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Review paper Reumatologia 2017; 55, 1: 2937

DOI: https://doi.org/10.5114/reum.2017.66685

An ever-challenging relationship: lupus and pregnancy

Andra Blnescu, Teodora Donisan, Dinu Blnescu


University of Medicine and Pharmacy Carol Davila, Bucharest, Romania

Abstract
Systemic lupus erythematous (SLE) is achronic inflammatory disease with an unknown etiology and
an autoimmune pathogenesis, and its clinical manifestations can involve multiple organs through
polymorphic biological changes. Nowadays, pregnancy is possible for most patients with SLE, and
good outcomes can be expected for both mother and child. This became possible as a consequence of
increasingly better monitoring and treatment of pregnant women with SLE. The following article out-
lines the problems associated with fertility, course of pregnancy, and breastfeeding in women with SLE.

Key words: systemic lupus erythematosus, pregnancy.

Introduction vention of unwanted pregnancies during high disease


activity periods and intake of teratogenic drugs [2].
Systemic lupus erythematous (SLE) is achronic in-
These patients have fewer contraceptive options be-
flammatory disease with protean manifestations, an
cause oral contraceptives contain estrogen and proges-
unknown etiology, and an autoimmune pathogenesis; it
terone; these two hormones might trigger disease flares.
is defined by the synthesis of autoantibodies (auto-Ab)
Even though clinical trials have generated inconsistent re-
directed against elements of the cellular nucleus, and
sults in this regard, it is recommended to avoid these hor-
its clinical manifestations can involve multiple organs
mone-containing contraceptives in SLE patients, especially
through polymorphic biological changes [1]. Since the dis-
if the disease is active [3]. However, in patients with inac-
ease is prevalent in females of reproductive age and its
tive SLE and negative anti-phospholipid antibodies, com-
pathogenesis involves the immune system and hormonal
bined hormonal contraceptives can be considered [2]. Ad-
alterations, pregnancy-related issues are extremely im-
portant for the mothers disease course, as well as for fetal ditionally, estrogen use increases the risk for thrombosis
development. Previously, pregnancy was contraindicated in patients with antiphospholipid or nephrotic syndromes.
for most patients with SLE; however, we are witnessing An accepted alternative is progesterone, but its long-term
amajor shift in this paradigm. Nowadays, pregnancy is use is limited by the risk of osteoporosis and must be care-
possible for most patients with SLE and good outcomes fully weighed against the risk of thrombosis [2, 4].
can be expected for both mother and child, through abet- Due to these reasons, mechanical contraceptive
ter understanding of the pathogenesis of the disease and methods are mainly recommended in patients with SLE,
due to advances in clinical management which triggered but even these are to be used with caution due to the
awidening body of evidence in relation to SLE-pregnancy increased risk of infection. Intrauterine devices (IUD), es-
association. Lately, there have been major changes in the pecially those covered only with copper, can be used for
management of pregnant women with lupus. all patients with SLE and/or antiphospholipid syndrome
free of any gynecological contraindication [2].
Systemic lupus erythematous
and contraception Systemic lupus erythematous and female
fertility
Women with SLE should be counseled about the use
of effective contraceptive measures, based on their dis- There are reports showing that female patients with
ease activity and thrombotic risk, especially for the pre- rheumatic inflammatory diseases, including SLE, have

Address for correspondence


Teodora Donisan, Sf. Maria Hospital, University of Medicine and Pharmacy Carol Davila, Bucharest, Romania, tel. +40740135024,
fax +40752087037, e-mail: teodora.donisan@gmail.com
Submitted: 21.01.2017, Accepted: 11.02.2017

