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 early treatment with hydroxychloroquine or intravenous
Received July 24, 2020; accepted December 11, 2020; immunoglobulin (IVIG) has proven to be effective in pre-
published online January 18, 2021
venting congenital heart block.

Abstract Keywords: antinuclear antibodies; congenital heart block;

neonatal lupus erythematosus; newborn; pediatric
Background: Neonatal lupus erythematosus is an auto- dermatology.
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- Introduction
syndrome-related antigen B (anti-SSB/La) or anti-U1 ribo-
nucleoprotein (anti-U1-RNP) antinuclear autoantibodies. Neonatal lupus erythematosus (NLE) is an acquired con-
Contents: Clinical manifestations include skin lesions, genital autoimmune disease, which occurs in fetuses and
congenital heart block, hepatobiliary involvement and infants of women with anti-Sjögren’s-syndrome-related
cytopenias. Most of the disorders disappear spontaneously antigen A (anti-SSA/Ro) and/or anti-Sjögren’s-syndrome-
after clearance of maternal antibodies. Cardiac symptoms, related antigen B (anti-SSB/La) antinuclear antibodies that
however, are not self-resolving and often pacemaker are transmitted across the placenta during pregnancy [1, 2].
implantation is required. Diagnosis is based on clinical Less frequently, NLE is associated with anti-U1 ribonu-
presentation and the presence of typical antibodies in the cleoprotein (anti-U1-RNP) antibodies [1, 2]. Mothers may be
mother’s or infant’s serum. affected by various rheumatic conditions such as systemic
Outlook: Neonatal lupus erythematosus may develop in lupus erythematous (SLE), Sjögren’s disease, rheumatoid
children born to anti-SSA/Ro or anti-SSB/La women with arthritis, mixed connective tissue disease, or an undiffer-
various systemic connective tissue diseases. However, in entiated autoimmune syndrome but, in 25–60% of cases,
half of the cases, the mother is asymptomatic, which may they are asymptomatic and unaware of their ailment [3].
delay the diagnosis and have negative impact on the While the presence of the autoantibodies is necessary for
child’s prognosis. Testing for antinuclear antibodies the offspring to develop NLE, only 1–2% of children of sero-
should be considered in every pregnant woman since positive mothers present symptoms [1, 4].
Most frequent manifestations of NLE are skin lesions and
*Corresponding author: Professor Lidia Rudnicka, MD, PhD, congenital heart block (CHB), while signs from the central
Department of Dermatology, Medical University of Warsaw, nervous system or hepatobiliary and hematological abnor-
Koszykowa 82A 02-008 Warsaw, Poland, Phone: +48 22 502 13 24, malities are less common. Cardiac are the only permanent
E-mail: lidia.rudnicka@dermatolodzy.com.pl. https://orcid.org/
symptoms that do not resolve with the disappearance of the
0000-0002-8308-1023
Julia Marta Derdulska and Agata Szykut-Badaczewska, Department of maternal antibodies from the infant’s system [2, 5].
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) Epidemiology
Dorota Mehrholz, Roman J. Nowicki, Wioletta Barańska-Rybak
and Aleksandra Wilkowska, Department of Dermatology, Medical Autoimmune diseases are fairly uncommon conditions
University of Gdańsk, Gdańsk, Poland. https://orcid.org/0000-0001- with the prevalence in the general population being 3–5%.
6411-9172 (D. Mehrholz). https://orcid.org/0000-0003-4768-1387
Most of them appear up to 10 times more frequently in
(R.J. Nowicki). https://orcid.org/0000-0002-4018-6706
(W. Barańska-Rybak). https://orcid.org/0000-0001-6316-983X women than men. The female-to-male ratio in Sjogren’s
(A. Wilkowska) 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 While these antibodies were also observed in mothers of
births in The USA and in 0.6 of 100,000 births overall [2]. It healthy infants, women who gave birth to children with CHB
affects offspring of women with anti-SSA/Ro or anti-SSB/ presented with significantly higher levels of anti-Ro60, anti-
La antibodies. These antibodies are most likely to be found Ro52 or anti-Ro52-p200 antibodies [10]. Anti-SSB/La anti-
in patients with Sjögren’s disease and SLE. Patients with bodies are believed to have stronger association with NLE
rheumatoid arthritis should also be tested for Sjögren’s since they have only been detected in mothers of affected
syndrome antibodies as their newborns may also develop and never healthy children [9]. In mothers with both, anti-
