Introduction
General Aspects
Systemic lupus erythematosus (SLE) is an autoimmune and multisystemic disorder of
the connective tissue that mainly affects women of childbearing age (about nine women
for each man). Immune anomalies, particularly the production of a series of antinuclear
antibodies, are another prominent feature of the disease.[1]
The SLE prevalence varies from 40 to 200 cases per 100,000 inhabitants, more common
among Africans and Asians descendants. In Brazil, its prevalence is around 8.7 per
100,000 inhabitants.[1]
[2]
The broad spectrum of clinical presentations includes mucous-cutaneous, muscle-skeletal,
hematological, cardiopulmonary, renal and central nervous system manifestations. The
most severe forms of organ involvement are lupus nephritis and neuropsychiatric lupus,
and these conditions may result in a significant reduction in life expectancy.[1] Lupus nephritis is one of the leading causes of death along with infections.[3]
The most common general symptoms are weight loss, anemia, arthralgia and/or arthritis,
being the involvement of the osteoarticular system the most frequent clinical manifestation.[1] Antiphospholipid syndrome can occur in association with SLE, and it is characterized
by arterial and venous thromboses, as well as recurrent morbidity in pregnancy.[4]
The American College of Rheumatology (ACR) proposed the criteria for the diagnosis
of SLE ([Table 1]).[5] To be classified as SLE, at least four criteria should occur in series or simultaneously.[1]
[4]
[6]
Table 1
American College of Rheumatology (ACR) criteria for the classification of systemic
lupus erythematosus
|
1.
|
Erythema malar.
|
|
2.
|
Discoid lupus.
|
|
3.
|
Photosensitivity.
|
|
4.
|
Oral ulcers.
|
|
5.
|
Arthritis.
|
|
6.
|
Serositis (pleuritis or pericarditis).
|
|
7.
|
Nephropathy (persistent proteinuria greater than 0.5 g/day and/or glomerular hematuria).
|
|
8.
|
Neurological disorders (convulsion or psychosis).
|
|
9.
|
Hematologic disorders (hemolytic anemia, leucopenia, thrombocytopenia).
|
|
10.
|
Immune disorder (presence of LE cells, anti-DNA or anti-Sm antibodies, false positive
VDRL test, anticardiolipin IgG or IgM antibodies, lupus anticoagulant).
|
|
11.
|
Antinuclear antibody (ANA).
|
Abbreviations: IgG, immunoglobulin G; IgM, immunoglobulin M; LE, lupus erythematosus;
Sm, smith; VDRL, venereal disease research laboratory.
A consensus group of experts on SLE, the Systemic Lupus International Collaborating
Clinics (SLICC), has proposed revised criteria for the diagnosis of SLE ([Table 2]). It requires either that a patient satisfies at least 4 out of 17 criteria, including
at least one of the 11 clinical criteria and one of the 6 immunologic criteria, or
that the patient has biopsy-proven nephritis compatible with SLE and positivity to
antinuclear antibodies (ANA) or anti-double-stranded DNA (dsDNA) antibodies.[7]
Table 2
Systemic lupus international collaborating clinics (SLICC) criteria for the classification
of systemic lupus erythematosus (4 of 17 criteria, including at least one clinical criterion and one immunologic criterion;
OR biopsy-proven lupus nephriti
s
[7]
|
Criterion
|
Clinical criteria
|
|
Acute cutaneous lupus
|
Lupus malar rash (do not count if malar discoid); bullous lupus; toxic epidermal necrolysis
variant of SLE; maculopapular lupus rash; photosensitive lupus rash (in the absence
of dermatomyositis);
OR subacute cutaneous lupus (nonindurated psoriasiform and/or annular polycyclic lesions
that resolve without scarring, although occasionally with postinflammatory dyspigmentation
or telangiectasias)
|
|
Chronic cutaneous lupus
|
Classic discoid rash; localized (above the neck); generalized (above and below the
neck); hypertrophic (verrucous) lupus; lupus panniculitis (profundus); mucosal lupus;
lupus erythematosus tumidus; chilblains lupus; OR discoid lupus/lichen planus overlap
|
|
Nonscarring alopecia
|
Diffuse thinning or hair fragility with visible broken hairs (in the absence of other