Reumatologia 2017; 55/1


30 Andra Blnescu, Teodora Donisan, Dinu Blnescu

asmaller number of children compared to age-matched current disease activity and disease flares in the re-
controls from the general population [5]. This difference cent past; SLE activity/flares (in the last 612 months
could be explained by reduced fertility, influenced by or at conception) are associated with increased risk
multiple factors, such as disease age of onset, disease for maternal subsequent flare during pregnancy and
activity, degree and severity of the visceral involvement puerperium), hypertensive complications, fetal mor-
and treatment. Other than the potential for reduced bidity and mortality, preterm delivery [2],
fertility, there is ahigher risk of miscarriage and preg- lupus nephritis (history or active at conception) is
nancy-related disorders, influenced by immune factors astrong predictor of poor maternal and fetal out-
represented mainly by the presence of anticardiolip- come(s) (fetal loss and preterm delivery) [2],
in antibodies [6]. Another indirect indicator of fertility, potential irreversible organ damage,
time to pregnancy, is prolonged in females with rheu- serological activity: low complement level, elevated
matoid inflammatory diseases; multiple factors could anti-dsDNA Ab titers are associated with increased
explain this prolongation, and decreased fertility can be risk for maternal SLE flares during pregnancy and
one major explanation [7]. pregnancy loss [2],
Fertility is not altered in most female patients with presence of APS/Ab is astrong predictor of adverse
SLE [8]. However, since SLE is asystemic inflammatory maternal and fetal outcomes, especially for patients
disease, which could involve any organ or system, there with persistent moderate-to-high aPL titers, LA and
are some risk factors with apotential negative impact multiple aPL positivity (high-risk aPL profile): in-
on female fertility. There are many mediators involved in creased risk of maternal vascular thrombotic events
reproductive processes such as pre-implantation or the during pregnancy, (pre-)eclampsia, APS-related preg-
blastocystendometrium interaction: inflammatory cy- nancy morbidity, preterm birth [2],
tokines, chemokines or growth factors; the dysfunction presence of anti-Ro or anti-La Ab is linked to devel-
of these mediators could explain reduced fertility. The opment of neonatal lupus, including alow risk for
most important factors with an impact on fertility are: congenital heart block (especially if there are moder-
the patients age (decreased fertility after 35 years), dis- ate-to-high anti-Ro titers); weak association with oth-
ease activity, involvement of specific organs and some er pregnancy complications [2],
treatments [9]. Nonsteroidal anti-inflammatory drugs current usage of certain drugs (such as cyclophos-
may interfere with ovulation, implantation and placen- phamide, methotrexate, mycophenolate, angiotensin
tation because they inhibit prostaglandin synthesis. converting enzyme inhibitors, angiotensin II receptor
Glucocorticoids (e.g. high doses of prednisone, above blockers, diuretics, HMG-CoA reductase inhibitors) [4];
7.5 mg daily) may induce transient suppression of the all drugs mentioned here should be stopped,
hypothalamic-pituitary-ovarian axis. Therefore, these smoking must be prohibited.
drugs can induce reversible infertility. Cyclophospha-
The ideal time for conception is during aprolonged
mide can cause irreversible infertility through ovarian
remission (with aduration of at least 6 months). The pa-
failure caused by the cumulative effect of high doses
tient should have normal blood pressure, no renal or neu-
[10]. Fertility preservation methods, especially GnRH
rological symptoms during the last year, no pulmonary
(gonadotropin-releasing hormones) analogues, should
hypertension, low titers of anti-dsDNA Ab, antiphospho-
be considered for all menstruating women with SLE who
lipid or anti-Ro Ab, no hematological abnormalities, and
are going to receive alkylating agents [2].
no biological inflammatory syndrome. The patient should
also receive corticosteroid therapy in doses < 15 mg daily
Before conception and should not receive any teratogenic treatments (dis-
The most important strategy, which ensures positive cussed further below) [11]. Remission of lupus nephritis is
outcomes for the mother and the baby, is planning the defined by normal values of creatinine and serum com-
pregnancy. plement, proteinuria < 500 mg/24 h, < 5 red blood cells/
The checklist of parameters to be considered for pre- field in urine. Pregnancy should be delayed if the patient
conception counseling and risk stratification in women does not fulfill all the criteria mentioned above.
with SLE and/or antiphospholipid syndrome (APS) has However, there are relatively few circumstances
been recently updated and published by EULAR (Euro- when the pregnancy is contraindicated in apatient with
pean League Against Rheumatism) [2]. SLE: pulmonary hypertension (systolic PAP > 50 mm),
Good planning includes athorough pre-conception severe ventilatory functional restriction, severe cardi-
assessment, with emphasis on the following issues: ac failure, chronic renal disease in stages 45, previous
factors with an impact on fertility (mentioned above), pre-eclampsia or HELLP syndrome, stroke or severe flare
previous pregnancies and their possible complications, of the disease in the previous 6 months [4].