NLE. These antibodies are also present in 0.1–1.5% of SSA/Ro and anti-SSB/La antibodies, the risk of developing
healthy women. Mothers of the children affected by NLE cutaneous symptoms by the infant is higher compared to
may have an active autoimmune disease but 25–60% of only anti-SSA/Ro [2]. Children of women who have exclu-
women are asymptomatic [1, 3]. 50% of them may develop sively anti-U1-RNP antibodies are prone to dermatological
symptoms of SLE or Sjögren’s disease within the next 3–5 but not cardiac manifestations [2], but one case of a woman
years from delivery [1, 7]. Only 1–2% of women with anti- with only anti-U1-RNP giving birth to infant with CHB has
SSA/Ro and/or anti-SSB/La antibodies are going to give also been reported [11]. Thus, women with all three types of
birth to a child with NLE. Nevertheless, the risk increases antibodies should be regularly monitored for fetal
up to 17–20% if any symptoms occurred in previous preg- bradycardia.
nancies [1, 2, 4].
Initial studies suggested female infants are two to three-
fold more prone to developing cardiac and dermatological Mechanisms
symptoms of NLE [3]. However, recent studies refute that
thesis proving this condition affects both sexes with similar There are no data explaining the mechanism leading to
frequency and the male–female ratio is 1:1.05 [1, 8]. development of clinical features of NLE. However, studies
suggest two possible mechanisms resulting in atrioven-
tricular heart block. One possible theory highlights the role
Pathogenesis of cellular apoptosis and translocation of the fetal auto-
antigens SSA/Ro and/or SSB/La to the surface of car-
Antigens and autoantibodies diomyocytes with the subsequent formation of complexes
with maternal autoantibodies. These opsonized car-
There are three types of antibodies in the pathogenesis of diomyocytes are phagocytosed by macrophages that
NLE – anti-SSA/Ro, anti-SSB/La and anti-U1-RNP [2]. Anti- release pro-inflammatory cytokines (with the major role of
SSA/Ro antibodies are directed against two cellular pro- tumor necrosis factor α [TNF-α] and transforming growth
teins with different molecular masses – 52 kD (Ro52) and factor β [TGF-β]) leading inflammation-induced injuries to
60 kD (Ro60). The Ro52 antigen is present in the nucleus atrioventricular node and its surrounding tissue. The sec-
and the cytoplasm whereas Ro60 in the nucleus and ond approach advocates the role of molecular mimicry. It
nucleolus. Anti-SSB/La antibodies target a 48 kD protein suggests that autoantibodies cross-react with cardiac
localized in the nucleus [1]. As a result of the process of cell L-type calcium channels inhibiting their essential role in
apoptosis during fetal development, these antigens are process of potential propagation leading to arrhythmias. It
displayed on the surface of the cells. In the second tri- is possible that both of these mechanisms may occur
mester, maternal autoantibodies (immunoglobulin G [IgG]) simultaneously [1, 2, 10].
start to cross the placenta and form complexes with the A report published in Pediatrics International in 2015
antigens in fetal organs. These complexes are then focused on the cytokine profile in two siblings with NLE of
opsonized and phagocytosed which triggers proin- which one developed CHB and the other typical skin rash.
flammatory process and subsequent tissue damage [2]. Although clinical and laboratory findings were very dif-
The type of antibodies and serum concentration corre- ferent, the authors emphasize that both infants had ele-
lates with clinical presentation of NLE. Most studies point to vated interleukin 6 (IL-6), IL-8, interferon gamma (INF-γ)
anti-Ro52 antibodies as the main agents in the pathogenesis, and monocyte chemoattractant protein-1 (MCP-1). Other
rather than anti-Ro60, as they were found in 85% of mothers cytokines, such as IL-12, IL-13 and IL-17, showed increased
of children with CHB [1, 9]. It has also been suggested that serum levels only in newborn with skin lesions. The
anti-Ro52-p200 antibodies to a specific fragment in the Ro52 authors indicate that clinical manifestations, especially the
peptide (amino acids 200 through 239, p200–239) play a presence or absence of cutaneous abnormalities may can
fundamental role in developing cardiac neonatal lupus [10]. depend on the cytokine profile [12].
 Derdulska et al.: Neonatal lupus erythematosus 531