causes, such as alopecia areata, drugs, iron deficiency, and androgenic alopecia)
|
|
Oral or nasal ulcers
|
Palate, buccal, tongue, OR nasal ulcers (in the absence of other causes, such as vasculitis, Behçet disease,
infection [herpesvirus], inflammatory bowel disease, reactive arthritis, and acidic
foods)
|
|
Joint disease
|
Synovitis involving two or more joints, characterized by swelling or effusion OR tenderness in two or more joints and at least 30 minutes of morning stiffness
|
|
Serositis
|
Typical pleurisy for more than one day, pleural effusions, or pleural rub, OR
typical pericardial pain (pain with recumbency improved by sitting forward) for more
than one day, pericardial effusion, pericardial rub, or pericarditis by electrocardiography
in the absence of other causes, such as infection, uremia, and Dressler's syndrome
|
|
Renal
|
Urine protein-to-creatinine ratio (or 24-hour urine protein) representing 500 mg protein/24
hours, OR red blood cell casts
|
|
Neurologic
|
Seizures; psychosis; mononeuritis multiplex (in the absence of other known causes,
such as primary vasculitis); myelitis; peripheral or cranial neuropathy (in the absence
of other known causes, such as primary vasculitis, infection, and diabetes mellitus);
OR acute confusional state (in the absence of other causes, including toxic/metabolic,
uremia, drugs)
|
|
Hemolytic anemia
|
Hemolytic anemia
|
|
Leukopenia or lymphopenia
|
Leukopenia (< 4,000/mm3 at least once) (in the absence of other known causes, such as Felty syndrome, drugs,
and portal hypertension), OR lymphopenia (< 1,000/mm3 at least once) (in the absence of other known causes, such as glucocorticoids, drugs,
and infection)
|
|
Thrombocytopenia
|
Thrombocytopenia (< 100,000/mm3) at least once in the absence of other known causes, such as drugs, portal hypertension,
and thrombotic thrombocytopenic purpura
|
|
Immunologic criteria
|
|
ANA
|
ANA level above laboratory reference range
|
|
Anti-dsDNA
|
Anti-dsDNA antibody level above laboratory reference range (or > 2-fold the reference
range if tested by ELISA)
|
|
Anti-Sm
|
Presence of antibody to Sm nuclear antigen
|
|
Antiphospholipid
|
Antiphospholipid antibody positivity as determined by any of the following: Positive
test result for lupus anticoagulant; false-positive test result for rapid plasma reagin;
medium- or high-titer anticardiolipin antibody level (IgA, IgG, or IgM); or positive
test result for anti-β 2-glycoprotein I (IgA, IgG, or IgM)
|
|
Low complement
|
Low C3; low C4; OR low CH50
|
|
Direct Coombs test
|
Direct Coombs test in the absence of hemolytic anemia
|
Abbreviations: ANA, antinuclear antibodies; ELISA, enzyme-linked immunosorbent assay;
SLE, systemic lupus erythematosus.
Systemic Lupus Erythematosus and Pregnancy
Considering the predilection of SLE in affecting women of childbearing age, pregnancy
is of particular importance, with relevant impact in maternal and perinatal health.[8] The incidence of SLE among pregnant women ranges from 1:660 to 1:2.952; therefore,
an understanding on how to manage these patients is essential.[9]
Although advances in the treatment of obstetric complications and improvements in
neonatal care have enabled lupus women to have pregnancies with better outcomes, SLE
persists associated with significant fetal and maternal morbidity.[8] Conditions with elevated levels of estrogen, such as pregnancy, have the potential
to exacerbate SLE. The incidence of disease outbreaks during pregnancy varies between
15 and 63%.[10]
The impact of pregnancy in the course of lupus remains controversial, especially in
relation to the incidence of flares. In contrast, the impact of lupus on gestation
is more clearly understood. Women with lupus are no less fertile; outcomes are characterized
by higher rates of fetal loss, preterm birth, and fetal growth restriction (FGR),
higher incidence of hypertensive disorders and maternal intensive care admission.