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An ever-challenging relationship: lupus and pregnancy 31

Good planning of the pregnancy and the major ad- but not in SLE. IL-6 stimulates angiogenesis, and alter-
vances made in the management of the pregnant pa- ations of its level may be associated with premature
tient with SLE led to asignificant decrease in the abor- birth or with impaired placental and fetal growth.
tion rate, from 43% in the 1960s to 17% in the 2000s [12]. Interleukin 33 is the most recent member of the IL-1
superfamily and apotentially important factor in the
Systemic lupus erythematous and pathogenesis of SLE and other autoimmune diseases.
pregnancy: pathogenetic characteristics This cytokine induces the activity of Th2 lymphocytes,
mastocytes, macrophages and NK cells, enhancing the
Because of the multi-organ involvement and the syn- synthesis of type Th2 cytokines. Also, IL-33 facilitates the
thesis of ahigh number of Ab, SLE may have acomplex invasion of the trophoblast and the proper development
influence on the pregnancy. However, the pathogenic of the placenta. Dysfunctions of this cytokine are associ-
mechanisms which form the basis of the clinical mani- ated with recurrent abortions [16].
festations during pregnancy or which have an influence Normal placental development is essential for anor-
on the pregnancy evolution in SLE are not completely mal pregnancy. Disorders of placental vasculature are
understood. The most often incriminated causes are the main cause of abortion in this disease [17]. In over
pregnancy-specific hormonal changes (mainly increased athird of pregnant SLE patients, the size of the placenta
levels of estrogens and prolactin) [13]. is reduced because of the placental vasculitis associat-
The developing placenta and embryo are foreign ed with ischemia. Ischemic changes may be aggravated
tissues for the mother and may trigger defense mech- by arterial thrombosis, especially when associated with
anisms. On the other hand, the product of conception APS. These alterations of the placental vessels may com-
must be defended from the mothers immunologic as- promise the nutrition and the oxygenation of the fetus,
sault. Hence, the maternal immune system must adapt delaying its growth and triggering premature rupture
to this new circumstance, and the regulatory T cells play of membranes. Pregnancy-associated disorders are the
an important part in this process [3]. From this perspec- hallmark of both primary APS and SLE-associated APS.
tive, it is easy to understand that an autoimmune dis- Over half of pregnancies positive for antiphospholip-
ease, such as SLE, can dramatically impair these mech- id Ab end in abortion, especially in patients with pre-
anisms and can lead to the development of significant vious abortions or fetal deaths. The major culprits for
reproductive disorders. During the periods of disease pregnancy-associated complications are thrombosis of
activity, the regulatory T lymphocytes are decreased and placental vessels and subsequent placental infarctions.
their suppressive function is correspondingly altered. Furthermore, Ab have adirect effect on the trophoblastic
In SLE, estrogens have acomplex and diverse mod- cells from the placenta, thus reducing the invasive ac-
ulatory effect on the immune response. During preg- tivity of the trophoblast, the cellular differentiation, the
nancy, the immune response is mainly Th2 type, while development of the syncytium and the synthesis of hCG
the cell-mediated immune response, the Th1 lympho- (human chorionic gonadotropin) [14]. Exposure of am-
cyte function, and the concentration of the cytokines niotic phospholipids and/or of 2-glycoprotein on the
produced by the Th1-cells: interleukins 2 and 12 (IL-2, surface of trophoblastic cells stimulates the binding of
IL-12), interferon (IFN-), tumor necrosis factor (TNF), anti-phospholipid Ab to cardiolipin and explains placen-
are depressed (which is essential for the fetus surviv- tal tropism of these Ab. However, the activity of these
al). On the other hand, the production of cytokines by Ab has an impact on the placentation process. Further-
the Th2 lymphocytes (IL-4, IL-10) and the humoral re- more, the anti-phospholipid Ab has been proven to in-
sponse are exacerbated; these changes are reversible terfere with the process of endometrial angiogenesis.
after birth, but may trigger disease flares [14]. Th17 In addition, the placental pathologic changes may
lymphocytes are another type of cells with aseeming- cause an imbalance between the release of angiogen-
ly important role during pregnancy. These cells produce ic and pro-inflammatory factors, followed by damage
IL-17, acytokine with significant proinflammatory ef- of the vascular endothelium and the onset of pre-ec-
fects. High concentrations of IL-17 have been found in lampsia [14]. New results from the PROMISSE study and
females with SLE with pre-eclampsia and recurrent from other research have proved that angiogenic factors
abortions [15]. Another important cytokine produced in play an important predictive role for pre-eclampsia [18].
excess in SLE is IL-10, which leads to continuous, exces- In pregnant women with or without SLE, pre-eclampsia
sive stimulation of B lymphocytes [13]. may be anticipated by increased levels of soluble fms-
Unlike other proinflammatory cytokines, the levels of like tyrosine-kinase, which inhibits the growth of placen-
IL-6 are decreased in SLE; also, during the last pregnancy tal blood vessels and by low levels of placental growth
trimester, IL-6 is increased in healthy pregnant women, factor, which stimulates local angiogenesis.

