichthyosiform genodermatosis, erythema annulare
. Hepatomegaly
centrifugum, familial annular erythema, infantile epi-
. Severe hepatic dysfunction
Hematology . Anemia dermodysplasia erythema, annular erythema of infancy,
. Thrombocytopenia and erythema gyratum atrophicans [1–3].
. Neutropenia
. Aplastic anemia
. Hemolytic anemia Uncommon findings
. Immune thrombocytopenic purpura
. Microangiopathic hemolytic anemia If the fetus acquires severe intrauterine anemia, it might
. Disseminated intravascular coagulation and develop a coping mechanism – extramedullary dermal
thrombosis
erythropoiesis – resulting in an atypical skin rash referred
Neurologic . Macrocephaly
. Hydrocephalus to as “blueberry muffin”. It affects the head, neck, trunk
. Lenticulostriate vasculopathy and extremities, can be induced or aggravated by exposure
. Rare e.g., seizures, strabismus, opsoclonus, cere- to UV light and resolves within few weeks [2]. A typical
bral hemorrhages, muscle tone abnormalities, “butterfly-shaped” malar rash is usually not observed in
. Developmental delay and learning disabilities
infants with NLE. However, there was a case report
Cardiac . Conduction tissue
describing such manifestation in a newborn. Lightly raised
a) Congenital Heart Block (CHB)
b) Transient sinus bradycardia rugged lesions may be present on the nose, cheeks and
c) Sinoatrial node dysfunction eyelids at birth. They disappeared within 6 months [19].
d) prolongations of the QT interval
e) Wolff–Parkinson–White syndrome
. Structural and inflammatory abnormalities
a) Dilated cardiomyopathy
b) Endocardial fibroelastosis
c) Myocardial fibrosis
d) Myocarditis
e) ASD
f) VSD
g) Patent foramen ovale
h) Persistent patent ductus arteriosus
i) Valvular defects
j) Aortic aneurysm
Pulmonary . Pneumonitis
Figure 1: The cutaneous lesions appear often after the first sun
. Necrotizing pulmonary capillaritis
exposure, but they are present commonly on the abdomen – in non-
. Alveolar hemorrhage
sun-exposed area.

Figure 2: In some patients, the lesions may be very discrete, as
presented.
Figure 3: Distribution of cutaneous lesions in infants with neonatal
lupus erythematosus.
Lesions resembling those in cutis marmorata telangiecta-
tica congenita have been observed in nine cases. They
usually develop on the limbs [20]. Cutaneous lesions might
mimic Stevens–Johnson syndrome as described in a case
report of an infant with multiple confluent reticulated dark
red patches with central sheet-like erosions and crusts on
the scalp, face, lips, trunk, extremities, buttock and genital
area along with numerous flaccid bullae on the leg. Sys-
temic corticosteroids along with Aquacel-Ag dressing and
betamethasone-gentamicin cream were induced and
resulted in positive outcome [21].
Histopathology and immunohistopathology
Histopathology usually shows interface dermatitis, vacuolar
alterations in the basal epidermis or granular deposits of IgG
at the dermoepidermal interface (Figure 4) and adnexal
Derdulska et al.: Neonatal lupus erythematosus 533
Figure 4: Direct immunofluorescence (lupus band test) shows the
presence of IgG at the dermo-epidermal junction.
The positive lupus band test may confirm the diagnosis in doubtful
cases.
structures and deposits of mucin in the dermis. In patients
with lesions resembling urticaria lymphocytic perivascular
and periadnexal infiltrates may be observed [1, 2, 22].
In 2014, Okada et al. has described a case in which
CD163-positive histiocytes in the infiltrated lesions were
discovered [23]. Amongst the infiltrating cells, there was a
clear division into small and medium-sized round cells.