It has been postulated that in a mother with active understood [16]. Cases of monozygotic and dizygotic twins in
systemic lupus erythematosus the development of NLE which only one of the pair developed NLE have been
may occur in the mechanism of the loss of immune toler- reported [12, 17]. In 2016, there was a 4-week-old female
ance to the fetus [13]. 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
Risk factors laboratory signs of autoimmune diseases. Gestational
mother, however, was affected by Sjogren syndrome and
While the interaction between maternal autoantibodies and tested positive for anti-SSA/Ro and anti-SSB/La antibodies.
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). Clinical presentation
Some studies point to a genetic susceptibility. It was
observed that infants with dermatological manifestations The clinical features of NLE include both reversible and
carry all three human leukocyte antigen (HLA) alleles irreversible conditions. In the first group, the most com-
DQB1*02, DRB1*03 and a polymorphism in the promoter mon are cutaneous symptoms whereas hepatobiliary,
region of the gene encoding TNF-α two times more fre- hematological or neurological findings are observed less
quently than unaffected children. Mothers with HLA-B8 frequently. Cardiac manifestations such as atrioventricular
and HLA-DR3 are at a higher risk of giving birth to children heart block are not only irreversible but also uniquely can
with atrioventricular heart block [2]. Another study points be detected before birth.
to HLA-B*15, HLA-C*02, HLA-DQ5 and HLA-DR10 antigens If an infant (or in case of cardiac manifestation a fetus)
as they were present in the mother and both of her children presents at least one of the above symptoms (Table 2) and it
[14]. Another significant factor is the concentration of or its mother is positive for NLE-specific antinuclear anti-
maternal autoantibodies – high titers of anti-SSA/Ro and/ bodies, the diagnosis of neonatal lupus erythematosus can
or anti-SSB/La antibodies predispose infants to atrioven- be established [1, 2].
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 Cutaneous manifestations
to be another risk factor as women with both hyper-
thyroidism and anti-SSA/Ro have given birth to children Cutaneous manifestations are present in 40% of cases;
with CHB 9-fold more frequently than women with only however, 80% of children with NLE are born without any
anti-SSA/Ro [2]. Some studies point that younger age, first dermatological symptoms [1]. These may develop in the
pregnancy and no exposure to steroids also may be con- first 3 months after birth, mostly following exposure to the
sidered risk factors [15]. sunlight. Ultraviolet (UV) light increases expression of
Some reports suggest that the interaction between antigens on the keratinocytes’ plasma membrane, there-
genetic predisposition, in utero environment and circulating fore, escalates interaction with the antibodies, resulting in
maternal antibodies is more complex than currently triggering or exacerbating skin lesions [7]. In about 20% of
cases lesions are present at birth, indicating that UV light
Table : Risk factors of neonatal lupus erythematosus (NLE). exposure is not essential for the development of cutaneous
lesions. This may be confirmed by the presence of cuta-
Risk factors Probable risk neous lesions in areas not exposed to the sunlight such as
factors
the diaper area or plantar surfaces [4, 7].
. Genetic susceptibility . Younger age Some of the observed skin abnormalities are secondary
a) Infant’s: HLA alleles DQB*, DRB* and . First pregnancy to other afflictions. Jaundice is a manifestation of an
a TNF-alpha gene polymorphism
NLE-related liver disorder whereas petechiae may indicate
b) Mother’s: Antigens HLA-B and HLA-DR . No exposure to
steroids
thrombocytopenia [7].
c) Both: HLA-B*, HLA-C*, HLA-DQ and
HLA-DR antigens Common lesions
. High titers of motherly anti-SSA/Ro and/or
anti-SSB/La antibodies
Typical cutaneous lesions resemble these observed in
. Hyperthyroidism
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.
 Derdulska et al.: Neonatal lupus erythematosus 533