Multiple factors have been identified in association with adverse outcomes, such as
lupus activity during pregnancy, previous nephropathy, maternal hypertension, and
positivity for anti-phospholipid antibodies.[8]
Thus, adopting a specific protocol of care for pregnant women with lupus should contribute
to reduce the frequency of maternal and fetal adverse outcomes, directly or indirectly
related to SLE, improving care standards and ensuring successful pregnancies. This
review aims to disclose the existing recommendations on prenatal care among health
professionals attending pregnant women affected by SLE, based on currently available
scientific evidence.
Results
Preconception Orientation
Adequate counselling, planning and care before, during and after the pregnancy must
be the goal of health professionals who look after women with SLE. Luckily, multidisciplinary
units are increasingly integrating different medical specialists (including obstetricians,
immunologists, rheumatologists, hematologists and nephrologists), which may allow
for a more coordinated management of pregnancy along with disease activity.[35]
The care of pregnant women with SLE must focus on three mainstays: a coordinated medical-obstetrical
care, a well-defined management protocol and a well-structured neonatal unit. Preconception
counselling is vital to assess the chance of both potential fetal and maternal complications;
that way, consistent information regarding specific risk for complications and the
expected management plan should be provided ([Table 3]).[35]
Pregnancy planning is a key-point for women with SLE. Postponing conception until
the disease is considered inactive for at least six months significantly improves
the outcomes of these pregnancies.[26]
[31]
[34]
[35] Women who present some form of irreparable organ injury are more likely to undergo
complications and even additional damage during and after pregnancy. Some conditions
should advise to delay pregnancy, such as severe disease flare within the previous
six months, recent stroke and active lupus nephritis.[32] In some situations, pregnancy may be contraindicated ([Table 4]).[26]
[34]
[35]
Table 4
Preconception visit checklist and contraindications to pregnancy in women with SLE[35]
|
Preconception visit checklist
|
Contraindications to pregnancy
|
|
Age?
|
Severe lupus flare within the previous 6 months
|
|
Any previous pregnancy?
|
Severe restrictive lung disease (FVC < 1 L)
|
|
Previous pregnancy complications?
|
Heart failure
|
|
Presence of severe irreversible damage?
|
Chronic renal failure (Cr > 28 mg/dL)
|
|
Recent or current lupus activity?
|
Stroke within the previous 6 months
|
|
Presence of antiphospholipid antibodies/syndrome?
|
Previous severe preeclampsia or HELLP syndrome despite therapy with aspirin and heparin
|
|
Other chronic medical conditions? (Hypertension, diabetes, etc.)
|
Severe pulmonary hypertension (estimated systolic PAP > 50 mm Hg or symptomatic)
|
|
Current treatment: any “forbidden” drugs? (including cyclophosphamide, methotrexate,
mycophenolate, angiotensin converting enzyme inhibitors, angiotensin II receptor blockers,
diuretics and statins)
|
|
|
Positivity of anti-SSA /anti-SSB?
|
|
|
Smoking?
|
Abbreviations: FVC, forced vital capacity; PAP, pulmonary arterial pressure.
At the preconception visit, obtaining a complete set of autoantibody profile is recommended,
including antiphospholipid (aPL) antibodies (anticardiolipin and lupus anticoagulant),
complement serum levels, anti-SSA and anti-SSB antibodies. Evaluating the pregnancy
risk and assessing the SLE activity and the organ function is important to maintain
disease control only in safe medications.[32]
A higher risk of complications is found among women with severe impairment of organ
function, with or without preexisting severe organ damage.[24] Besides, the diagnosis of SLE during pregnancy is also related to the occurrence
of complications, significantly affecting maternal and fetal outcomes.[30]
Prenatal Follow-up
General Findings
The prenatal care of a woman with SLE requires close collaboration between the obstetrician
and the clinicians (rheumatologist, nephrologist or hematologist), and management
in a high-risk referral center. An evaluation by the clinician should occur every
4–6 weeks, whereas the obstetric visit should be every 4 weeks until 20 weeks of gestation;
then, every 2 weeks until 28 weeks, and then, weekly until the expected delivery date.[34]
At every prenatal visit, blood pressure, weight gain, uterine size, fetal heart rate
and urinalysis (through a quick outpatient analysis with the dipstick testing) should
be assessed, as well as inquiring about symptoms related to lupus flares.[34]
The differential diagnosis of complications that may arise during pregnancy is not
easy. Signs and symptoms of lupus flares often mimic the ones of normal pregnancy.