The small cells were predominantly CD3-positive with the
majority being CD8-positive, rather than CD4-positive and
the medium-sized cells stained positive for KP-1 (CD68) and
CD163 but were negative for S-100 and CD-1a. The authors
concluded that the medium sized infiltrating cells are non-
Langerhans histiocytes-M2 macrophages. It is, however,
unclear whether the presence of CD163-positive histiocytes
is just an isolated case of NLE or a newly found typical
feature [23].
There has also been a case of a 1-month-old male infant
with an unusual for NLE histiocytoid neutrophilic derma-
titis. The patient presented typical annular erythematous
plaques, histopathology of the skin, however, displayed an
interstitial infiltration of mononuclear cells mixed with
segmented neutrophils. Immunohistochemistry revealed
the mononuclear cells to be positive for CD68, CD33 and
myeloperoxidase which suggests that the cells derived
from myeloid lineage [24]. Neutrophilic infiltration has also
been reported in a 26-day-old female infant with eryth-
ematosus targetoid macules primarily on the trunk and
then the whole body surface. Cases of neutrophilic der-
matosis in patients with lupus erythematosus and NLE
have been described in the literature as “nonbullous neu-
trophilic dermatosis of lupus erythematosus” [22].
These cases indicate that NLE should be included in
the differential diagnosis of histiocytoid neutrophilic der-
matitis and neutrophilic dermatitis [24].
534 Derdulska et al.: Neonatal lupus erythematosus
Hepatobiliary manifestations
Asymptomatic elevation of aminotransferases, hepa-
tomegaly and elevated gamma-glutamyl transferase are the
most common hepatobiliary manifestations affecting 10–
25% of infants and usually accompanying either cardiac or
cutaneous abnormalities but in some cases may present as
isolated symptoms [1, 5, 25, 26]. In cases of severe hepatic
dysfunction, biopsy reveals mild bile duct obstruction, por-
tal fibrosis, and sporadic giant cell transformation resem-
bling idiopathic neonatal giant cell hepatitis [2, 4].
Hematological manifestations
Both hepatobiliary and hematological involvement usually
coexist with other abnormalities but a case of an isolated
anti-Ro/SSA thrombocytopenia in an infant has been
reported [27].
Typical hematological symptoms occur in 10–20% of
infants and include anemia, thrombocytopenia, less fre-
quently neutropenia and aplastic anemia [1]. The patho-
genesis of cytopenias is based rather on the suppressive
effect of the maternal antibodies on the bone marrow as
opposed to peripheral destruction of blood cells. However,
hemolytic anemia has been reported [2] with one case of
warm antibody hemolytic anemia [28].
Other infrequent manifestations include immune
thrombocytopenic purpura, microangiopathic hemolytic
anemia, disseminated intravascular coagulation and
thrombosis which stems from the transplacental passage of
antiphospholipid antibodies [2].
Neurological manifestations
Neurological abnormalities appear less frequently and
usually present as macrocephaly with or without asso-
ciated hydrocephalus [1]. Another common pathology is
lenticulostriate vasculopathy that leads to cerebral dys-
maturation, ventriculomegaly and dysgenesis of structures
that the lenticulostriate vasculature supplies with blood
but at the time of birth most of the newborns show no
clinical neurological symptoms [2].
One study carried out in 50 infants born to mothers with
NLE-specific antibodies described different echo-
encephalographic abnormalities revealed in cerebral ultra-
sound. A total of nine children presented radiologic neuro-
logical symptoms, which included: mild or moderate
cerebral ventricular dilation, ependymal or subependymal
pseudocyst, subependymal or intraventricular hemorrhage,
large cable septum pellucidum, increased periventricular
white matter echogenicity, peripheral cerebral areas dilation
and lenticulostriate vasculopathy. In each case, however,
the abnormalities were clinically asymptomatic [5].