Figure 2: In some patients, the lesions may be very discrete, as Figure 4: Direct immunofluorescence (lupus band test) shows the
presented. 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
Figure 3: Distribution of cutaneous lesions in infants with neonatal is just an isolated case of NLE or a newly found typical
lupus erythematosus. feature [23].
There has also been a case of a 1-month-old male infant
Lesions resembling those in cutis marmorata telangiecta-
with an unusual for NLE histiocytoid neutrophilic derma-
tica congenita have been observed in nine cases. They
titis. The patient presented typical annular erythematous
usually develop on the limbs [20]. Cutaneous lesions might
plaques, histopathology of the skin, however, displayed an
mimic Stevens–Johnson syndrome as described in a case
interstitial infiltration of mononuclear cells mixed with
report of an infant with multiple confluent reticulated dark
segmented neutrophils. Immunohistochemistry revealed
red patches with central sheet-like erosions and crusts on
the mononuclear cells to be positive for CD68, CD33 and
the scalp, face, lips, trunk, extremities, buttock and genital
myeloperoxidase which suggests that the cells derived
area along with numerous flaccid bullae on the leg. Sys-
from myeloid lineage [24]. Neutrophilic infiltration has also
temic corticosteroids along with Aquacel-Ag dressing and
been reported in a 26-day-old female infant with eryth-
betamethasone-gentamicin cream were induced and
ematosus targetoid macules primarily on the trunk and
resulted in positive outcome [21].
then the whole body surface. Cases of neutrophilic der-
matosis in patients with lupus erythematosus and NLE
Histopathology and immunohistopathology have been described in the literature as “nonbullous neu-
trophilic dermatosis of lupus erythematosus” [22].
Histopathology usually shows interface dermatitis, vacuolar These cases indicate that NLE should be included in
alterations in the basal epidermis or granular deposits of IgG the differential diagnosis of histiocytoid neutrophilic der-
at the dermoepidermal interface (Figure 4) and adnexal matitis and neutrophilic dermatitis [24].
534 Derdulska et al.: Neonatal lupus erythematosus

Hepatobiliary manifestations large cable septum pellucidum, increased periventricular

white matter echogenicity, peripheral cerebral areas dilation
Asymptomatic elevation of aminotransferases, hepa- and lenticulostriate vasculopathy. In each case, however,
tomegaly and elevated gamma-glutamyl transferase are the the abnormalities were clinically asymptomatic [5].
most common hepatobiliary manifestations affecting 10– Some clinical abnormalities may be observed later on
25% of infants and usually accompanying either cardiac or in the infant’s life. The children may develop seizures,
cutaneous abnormalities but in some cases may present as strabismus, opsoclonus, static encephalopathies, truncal
isolated symptoms [1, 5, 25, 26]. In cases of severe hepatic hypotonia, spastic paresis, myelopathies, cerebral hem-
dysfunction, biopsy reveals mild bile duct obstruction, por- orrhages, muscle tone abnormalities, developmental
tal fibrosis, and sporadic giant cell transformation resem- delay, attention deficits, hyperactivity, obsession, com-
bling idiopathic neonatal giant cell hepatitis [2, 4]. 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-
Hematological manifestations guage delay and learning disabilities, especially dyslexia
[29].
Both hepatobiliary and hematological involvement usually Amongst rare neurological findings one case of acute
coexist with other abnormalities but a case of an isolated ischemic stroke as a result of central neural system vas-
anti-Ro/SSA thrombocytopenia in an infant has been culitis in a 2-month-old female infant has been reported.
reported [27]. Girl was positive to anti-SSA/Ro antibodies and did not
Typical hematological symptoms occur in 10–20% of present any other clinical features of NLE which is unique
infants and include anemia, thrombocytopenia, less fre- for neurological manifestations [30].
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 Cardiac manifestations
opposed to peripheral destruction of blood cells. However,
hemolytic anemia has been reported [2] with one case of Neonatal lupus may have an impact on myocardium and
warm antibody hemolytic anemia [28]. endocardium but the most common feature is the injury to
Other infrequent manifestations include immune the cardiac conduction tissue leading to defects such as
thrombocytopenic purpura, microangiopathic hemolytic congenital atrioventricular block which is the most severe
anemia, disseminated intravascular coagulation and and in some cases lethal manifestation of NLE [2]. The
thrombosis which stems from the transplacental passage of development of the congenital heart block usually occurs
antiphospholipid antibodies [2]. 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
Neurological manifestations atrioventricular block is usually complete but first- and
second-degree blocks may also occur and, on the contrary
Neurological abnormalities appear less frequently and to the third-degree, they can resolve completely during the
usually present as macrocephaly with or without asso- first few months after birth [7]. However, with time they
ciated hydrocephalus [1]. Another common pathology is might also develop into an irreversible complete heart
lenticulostriate vasculopathy that leads to cerebral dys- block [5]. Damage to the conduction tissue might less fre-
maturation, ventriculomegaly and dysgenesis of structures quently lead to transient sinus bradycardia, sinoatrial node
that the lenticulostriate vasculature supplies with blood dysfunction, prolongations of the QT interval and Wolff–
but at the time of birth most of the newborns show no Parkinson–White syndrome [31, 32].
clinical neurological symptoms [2]. A late cardiac manifestation is dilated cardiomyopathy
One study carried out in 50 infants born to mothers with which affects approximately 10% of infants presenting
NLE-specific antibodies described different echo- with CHB but may also present as an isolated abnormality
encephalographic abnormalities revealed in cerebral ultra- [11]. The abnormality is usually detected in utero but it
sound. A total of nine children presented radiologic neuro- might develop after birth. In this case, we distinguish two
logical symptoms, which included: mild or moderate subgroups: neonatal dilated cardiomyopathy (DCM) diag-
cerebral ventricular dilation, ependymal or subependymal nosed during the first 28 days of life and late-onset DCM
pseudocyst, subependymal or intraventricular hemorrhage, developing after this period of time. Patients of non-
 Derdulska et al.: Neonatal lupus erythematosus 535