Those flares are less frequent in the third trimester, although they may occur at
any time during pregnancy or in the immediate postpartum period.[34]
Laboratory Evaluation during Prenatal Care
In addition to routine pregnancy booking, blood tests (which include a full blood
count), baseline tests of renal and hepatic function and baseline urinary protein
quantified by a 24-hour collection should be obtained.[24] Complement studies should comprise further tests (C3, C4, CH5O), anticardiolipin
antibodies, anti-dsDNA, lupus anticoagulant and anti-SSA and SSB.
Disease Activity during Prenatal Care (Flares)
Changes in hormonal levels through pregnancy prompt to a shift from Th1 to Th2 lymphocyte
dominance; consequently, autoimmune disorders involving Th2-response, such as SLE,
are expected to flare.[24]
It is generally agreed that pregnancy may lead to higher rates of disease flares,
with rates from 25 to 65% being reported.[18]
[31]
[37] Different organ systems may have variable response to pregnancy; musculoskeletal
flares are less common, whereas renal and hematological flares are more common.[31] The risk of flare seems to be related to the occurrence of disease activity 6–12
months before conception.[15]
[19]
[22]
[24]
[30]
A higher risk of flare during pregnancy is noticed when lupus nephritis occurs at
conception, even in women in remission.[13]
[21]
[24]
[30] One study showed a 30% flare rate during pregnancy or postpartum among 113 pregnancies
in women with preexisting lupus nephritis evaluated; other studies suggest a likelihood
of up to 60%.[24] Besides, different reports in the literature indicate lupus nephritis as a predictive
of poor prognosis for pregnancy.[23]
It may be difficult to distinguish pregnancy-related signs and symptoms from those
of SLE. Therefore, an appropriate assessment by experienced physicians is important.[24]
[37]
[38] Ambiguous manifestations include fatigue, headaches, arthralgia, edema, hair loss,
dyspnea, malar and palmar erythema, anemia and thrombocytopenia. Hence, baseline blood
counts and urinalysis with measurement of proteinuria assessed early in gestation
are helpful to monitor disease status and identify flares.[24]
During pregnancy, liver production of serum C3 and C4 increases, so their levels may
persist within the range of normality in cases of active SLE. Relative variations
are more important, rather than absolute levels, with a drop of ≥ 25% in serum complement
levels suggesting lupus flare.[24]
Pregnancy-specific disease activity scales (such as systemic lupus erythematosus pregnancy
disease activity index [SLEPDAI] and lupus activity index in pregnancy [LAI-P]) have
been developed, but mostly remain as research tools. In practice, the clinical judgment
of an experienced clinician is still considered the gold standard.[25]
[31]
[32] The SLEPDAI scale is a similar instrument to the systemic lupus erythematosus disease
activity index (SLEDAI) for assessment of lupus activity, assigning different scores
for the various clinical and laboratory manifestations of lupus activity, however
taking into account the physiological changes of gestation and the main pathologies
of the pregnancy-puerperal cycle that can mimic SLE in activity. Its score ranges
from zero to 105 and stratifies the disease activity: absent (up to 4 points), mild
to moderate (5–12 points) and severe (up to 12 points) ([Table 5]).[36]
Table 5
Systemic lupus erythematosus pregnancy disease activity index (SLEPDAI) instrument
to stratify SLE activity during pregnancy[36]
|
Score
|
Descriptor
|
Modified for pregnancy
|
Considerations
|
|
8
|
Seizure
|
Yes
|
(r/o eclampsia)
|
|
8
|
Psychosis
|
No
|
|
|
8
|