Some clinical abnormalities may be observed later on
in the infant’s life. The children may develop seizures,
strabismus, opsoclonus, static encephalopathies, truncal
hypotonia, spastic paresis, myelopathies, cerebral hem-
orrhages, muscle tone abnormalities, developmental
delay, attention deficits, hyperactivity, obsession, com-
pulsion and tic disorders [2]. Reports suggest that if the
mother is affected by SLE or has circulating anti-
phospholipid antibodies her child may be prone to lan-
guage delay and learning disabilities, especially dyslexia
[29].
Amongst rare neurological findings one case of acute
ischemic stroke as a result of central neural system vas-
culitis in a 2-month-old female infant has been reported.
Girl was positive to anti-SSA/Ro antibodies and did not
present any other clinical features of NLE which is unique
for neurological manifestations [30].
Cardiac manifestations
Neonatal lupus may have an impact on myocardium and
endocardium but the most common feature is the injury to
the cardiac conduction tissue leading to defects such as
congenital atrioventricular block which is the most severe
and in some cases lethal manifestation of NLE [2]. The
development of the congenital heart block usually occurs
between the 18th and 24th gestational week and it may be
detected prenatally as it usually presents as fetal brady-
cardia with the ventricular rate of 40–60/min [5]. The
atrioventricular block is usually complete but first- and
second-degree blocks may also occur and, on the contrary
to the third-degree, they can resolve completely during the
first few months after birth [7]. However, with time they
might also develop into an irreversible complete heart
block [5]. Damage to the conduction tissue might less fre-
quently lead to transient sinus bradycardia, sinoatrial node
dysfunction, prolongations of the QT interval and Wolff–
Parkinson–White syndrome [31, 32].
A late cardiac manifestation is dilated cardiomyopathy
which affects approximately 10% of infants presenting
with CHB but may also present as an isolated abnormality
[11]. The abnormality is usually detected in utero but it
might develop after birth. In this case, we distinguish two
subgroups: neonatal dilated cardiomyopathy (DCM) diag-
nosed during the first 28 days of life and late-onset DCM
developing after this period of time. Patients of non-

European origin or those with in utero mitral valve insuf-
ficiency are more prone to late-onset DCM while neonatal
DCM is more frequent in patients affected by hydrops,
endocardial elastosis and pericardial effusion [33]. The
impairment to the myocardium is often secondary to
endocardial fibroelastosis and myocardial fibrosis.
Another disorder is myocarditis although it occurs rather
rarely [1]. Both myocarditis and endocardial fibroelastosis
are suggested to stem from infiltrates of inflammation-
inducing cells and deposition of immunoglobulin, com-
plement and fibrin in the myocardium [2].
Although structural abnormalities are uncommon
findings and most of the newborns present with anatomi-
cally intact hearts defects such as ostium secundum type
atrial septal defect, ventricular septal defect, patent fora-
men ovale, persistent patent ductus arteriosus, fusion of
the chordae tendineae of the tricuspid valve, pulmonary
stenosis and pulmonary valvular dysplasia have also been
observed in numerous cases [1, 2, 34, 35].
The transplacental passage of maternal antibodies
also causes inflammation in the aortic adventitia and may
lead to dilatation of the ascending aorta and in con-
sequence formation of aortic aneurysm. Since slow heart
rate induces increased stroke volume and promotes pro-
gression of the aortic dilation the insertion of pacemaker is
usually sufficient [36].
Unusual findings
Pulmonary involvement is quite unusual and if occurs it is
usually indicative of infantile primary SLE. The clinical
manifestations include cough, tachypnoea, hypoxemia,
while the chest radiograph reveals interstitial lung infil-
trates. The literature describes afflictions such as necrot-
izing pulmonary capillaritis, pneumonitis and alveolar
hemorrhage [37].
There has been a case report of a preterm infant with a
third-degree heart block who has developed acute respi-
ratory failure, probably due to the NLE-related pneumo-
nitis. Chest radiograms revealed symmetrical diffuse
interstitial infiltrates. After excluding other possibilities
such as pulmonary embolism, the infant was diagnosed
with acute lupus pneumonitis. Intravenous methyl-
prednisolone therapy followed by oral prednisolone
brought satisfactory results [38]. Corticosteroids and
immunosuppressants have reportedly given positive
results also in other cases of pulmonary involvement [2].