European origin or those with in utero mitral valve insuf- newborns have characteristic faces with midfacial hypo-
ficiency are more prone to late-onset DCM while neonatal plasia and present shortening of limbs as well as punctuate
DCM is more frequent in patients affected by hydrops, calcifications of the epiphyses [2, 7].
endocardial elastosis and pericardial effusion [33]. The Hematuria, hypertension, glomerulonephritis result-
impairment to the myocardium is often secondary to ing in edema and congenital nephrotic syndrome have also
endocardial fibroelastosis and myocardial fibrosis. been observed. Renal involvement such as nephritis and
Another disorder is myocarditis although it occurs rather nephritic presentations can indicate infantile primary SLE
rarely [1]. Both myocarditis and endocardial fibroelastosis rather than NLE [2]. Other renal abnormalities include
are suggested to stem from infiltrates of inflammation- proteinuria, elevated serum creatinine and decreased cre-
inducing cells and deposition of immunoglobulin, com- atinine clearance rate [8]. If pharmacological treatment is
plement and fibrin in the myocardium [2]. required, corticosteroids and immunosuppressive therapy
Although structural abnormalities are uncommon have been reported successful [2].
findings and most of the newborns present with anatomi- Other ramifications include endocrine dysfunctions
cally intact hearts defects such as ostium secundum type including thyroid and adrenal glands. Due to the trans-
atrial septal defect, ventricular septal defect, patent fora- placental passage of antibodies directed against thyroid
men ovale, persistent patent ductus arteriosus, fusion of antigens, the newborn may develop both hypo- or hyper-
the chordae tendineae of the tricuspid valve, pulmonary thyroid disease of neonates. In the transplacental passage
stenosis and pulmonary valvular dysplasia have also been includes antiphospholipid antibodies, infant may present
observed in numerous cases [1, 2, 34, 35]. adrenal hemorrhage and insufficiency [2].
The transplacental passage of maternal antibodies Autoimmune sensorineural hearing loss was descri-
also causes inflammation in the aortic adventitia and may bed as an isolated sequela of NLE in a 12-year-old boy who
lead to dilatation of the ascending aorta and in con- has undergone pacemaker implantation surgery as an
sequence formation of aortic aneurysm. Since slow heart infant. He presented nausea, nystagmus, dizziness, tinni-
rate induces increased stroke volume and promotes pro- tus, vertigo and hearing loss. After excluding other possi-
gression of the aortic dilation the insertion of pacemaker is ble reasons, the diagnosis of autoimmune hearing loss was
usually sufficient [36]. made. The pathogenetic role of anti-SSA/Ro antibodies in
inner ear damage is still being investigated [39].