Reumatologia 2017; 55/1


32 Andra Blnescu, Teodora Donisan, Dinu Blnescu

Moreover, the placenta releases microparticles in- All these manifestations may be present during
volved in oxidative stress, and the levels of circulating pregnancy, but the butterfly rash is rare in pregnant
vascular endothelial growth factor (VEGF) and pro-an- women and Raynaud phenomenon is uncommon
giogenic factors mentioned above are decreased even during pregnancy [1]. It may be difficult to differentiate
45 weeks prior to the onset of clinical signs. If these between cutaneous manifestations of SLE and melas-
results are clearly confirmed, the above-mentioned mol- ma, the facial hyperpigmentation specific to pregnant
ecules may be considered biomarkers which can antic- women, which is also photosensitive. Also, alopecia,
ipate the onset of pregnancy complications in SLE pa- which may be induced by the disease or by the treat-
tients [14]. Additionally, in some cases of pre-eclampsia, ment, may occur independently from SLE during preg-
it was determined that lipid-rich foam cells accumulate nancy or during the first months after delivery.
in the walls of the uterine spiral arteries, similar to the During pregnancy, pleuritis is the most common form
early stages of atherosclerosis. of serositis (pericarditis and peritonitis occur very rarely).
All these phenomena may cause miscarriage or Renal involvement is extremely important in preg-
pre-eclampsia or may impair fetal growth [19]. No ab- nant women with SLE and represents the most important
normalities have been described in the aborted fetuses. prognostic factor. All clinical trials have shown asignif-
However, some babies born to antiphospholipid Ab-pos- icant increase in abortion and/or premature birth rates
itive mothers have been proven to have similar biologi- in pregnant women with SLE and renal involvement,
cal abnormalities [20]. compared to those without nephropathy [22]. Creatinine
Estrogens stimulate and control the release of pro- clearance < 65 ml/min/m2 or proteinuria > 2.4 g/24 h
lactin, which, in turn, stimulates T-lymphocyte prolifera- are major risk factors for miscarriage and are associated
tion, B-lymphocyte maturation and Ab synthesis. More- with abortion in more than 50% of cases [22].
Apart from renal disease, neuropsychiatric involve-
over, the level of prolactin appears to be correlated with
ment is one of the main prognostic factors. Neuropsychi-
disease activity in female patients with SLE.
atric disorders may be very diverse: headache, peripheral
Therefore, all the circumstances in which the estro-
neuropathies, cranial nerve involvement, partial or gen-
gen levels are increased (pregnancy, hormone replace-
eralized seizures, strokes, acute lymphocytic meningitis.
ment therapy, estrogen-containing contraceptives) can
Psychiatric involvement can also be very heterogeneous,
induce disease flares.
ranging from mild memory, perception and orientation
impairment up to psychosis. Although rare, estrogen-in-
Clinical particularities of systemic lupus duced chorea can occur in pregnant women with SLE [17].
erythematous during pregnancy Cardiovascular disorders may consist of pericardi-
In most cases, there are no significant differences tis, myocarditis, arrhythmias or conduction disorders,
heart failure, nonbacterial verrucous endocarditis de-
between the clinical picture of SLE in pregnancy and the
scribed by Libman and Sacks, and coronary disease
usual one. If the disease onset overlaps with pregnan-
caused by vasculitis or by increased atherosclerosis in
cy (very rarely), joint manifestations and constitutional
patients receiving corticotherapy. Thrombosis, either ve-
symptoms may sometimes be mistakenly considered to
nous (mainly in deep veins of lower limbs) or arterial, is
be pregnancy-related [21].
another possible complication occurring in SLE patients
Joint pain and inflammation occur mainly in the
and more common in pregnant patients [22]. Hyperten-
hands, elbows, shoulders and knees. Joint pain is asso-
sion is more common in SLE patients during pregnancy:
ciated with stiffness, and the swelling is generally sym-
25% of pregnancies are associated with hypertension in
metrical, but the arthropathy is non-erosive and does
SLE patients, especially if they received corticotherapy
not cause deformities [11].
or had previous nephritis [11].
Mucocutaneous manifestations are also common. Pregnant SLE patients have ahigher risk of other
The most specific ones are the following: butterfly ma- medical complications, such as gestational diabetes
lar rash (vespertiglio), generalized rash, photosensitivi- and infections, compared to healthy pregnant women,
ty, but also multiple nonspecific cutaneous manifesta- and maternal mortality is higher in this population of
tions: panniculitis, hives, vasculitis, livedo reticularis, patients [22].
oral ulcerations, circumscribed alopecia, and Raynaud
phenomenon. Besides these acute signs, there are sub-
Effect of pregnancy on systemic lupus
acute manifestations such as polycyclic annular and
papulosquamous (psoriasiform) lesions, and also chron-
erythematous
ic manifestations, such as discoid lupus and lupus pro- The flares of SLE are 3 times more common in the
fundus. first trimester of pregnancy, 1.5 times more common