Organic brain syndrome
|
No
|
|
|
8
|
Visual disturbance
|
No
|
(hypertension is already considered an exclusion in SELENA-SLEDAI and SLEDAI)
|
|
8
|
Cranial nerve disorder
|
Yes
|
(r/o Bell palsy)
|
|
8
|
Lupus headache
|
Yes
|
(r/o Bell palsy)
|
|
8
|
CVA
|
Yes
|
(r/o eclampsia)
|
|
8
|
Vasculitis
|
Yes
|
(consider palmar erythema)
|
|
4
|
Arthritis
|
Yes
|
(consider bland knee effusions)
|
|
4
|
Myositis
|
No
|
|
|
4
|
Urinary casts
|
No
|
|
|
4
|
Hematuria
|
Yes
|
(r/o cystitis and vaginal RBC reflective of placental problems)
|
|
4
|
Proteinuria
|
Yes
|
(r/o eclampsia)
|
|
4
|
Pyuria
|
Yes
|
(r/o infection)
|
|
2
|
Rash
|
Yes
|
(consider chloasma)
|
|
2
|
Alopecia
|
Yes
|
(consider normal postpartum alopecia)
|
|
2
|
Mucosal Ulcers
|
No
|
|
|
2
|
Pleurisy
|
Yes
|
(hyperventilation may be secondary to progesterone, dyspnea secondary to enlarging
uterus)
|
|
2
|
Pericarditis
|
No
|
|
|
2
|
Low complement
|
Yes
|
(complements normally rise during pregnancy)
|
|
2
|
Increased DNA binding
|
No
|
|
|
1
|
Thrombocytopenia
|
Yes
|
(r/o preeclampsia, HELLP syndrome, incidental thrombocytopenia of pregnancy)
|
|
1
|
Leukopenia
|
Yes
|
(consider normal rise of leukocyte count during pregnancy)
|
|
1
|
Fever
|
No
|
|
Abbreviation: CVA, cerebrovascular accident; RBC, red blood cell; r/o: rule out, SELENA-SLEDAI,
safety of estrogens in lupus erythematosus national assessment- systemic lupus erythematosus
pregnancy activity index; SLEDAI, systemic lupus erythematosus pregnancy activity
index.
A recent meta-analysis reported rates ranging from 1.5 to 83% for a lupus nephrites
flare during pregnancy,[33] corroborating with data from previous studies.[38] Thus, it is strongly recommended a close monitoring, with monthly assessments of
disease activity (with special attention to renal function). Besides, the risk of
hypertensive disorders of pregnancy increases in the setting of active lupus nephritis.[14]
[33]
The frequency of preeclampsia varies from 7.5 to 22.5% for all women with SLE.[12]
[15]
[18]
[20]
[39] Lupus renal involvement is often associated with hypertension, and the preeclampsia
diagnosis is difficult, since it may be superimposed on chronic hypertension.[39]
Likewise, in cases of SLE women with glomerular lesions, increased proteinuria may
be observed, due to the enlarged glomerular filtration rate during pregnancy, with
this fact not being related to preeclampsia. Thus, the diagnosis of preeclampsia can
get more difficult because of increasing blood pressure and proteinuria at term.[38]
[39]
The differential diagnosis of preeclampsia in lupus patients may be facilitated by
changes in the measures of C3, C4 and CH50, since a reduction in those levels is expected
during lupus activity.[39] Other laboratory test findings may be helpful to successfully perform a differential
diagnosis: abnormal urinary sedimentation with the presence of erythrocyte dysmorphism
or cell casts and increased anti-DNA antibody titers (all found in lupus nephritis).[23]
New onset SLE during pregnancy can be considered as SLE activity and might be associated
with worse outcome. Differentiating the diagnosis of preeclampsia from new onset SLE
during pregnancy is a challenge and frequently delays the diagnosis of SLE. However,
a Chinese study indicated that new onset SLE during the third trimester of pregnancy
might have a better outcome.[17]
Among patients with stable condition at the time of conception, it is expected that
disease activity will not worsen, and even if so, the flare is usually mild and occasionally
involves some kind of treatment modification.[28]
Evaluation of Fetal Growth and Vitality
Fetal complications are frequently observed in patients with SLE. Overall, miscarriages