Unusual findings

Pulmonary involvement is quite unusual and if occurs it is

Prenatal screening, treatment and
usually indicative of infantile primary SLE. The clinical prevention
manifestations include cough, tachypnoea, hypoxemia,
while the chest radiograph reveals interstitial lung infil- Every pregnant woman, regardless of being symptomatic
trates. The literature describes afflictions such as necrot- or not, ought to be tested for antinuclear antibodies. Most
izing pulmonary capillaritis, pneumonitis and alveolar of the manifestations of NLE present only after birth and
hemorrhage [37]. fetal echocardiography is the only diagnostic method
There has been a case report of a preterm infant with a which can be applied prenatally if the mother tests positive
third-degree heart block who has developed acute respi- for specific antibodies. Fetal echocardiography is a safe
ratory failure, probably due to the NLE-related pneumo- and non-invasive examination enabling assessment of the
nitis. Chest radiograms revealed symmetrical diffuse heart’s structure and rhythm. Screening should be initiated
interstitial infiltrates. After excluding other possibilities in the 16th gestational week and if no abnormalities are
such as pulmonary embolism, the infant was diagnosed detected the frequency might be decreased after the 26th
with acute lupus pneumonitis. Intravenous methyl- week. Even though cardiac symptoms are seldom identi-
prednisolone therapy followed by oral prednisolone fied after that and even more infrequently after birth the
brought satisfactory results [38]. Corticosteroids and newborn should be observed during the first 28 days of its
immunosuppressants have reportedly given positive life as 2% of CHB cases present postnatally [1].
results also in other cases of pulmonary involvement [2]. Initial data advocated the role of fluorinated corti-
Another unique finding is rhizomelic chon- costeroids (betamethasone and dexamethasone) in pre-
drodysplasia punctata which usually accompanies cuta- venting cardiac abnormalities, especially the progression
neous or central nervous system manifestations. Affected 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- Postnatal management

sions. Newest studies, however, denote this thesis and
highlight the safety issue of corticosteroid therapy In most cases of cutaneous, hepatobiliary, hematological
[40, 41]. and neurological involvement, the symptoms fade spon-
In recent years, the possible application of anti- taneously within 6–8 months as maternal antibodies
malarial drugs, especially hydroxychloroquine is being resolve, further treatment is usually unnecessary and
discussed. Antimalarial drugs belong to standard medi- residual complications are uncommon (Table 3).
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 Prognosis
decrease the risk of developing cardiac manifestations
[42, 43]. The treatment seems to not affect the risk of non- The prognosis varies depending on clinical manifestations.
cardiac manifestations of NLE. It has been shown that In cases of isolated cutaneous, hepatic, hematological or
hydroxychloroquine prevents the stimulation of Toll-like neurological abnormalities, the patients rarely require
receptors 7 (TLR-7) thus inhibits a chain reaction leading treatment and prognosis is very good. The presence of car-
to secretion of pro-inflammatory agents and subsequent diac involvement is associated with poor prognosis espe-
cardiac fibrosis [44]. It is suggested that hydroxy- cially if any of the following occurs: gestational age
chloroquine treatment should be initiated between the <20 weeks at diagnosis, ventricular rate <55 beats per minute
sixth and 10th gestational weeks at a dose of 400 mg (bpm), hydrops fetalis, impaired left ventricular function,
orally once a day [1, 44]. Positive outcome in preventing cardiomegaly, atrioventricular valve regurgitation, endo-
CBH has been reached in seven out of eight pregnancies cardial fibroelastosis, low aortic flow velocity [1, 47, 48]. The
by inducing intravenous immunoglobulin (IVIG) at 14 mortality rate in CHB varies between 10 and 29% (on average
and 18 weeks of gestation at the dose of 1 g/kg in a study 20%) and 63–93% of the surviving patients require a pace-
carried out in China in 2016 [45]. maker implantation [1, 2, 4, 5, 40, 48].

Table : Management of various manifestations [, , , , ].

Manifestations Typical management Atypical management

Cutaneous – Lesions leave no mark – Non-transient abnormalities (skin atrophy, scarring,

– Applying sunscreen telangiectasias, dyspigmentation or pitting in 10–25% of
– Avoiding ultraviolet exposure cases
– Low-potency topical corticosteroids when risk of scarring
or skin atrophy
Hepatobiliary – Not needed – transient abnormalities – Severe or persistent cases – corticosteroids at an initial
dose of 1–2 mg/kg for 5 days then gradually decreased
Hematological – Not needed – transient abnormalities – 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
Neurological – Not needed – transient abnormalities – 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)
Cardiac – Echocardiography is recommended even in asympto- – Fetal distress – early delivery might be required
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
 Derdulska et al.: Neonatal lupus erythematosus 537

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