Another unique finding is rhizomelic chon-
drodysplasia punctata which usually accompanies cuta-
neous or central nervous system manifestations. Affected
Derdulska et al.: Neonatal lupus erythematosus 535
newborns have characteristic faces with midfacial hypo-
plasia and present shortening of limbs as well as punctuate
calcifications of the epiphyses [2, 7].
Hematuria, hypertension, glomerulonephritis result-
ing in edema and congenital nephrotic syndrome have also
been observed. Renal involvement such as nephritis and
nephritic presentations can indicate infantile primary SLE
rather than NLE [2]. Other renal abnormalities include
proteinuria, elevated serum creatinine and decreased cre-
atinine clearance rate [8]. If pharmacological treatment is
required, corticosteroids and immunosuppressive therapy
have been reported successful [2].
Other ramifications include endocrine dysfunctions
including thyroid and adrenal glands. Due to the trans-
placental passage of antibodies directed against thyroid
antigens, the newborn may develop both hypo- or hyper-
thyroid disease of neonates. In the transplacental passage
includes antiphospholipid antibodies, infant may present
adrenal hemorrhage and insufficiency [2].
Autoimmune sensorineural hearing loss was descri-
bed as an isolated sequela of NLE in a 12-year-old boy who
has undergone pacemaker implantation surgery as an
infant. He presented nausea, nystagmus, dizziness, tinni-
tus, vertigo and hearing loss. After excluding other possi-
ble reasons, the diagnosis of autoimmune hearing loss was
made. The pathogenetic role of anti-SSA/Ro antibodies in
inner ear damage is still being investigated [39].
Prenatal screening, treatment and
prevention
Every pregnant woman, regardless of being symptomatic
or not, ought to be tested for antinuclear antibodies. Most
of the manifestations of NLE present only after birth and
fetal echocardiography is the only diagnostic method
which can be applied prenatally if the mother tests positive
for specific antibodies. Fetal echocardiography is a safe
and non-invasive examination enabling assessment of the
heart’s structure and rhythm. Screening should be initiated
in the 16th gestational week and if no abnormalities are
detected the frequency might be decreased after the 26th
week. Even though cardiac symptoms are seldom identi-
fied after that and even more infrequently after birth the
newborn should be observed during the first 28 days of its
life as 2% of CHB cases present postnatally [1].
Initial data advocated the role of fluorinated corti-
costeroids (betamethasone and dexamethasone) in pre-
venting cardiac abnormalities, especially the progression
of second-degree block to third-degree block, and other
536 Derdulska et al.: Neonatal lupus erythematosus
complications such as hydrops fetalis and in utero effu-
sions. Newest studies, however, denote this thesis and
highlight the safety issue of corticosteroid therapy
[40, 41].
In recent years, the possible application of anti-
malarial drugs, especially hydroxychloroquine is being
discussed. Antimalarial drugs belong to standard medi-
cations in SLE, but they were usually discontinued before
a planned pregnancy in an attempt to avoid a negative
effect on the fetus. The latest studies suggest that expo-
sure to hydroxychloroquine during fetal life may
decrease the risk of developing cardiac manifestations
[42, 43]. The treatment seems to not affect the risk of non-
cardiac manifestations of NLE. It has been shown that
hydroxychloroquine prevents the stimulation of Toll-like
receptors 7 (TLR-7) thus inhibits a chain reaction leading
to secretion of pro-inflammatory agents and subsequent
cardiac fibrosis [44]. It is suggested that hydroxy-
chloroquine treatment should be initiated between the
sixth and 10th gestational weeks at a dose of 400 mg
orally once a day [1, 44]. Positive outcome in preventing
CBH has been reached in seven out of eight pregnancies
by inducing intravenous immunoglobulin (IVIG) at 14
and 18 weeks of gestation at the dose of 1 g/kg in a study
carried out in China in 2016 [45].