and stillbirth may occur in ∼ 20% of pregnancies in SLE patients.[11]
[15]
[26]
[30] Patients with a history of nephritis, in special, have an increased risk for such
adverse outcomes.[14]
[16]
The rate of FGR is estimated to be near of 30%, observed even in mild disease, with
an increased risk if there is renal involvement. Small-for-gestational-age is a more
common outcome in those born prematurely, but can occur at all gestational ages.[20]
[22]
[37]
[39] Several studies concluded that the small-for-gestational-age rate outcome among
SLE women tends to be higher, condition strongly associated to the presence of disease
flare-ups during pregnancy.[23]
Serial obstetric sonography is the most important method to guide surveillance for
fetal growth. Crown–rump length measurement in the first trimester presents as the
most precise measurement. At 16 to 22 weeks of gestation, an anatomic survey considering
diagnosis of fetal anomalies should be followed, also serving to allow the first monitoring
of growth. At each 4-week periods, new scans should take place, with measurement of
amniotic fluid volume. If preeclampsia or FGR are diagnosed, the interval can be reduced
to 3 weeks.[39]
Fetal vitality surveillance is an important part of the prenatal care of SLE patients.
This should include the nonstress test (NST), the biophysical profile (BPP), and fetal
umbilical artery Doppler velocimetry, starting at 26 to 28 weeks and continuing weekly
until birth.[39]
In patients with SLE, alterations of umbilical artery Doppler velocimetry should be
managed similarly to those without the condition. Normal evaluation of these tests
has a high negative predictive value for fetal death.[29] Association between abnormal uterine artery Doppler and later fetal loss, preeclampsia,
FGR and preterm labor were also described.[29]
Because of the risk of fetal congenital heart block, for women with anti-SSA/SSB antibodies,
a fetal echocardiography should be performed at 18–20 weeks and 26–28 weeks to exclude
fetal congenital heart block. An urgent referral to a tertiary care center should
be prompted in case of any fetal heart rate abnormality, mostly a slow heart rate.[24]
Recommended SLE Treatment during Pregnancy
Considering the harmful effects of active disease on both mother and fetus, an appropriate
reflection between the risks and benefits of this treatment must take place.[26]
[30]
In practice, it is frequent that SLE women to discontinue their medication before
conception, due to fear of fetotoxicity, without proper doctor counseling. However,
discontinuation of the medication may lead to active SLE and unfavorable pregnancy
outcomes.[28]
Usually, the immunosuppressive treatment in pregnant women with quiescent lupus should
not be changed. The most frequently used agents in lupus patients are glucocorticoids
and hydroxychloroquine, which should be maintained.[27]
Prednisone at a dosage of 5–10 mg per day is usually considered safe.[27] Lupus flares that fit into mild activity can be treated with low-dose prednisone
(less than 20 mg/d). Higher doses of corticosteroids, including pulse dose steroids,
are options to treat moderate to severe lupus activity.[37]
[38]
Hydroxychloroquine is not a teratogenic drug. Its use is recommended to prevent disease
activity and reduce the risk of cardiac-neonatal lupus in patients who are carriers
of anti-SSA/-antibody.[11]
[27]
[28] In addition, it improves the prognosis of SLE nephritis and prevents death.[38]
Azathioprine is considered safe, especially if compared with other immunosuppressive
drugs. Many studies sustain a transition to this option if the patient wishes to conceive.