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An ever-challenging relationship: lupus and pregnancy 33

in the second and third trimesters, and 6 times more lupus [25]. Other pathologies linked to areserved prog-
common postpartum [3]. The rate of the flare episodes nosis for the pregnancy in women with SLE are lupus
depends on the activity of the disease at the time of nephritis with hypertension, diabetes mellitus, throm-
conception [23]. Disease flares occur during pregnancy bosis, pre-eclampsia, urinary tract infections, premature
in 733% and 5665% of cases if the disease was inac- rupture of membranes, previous pregnancies not carried
tive or active, respectively. to term (although pregnancies can have different cours-
es in the same SLE patient) or treatment (high-dose cor-
Effect of systemic lupus erythematous on ticoids, immunosuppressive agents) [26].
conception and pregnancy
Laboratory diagnosis in pregnancy
In SLE women (with or without APS), prematurity,
preeclampsia and HELLP syndrome (eclampsia/Hemo- Anemia is more common in pregnant women with
lysis, Elevated Liver enzyme levels, Low Platelet count) SLE because the iron requirements are increased, but
rates approximate 2535%, 1015% and 1.01.5%, re- also because of the usual causes of anemia associat-
spectively [2]. ed with SLE (simple chronic anemia, hemolytic anemia,
So, SLE can have an impact on the pregnancy course iron deficiency anemia caused by treatment-induced di-
during any of the trimesters as well as in the postpar- gestive losses of iron). During pregnancy, the decreased
tum period. The disease can be associated with ahigher white blood cell count specific to SLE may be absent;
risk of abortion and premature births (caused by pre-ec- moreover, slight leucocytosis may be observed in some
lampsia, premature rupture of membranes, placental cases, even in the absence of concomitant infections or
insufficiency, or high doses of corticosteroids), perinatal corticosteroid therapy [27]. Usually, the platelet count is
deaths caused by exacerbations of renal disease and normal in pregnant women with SLE, but severe throm-
infections, intrauterine growth restriction and neonatal bocytopenia can occur in certain situations, e.g. during
lupus [14]. Increased levels of ferritin caused by the in- disease flares, HELLP syndrome, APS, or pre-eclampsia.
flammatory process and decreased levels of estradiol, Inflammatory markers are usually increased during
suggestive for placental insufficiency, are associated pregnancy, and because of this they are no longer an
with higher risk of premature birth [24]. appropriate measure for disease activity. However, ESR
The PROMISSE study (Predictors of Pregnancy Out- values over 50 mm/h cannot be explained by pregnancy
come: Biomarkers in APL Syndrome and SLE), amulti- and should raise concern for the obstetrician. Moreover,
centric, prospective trial that enrolled 492 pregnant the complement levels are increased because estrogens
women with SLE, showed the occurrence of severe enhance its hepatic synthesis; therefore, if the disease is
adverse pregnancy outcomes (pre-eclampsia before not very active, the serum complement can be normal in
the gestational age of 34-weeks, fetal/neonatal death, pregnant SLE patients. Nevertheless, decreased comple-
abortion, premature birth before 30 weeks of gestation) ment levels are suggestive for an increased risk of pre-
in 12% of patients and moderate adverse pregnancy mature birth (only 16% of pregnant women with SLE and
outcomes (pre-eclampsia after the gestational age of decreased complement levels have aterm delivery) [25].
34-weeks, premature birth between 30 and 36 weeks Renal function and urinalysis should be assessed on
of gestation, or intrauterine growth restriction) in 10% amonthly basis in SLE pregnant women, and any suspi-
of cases [18]. Moreover, the study led to the identifica- cion of renal involvement should be confirmed by mea-
tion of certain biomarkers circulating angiogenic fac- suring proteinuria over 24 hours.
tors (soluble fms-like tyrosine kinase, soluble endoglin), Pre-eclampsia is acomplication of pregnancy occur-
which were associated with severe adverse events. ring in 20% of pregnant women with SLE, compared to 7%
The normal pregnancy course in SLE patients can be in patients without this disease [25]. It is more common
affected by factors linked to the clinical and biological in patients with lupus nephropathy. This complication
activity of the disease during the previous 612 months is sometimes difficult to distinguish from an SLE flare,
before conception (especially renal function, serum lev- since both clinical entities have multiple similar traits:
els of complement, anti-dsDNA Ab); therefore, planning proteinuria, arterial hypertension, persistent elevated
the pregnancy and choosing the most appropriate tim- BUN, edemas, and thrombocytopenia. There are cases
ing are of paramount importance. Hence, previous renal when both conditions can be present at the same time
dysfunction is associated with ahigh rate of maternal [22]. The diagnosis of pre-eclampsia is more probable
complications, antiphospholipid Ab are associated with when the onset of proteinuria occurred after 20 weeks
an increased risk of spontaneous abortion and anti-Ro of gestation, in cases with isolated proteinuria without
and anti-La Ab are predictive for the risk of neonatal other alterations of urinalysis, in cases with seizures and