Table : Management of various manifestations [, , , , ].
Manifestations Typical management
Cutaneous – Lesions leave no mark
– Applying sunscreen
– Avoiding ultraviolet exposure
Hepatobiliary – Not needed – transient abnormalities
Hematological – Not needed – transient abnormalities
Neurological – Not needed – transient abnormalities
Cardiac – Echocardiography is recommended even in asympto-
matic children of anti-SSA/Ro and/or anti-SSB/La pos-
itive mothers as postnatal insertion of a pacemaker as
first-degree heart block may be clinically silent and
progress in CHB prenatal treatment is rather non-
existent
Postnatal management
In most cases of cutaneous, hepatobiliary, hematological
and neurological involvement, the symptoms fade spon-
taneously within 6–8 months as maternal antibodies
resolve, further treatment is usually unnecessary and
residual complications are uncommon (Table 3).
Prognosis
The prognosis varies depending on clinical manifestations.
In cases of isolated cutaneous, hepatic, hematological or
neurological abnormalities, the patients rarely require
treatment and prognosis is very good. The presence of car-
diac involvement is associated with poor prognosis espe-
cially if any of the following occurs: gestational age
<20 weeks at diagnosis, ventricular rate <55 beats per minute
(bpm), hydrops fetalis, impaired left ventricular function,
cardiomegaly, atrioventricular valve regurgitation, endo-
cardial fibroelastosis, low aortic flow velocity [1, 47, 48]. The
mortality rate in CHB varies between 10 and 29% (on average
20%) and 63–93% of the surviving patients require a pace-
maker implantation [1, 2, 4, 5, 40, 48].
Atypical management
– Non-transient abnormalities (skin atrophy, scarring,
telangiectasias, dyspigmentation or pitting in 10–25% of
cases
– Low-potency topical corticosteroids when risk of scarring
or skin atrophy
– Severe or persistent cases – corticosteroids at an initial
dose of 1–2 mg/kg for 5 days then gradually decreased
– Symptomatic anemia or thrombocytopenia – blood or
platelets transfusion
– Refractory anemia or thrombocytopenia – corticosteroids
therapy at a dose of 1–2 mg/kg for 5 days or intravenous
immunoglobulins (IVIG) at a dose of 1 g/kg for 1–2 days
– Severe cases – intravenous immunoglobulins at the dose
of 2 g/kg (a case of a 3-month-old infant with NLE pre-
senting with hydrocephalus due to bilateral subdural
collections (46)
– Fetal distress – early delivery might be required

Children diagnosed with NLE are at a higher risk of
developing autoimmune diseases later in life such as
juvenile idiopathic arthritis, psoriasis, thyroid disease for
instance Hashimoto thyroiditis, iritis and type 1 diabetes
mellitus [48]. The children are prone to growth retardation
and neurodevelopmental problems [45].
Conclusions
NLE is a disease that can affect many organs including the
skin, heart, liver, bone marrow and central nervous system.
Most of the symptoms disappear without any medical
intervention; however, cardiac involvement usually leads
to pacemaker implantation and is associated with poor
prognosis. Nowadays, research concentrates on pre-
vention and treatment of CHB prenatally with hydroxy-
chloroquine and immunoglobulin; however, a satisfying
outcome has not yet been reached. Newborns presenting
with any symptoms of NLE should be monitored for late-
onset cardiac manifestations, aortic root dilation, growth
restriction, neurological and developmental impairment
and autoimmune diseases such as SLE.
Research funding: None declared.
Author contributions: All authors have accepted
responsibility for the entire content of this manuscript
and approved its submission.
Competing interests: Authors state no conflict of interest.
Ethical approval: Not applicable.
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