However, some other reports recently pointed out concerns about late developmental
delays in children who were exposed to azathioprine during pregnancy,[28]
[38] as well as neonatal leucopenia and/or thrombocytopenia.[27]
Regarding cyclosporine and tacrolimus, the FDA classifies as category C; however,
some meta-analysis studies did not find significant differences related to birth defects
when pregnant women were exposed to them.[27]
[37]
Cyclophosphamide should not be prescribed during the first trimester, because of its
association to chromosomal impairment. During the second or third trimester, it should
be reserved only to severe flares unamenable with methylprednisolone pulses or other
drugs. The use of cyclophosphamide during the second and third trimesters does not
seem to increase the risk for congenital abnormalities. Nevertheless, miscarriages
and preterm birth may be more frequent.[27]
[37]
Leflunomide is associated to teratogenic and fetotoxic effects in animals, and its
metabolite is detectable in plasma up to 2 years after discontinuation. Thus, in pregnant
women, it is formally contraindicated; and pregnancy must be excluded before starting
it.[27]
Methotrexate is another teratogenic drug, classified by the FDA as X (contraindicated
in pregnancy). If used in the first trimester, it is associated to FGR and some major
malformations, such as absence or hypoplasia of the frontal bones, craniosynostosis,
large fontanelle and ocular hypertelorism.[27]
During the first trimester, rituximab has very low transplacental transfer, with some
studies reporting safe pregnancies and deliveries in those cases of exposure. However,
during the second or third trimester, it can cross the placenta and induce severe
neonatal lymphopenia.[27]
[37] Hence, in these cases, live vaccines should be avoided in those children during
the first 6 months of life.[27]
Handling some complications that often affect pregnant women with SLE justifies a
short statement. Since arterial hypertension is a common condition among patients
with lupus nephritis, an appropriate management of blood pressure in pregnancy may
reduce the progression of the disease and avoid several adverse pregnancy outcomes.
Labetalol, nifedipine or methyldopa are safe drugs for treating hypertension. Angiotensin-converting-enzyme
inhibitors should be avoided due to their association to multiple congenital abnormalities.[27]
Low-dose aspirin is recommended, since it reduces the risk of preeclampsia and perinatal
death; besides, it is associated with an increase in the birth weight of those with
risk factors, including renal disease. Full anticoagulation with low-molecular weight
heparin (LMWH) is recommended if there has been a previous thromboembolic event.[27]
Calcium supplementation is required, mainly for those women in use of corticosteroids
and heparin. Supplemental vitamin D does not reduce the risks of unfavorable outcomes.[25]
Delivery Assistance
Women with SLE have an increased risk of preterm delivery. This may occur spontaneously
or because of maternal and/or fetal complications (such as severe lupus flare, preeclampsia
and FGR).[24]
In gestational age between 24 weeks and 34 weeks and 6 days, accelerating of fetal
lung maturation is essential, with two intramuscular steroid injections (preferably,
betamethasone), independently of any maternal steroids administrated before.[24]
Magnesium sulfate should be considered when gestational age is < 32 weeks, due to
its neuroprotective benefits to the fetus. As it is well known, it ought to be administrated
in cases of severe preeclampsia.[24]
The aim in a pregnant SLE patient should be to accomplish a spontaneous labor at term
with vaginal delivery. However, available data have revealed that women with SLE are
more expected to undergo a cesarean section (> 33%; odds ratio [OR] 1.7; confidence
interval [CI] 95% 1.6–1.9). In spite of that, it is recommended that C-sections should
be reserved only for obstetric indications, due to its extra risk factor for venous
thromboembolism (VTE), blood loss and infection, as well as repercussions for future
gestations.[24]
Adjusting maternal medication for labor may be required. Intravenous hydrocortisone
may be necessary to overcome the physiological stress of labor if long-term oral steroids
have been taken. If a woman receives standard prophylactic LMWH, it should be discontinued
at the onset of spontaneous labor, as well as on the night before induced labor or
elective cesarean section. Regional anesthesia (epidural or spinal) can be performed
12 hours after the last LMWH dose.[24]
Postpartum Care
Rigorous monitoring for severe maternal exacerbations is strongly recommended for
those who had anticipated delivery because of a SLE flare or coexisting preeclampsia.
The treatment for postpartum active SLE is similar to that for non-pregnant women.
Nonetheless, it should be noticed that several medications for aggressive therapy
are not recommended during breastfeeding. Thus, the risks and benefits of continuing
breastfeeding must be clarified to the lactating mother.[28]
All women who received antenatal LMWH should continue its use for 6 weeks postpartum,
in a prophylactic dosage, since puerperium is also a period of increased VTE risk.