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34 Andra Blnescu, Teodora Donisan, Dinu Blnescu

in patients with previous pre-eclampsia. Furthermore, Treatment of patients with rheumatic disease be-
many of the clinical signs of SLE are absent in pre-ec- fore/during pregnancy and lactation should aim to
lampsia, such as arthritis and cutaneous involvement; prevent or suppress disease activity in the mother
on the other hand, pre-eclampsia is more commonly as- and expose the fetus/child to no harm.
sociated with HELLP syndrome, increased serum levels The risk of drug therapy for the child should be
of uric acid or decreased urinary calcium levels. Protein- weighed against the risk that untreated maternal
uria with hematuria and urinary casts, decreased serum disease represents for the patient and the fetus or
complement levels (C3 and C4), and positive anti-nuclear child.
antibodies are more suggestive for lupus nephritis. The decision on drug therapy during pregnancy and
Presence of anti-dsDNA Ab in pregnant women with lactation should be based on agreement between
SLE is associated with renal dysfunction and an increased the internist/rheumatologist, gynecologist/obstetri-
risk for premature delivery. SS-Aand anti-Ro antibodies cian and the patient, and including other healthcare
are present in 30% of SLE cases and in Sjgren syndrome providers when appropriate.
[27]. These Ab are important because they are associated Based on this analysis, EULAR divided the antirheu-
with certain subtypes of the disease (subacute cutane- matic drugs into the following categories:
ous lupus) with some particular clinical manifestations Antirheumatic drugs proven compatible with preg-
(photosensitivity), and especially with neonatal lupus. nancy, which should be continued in pregnancy for
SS-B or anti-La Ab (also identified in Sjgren syndrome) maintenance of remission or treatment of adisease
are always accompanied by the previously mentioned flare:
Ab: they can be identified in 15% of patients and are hydroxychloroquine, chloroquine, sulfasalazine,
usually missing in those with nephropathy. Anti-Ro and azathioprine, cyclosporine, tacrolimus
anti-La Ab must be tested before and during pregnancy: Drugs with teratogenic effect which should be with-
if the results are positive, afetal echocardiogram must drawn before pregnancy:
be performed weekly during weeks 1624 of gestation. methotrexate, mycophenolate mofetil and cyclo-
Anti-cardiolipin Ab are associated with an increased risk phosphamide
of abortion or premature birth; therefore, they must be Drugs which can be considered in pregnancy if
monitored carefully throughout the pregnancy [28]. needed to control active disease symptoms
NSAIDs should be restricted to the first and second
Pregnancy monitoring trimesters
corticosteroids in low doses
EULAR recommendations also include pregnancy
monitoring. Women with SLE and/or APS should under- Drugs which should be considered only in severe,
go supplementary fetal surveillance with Doppler ultra- refractory maternal disease during pregnancy:
sonography and biometric parameters, particularly in methylprednisolone pulses, intravenous immuno-
the third trimester to screen for placental insufficiency globulin, or second or third trimester use of cyclo-
and small for gestational age fetuses [2]. phosphamide
Fetal echocardiography is recommended in cases of Drugs with insufficient documentation concerning
suspected fetal dysrhythmia or myocarditis, especially use in pregnancy, which should be avoided until fur-
in patients with positive anti-Ro/SSA and/or anti-La/ ther evidence is available:
SSB Ab, when supplementary fetal surveillance between leflunomide, selective COX-2 inhibitor, belimumab.
week 16 and week 24 is recommended [2, 27]. Generally, the types of medications used in SLE
which can be considered during pregnancy are NSAIDs,
corticosteroids, immunosuppressive agents, and biolog-
Systemic lupus erythematous treatment
ical agents [30].
during pregnancy NSAIDs are widely used in less severe cases, char-
In 2016, EULAR published an extensive analysis of acterized mainly by serositis and cutaneous or articular
the data associated with the use of antirheumatic drugs manifestations. An increasing trend in the number of
during pregnancy and breastfeeding. In this paper, abortions has been reported in women who have used
EULAR defined 4 overarching principles which should NSAIDs around the time of conception. Acetaminophen
guide the therapy in such situations [29]. These princi- and aspirin are the most used NSAIDs during pregnancy.
ples are as follows: Since these two drugs cross the placenta, they can in-
Family planning should be addressed in each pa- hibit prostaglandin synthesis and are occasionally asso-
tient of reproductive age and adjustment of therapy ciated with premature closure of the ductus arteriosus
considered before aplanned pregnancy. and fetal pulmonary hypertension. Therefore, aspirin

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An ever-challenging relationship: lupus and pregnancy 35

and other NSAIDs should be used in lower doses than can cause fetal growth restriction, prematurity, transient
usual and should be avoided during the last trimester. neonatal immunosuppression, leukopenia or pancyto-
However, lately, it is recommended that low doses of as- penia, and ovarian follicle disorders in female neonates,
pirin should be administered throughout the pregnancy with alater impact on fertility. There is no increased rate
because it can have positive effects for the mother by of spontaneous abortion in patients treated with aza-
preventing arterial hypertension and pre-eclampsia [31]. thioprine.
Many studies have proven that aspirin has no terato- Hydroxychloroquine is safe during pregnancy, as it
genic effects. In high doses, it can cause prolonged labor, is not associated with an increased rate of congenital
peripartum anemia and neonatal hemorrhage. Because malformations [10]. However, isolated cases of ocular
of the limited data available so far about the use of COX-2 (retinal pigment deposits) and auditory abnormalities,
specific NSAIDs, it is recommended to avoid their use mental retardation and spontaneous abortions have
during pregnancy. been reported. Continuation of hydroxychloroquine
Corticosteroids are the main therapy for pregnant treatment if the patient became pregnant is widely ac-
women with SLE, in severe cases, with renal or neuro- cepted, even though the disease might be in remission.
logical involvement, where high doses (11.5 mg/kgc/ Moreover, withdrawal of hydroxychloroquine is consid-
day) or pulse-therapy with methyl-prednisolone may be ered arisk factor for pregnancy [12]. HCQ may reduce
needed. Prophylaxis with prednisone is not necessary if the odds of CHB occurrence in fetuses exposed to ma-
the patient is in remission. The risk of cortico-adrenal ternal anti-Ro/SSA Ab, especially in mothers who have
insufficiency caused by the suppression of the hypo- already had achild with congenital heart block [2].
thalamic-pituitary-adrenal axis in the fetus is relatively Other immunosuppressive drugs, such as cyclo-
low, because most corticosteroids are metabolized by phosphamide, mycophenolate mofetil, methotrexate,
specific enzymes from the placenta into inactive prod- chlorambucil, and cyclosporine, may cause fetal abnor-
ucts; therefore, the fetal levels reach only 10% of the malities and are contraindicated in pregnant women.
maternal plasmatic levels. Only the fluorinated corti- Biological agents: The only biological agent approved
costeroids (e.g. dexamethasone, betamethasone) can currently for SLE treatment is belimumab (humanized
cross the placenta and end up in the fetal blood stream. monoclonal Ab anti-BLyS/BAFF, which inhibits B-lympho-
Hence, these drugs should be chosen if the patient to cyte activation). Experimental studies performed in mon-
be treated is the fetus (e.g. in cases of atrioventricular keys showed that belimumab has no teratogenic effects
block). Doses up to 20 mg/day of prednisone are consid- and does not cause other adverse events, although it cross-
ered to be safe. Methylprednisolone can also be consid- es the placenta and may cause adecrease in the count of
ered during pregnancy, because the rate of its placental B-lymphocytes in babies. Because there are no data avail-