Afterward, the postpartum VTE risk should be assessed.[24]
In patients with SLE, postpartum counseling to offer safe contraception is particularly
important. Good choices are long-acting reversible contraception (LARC) methods. They
are considered reliable and less dependent on patient commitment.[24] Progestogen-only methods are safe and may become a suitable option.[24]
Estrogen-containing contraceptives must not be used by women with aPL antibodies or
antiphospholipid syndrome (APS), moderate to severe active SLE (including lupus nephritis)
and some other conditions, such as hypertension, smoking, obesity or previous VTE,
since they increase a woman's VTE risk. In cases of well-defined SLE with stable and/or
low-active disease, the use of combined oral contraceptive may be suitable if wished.[24] Barrier methods present a high failure rate (15–32%); thus, they should not be used
as single methods.[24]
Discussion
It is well established that pregnant women with SLE present a higher risk for maternal
complications and pregnancy wastage, in spite of significant progress concerning success
rates lately. During pregnancy, the disease activity may worsen and consequently rise
the risk of other maternal and fetal complications. Therefore, holding an adequate
control of disease activity and treating flares quickly must be a core-objective during
prenatal care. Multidisciplinary care, coordinated by obstetricians and clinicians,
with close monitoring, should allow for early diagnosis of complications.
Considering the data obtained on this review, the disease activity should be systematically
evaluated by SLEPDAI,[25]
[31]
[32]
[36] since it presents as the factor that guides adjustment or change in medication.
All pregnant women with clinical suspicion of active or poorly controlled disease
should be hospitalized due to the severity of the maternal condition and fast deterioration
of fetal vitality conditions that may be associated with this event.[24]
[25]
Regarding the appropriate treatment, prednisone is an immunosuppressant that can be
safely used during pregnancy. The association with gestational diabetes in lupus is
low and is not a limiting factor for the use of medication. However, pregnant women
using high doses should be screened for gestational diabetes.[24] Hydroxychloroquine may be used during gestation, since it is associated with reduced
disease activity.[27]
[40]
[41]
Azathioprine, tacrolimus and cyclosporine could be used as a therapeutic option in
cases resistant to prednisone. Non-steroidal anti-inflammatory drugs, leflunomide,
cyclophosphamide, methotrexate and mycophenolate mofetil should not be prescribed.[27]
[28]
[37]
[40]
[41]
Furthermore, prophylaxis of preeclampsia should be performed with AAS 100mg/d between
12 and34 weeks of gestation and calcium carbonate 1.5 g/d throughout the entire gestational
period.[24]
[40]
We strongly recommend follow-up of fetal growth and vitality with serial sonography
(at least one per trimester), Doppler velocimetry assessment from 26 weeks (repeated
every 2 weeks if normal and weekly if altered), NST from 28 weeks and fetal echocardiography
between 24 and 30 weeks for patients with anti-SSA.[29]
[39]
[42]
Labor delivery must be determined according to obstetric indication and should occur
no later than full-term. In the cases of patients taking corticosteroids at immunosuppressive
dose (1 mg/kg), we recommend prophylactic antibiotics due to the risk of infections
and sepsis.[27]
[31]
Contraceptive counseling may include LARC or progestogen-only methods and surgical
sterilization (with social or medical indication). Combined oral contraceptives present
relative contraindication, considering the risk of VTE.[24]
[40]
After all, it is important to notice that the present study had some limitations:
randomized trials did not integrate this review, which would certainly increase its
degree of evidence. However, it should be emphasized that SLE in pregnancy is a condition
whose incidence is not so high, which could justify the lack of these trials. In addition,
one cannot deny the existence of a publication bias, with often the best results disclosed
to the scientific community.
On the other hand, there are strengths of this study that should be underlined: a
wide variety of studies performed in different countries, with the opinions of several
experts, each with varied backgrounds, were part of this integrative review. Besides,
the lack of available meta-analysis reinforces the importance of including other reviews
made by these specialists.