transfer is similar to prednisone and it has asimilar rate able about the safety in humans, belimumab is currently
of placental transfer [32]. contraindicated for pregnant women with SLE [10].
Pregnant patients receiving corticotherapy should Research is currently underway to identify the best
be monitored regularly, because they may have ahigher treatment for the pregnant patient with APS. Lately,
rate of pre-eclampsia, gestational diabetes, hyperten- corticotherapy has been replaced by aform of antico-
sion, premature rupture of membranes, fetal growth agulant or antiplatelet therapy [19]. Current discussions
retardation and infections [3]. No cases of congenital regard the use of aspirin, heparin, or both. Administra-
malformations have been reported in exposed fetus- tion of low doses of aspirin has decreased the rate of
es, except very rare cases of cleft lip [10]. Supplemen- abortion in patients with APS. However, aspirin is not
tal cortisone should be administered before delivery in sufficient for those with previous thrombo-embolism or
patients who have received chronic corticotherapy, in pre-eclampsia; in such cases, it is recommended to use
order to prevent an Addisonian crisis during labor and in addition an anticoagulant agent, e.g. low molecular
delivery. After birth, the tapering of cortisone should be weight heparins (LMWH). Still, the ability of LMWH to
performed with caution, because of the high risk of dis- prevent recurrent abortions in patients with previous
ease flare. miscarriages remains to be proven [22]. Even in patients
Azathioprine is the only immunosuppressive agent al- with thrombophilia, there is much debate around the
lowed during pregnancy, in daily doses below 2 mg/kgc positive effect of LMWH on the pregnancys outcome.
[32]. This treatment should be reserved for severe cases, Oral anticoagulant agents cannot be used because they
where corticotherapy was ineffective or contraindicated can impair the development of the fetus, especially in
[10]. This drug crosses the placenta and is transformed weeks 612 of gestation. Therefore, women who were
into an inactive metabolite, thiouric acid. Therefore, aza- receiving oral anticoagulants before pregnancy must be
thioprine has minimal effects on the fetus, although it switched to subcutaneous heparin.

Reumatologia 2017; 55/1


36 Andra Blnescu, Teodora Donisan, Dinu Blnescu

The most difficult aspects of lupus therapy during ahealthy baby) outcomes. Planning should take into
pregnancy are related to the treatment of disease flares; account the individual risk factors for the mother and
usually, in such circumstances, amultidisciplinary team the baby and should be followed by careful clinical, bi-
including agynecologist, rheumatologist, and neonatol- ological and therapeutic monitoring, before and during
ogist must be involved. pregnancy and in the perinatal period, performed by an
experienced multidisciplinary team.
Breastfeeding in systemic lupus
erythematous
The authors declare no conflict of interest..
Traditionally, breastfeeding has been considered
atrigger for SLE flares. However, recent data have shown References
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