Pregnancy and Systemic Lupus Erythematosus: at a Single Institution

Clinic Rev Allerg Immunol (2010) 38:302–306
DOI 10.1007/s12016-009-8161-y
Pregnancy and Systemic Lupus Erythematosus:
Review of Clinical Features and Outcome of 51 Pregnancies
at a Single Institution
Graziela Carvalheiras & Pedro Vita & Susana Marta & Rita Trovão & Fátima Farinha &
Jorge Braga & Guilherme Rocha & Isabel Almeida & António Marinho &
Teresa Mendonça & Paulo Barbosa & João Correia & Carlos Vasconcelos
Published online: 15 July 2009
# Humana Press Inc. 2009
Abstract Systemic lupus erythematosus (SLE) is mainly a
disease of fertile women and the coexistence of pregnancy
is by no means a rare event. How SLE and its treatment
affects pregnancy outcome is still a matter of debate.
Assessment of the reciprocal clinical impact of SLE and
pregnancy was investigated in a cohort study. We reviewed
the clinical features, treatment, and outcomes of 43
pregnant SLE patients with 51 pregnancies followed from
1993 to 2007 at a tertiary university hospital. The age of
patients was 28.7±5.4 years and SLE was diagnosed at age
of 23.0±6.1 years. Previous manifestations of SLE included
lupus nephritis (14 patients) and secondary antiphospholipid syndrome (11 patients). Thirty-five pregnant patients
(69%) were in remission for more than 6 months at the
onset of pregnancy. Patients were being treated with low
G. Carvalheiras (*) : P. Vita
Serviço de Medicina, Centro Hospitalar do Porto,
Hospital Santo António,
Porto, Portugal
e-mail: [email protected]
S. Marta : R. Trovão : J. Braga
Serviço de Obstetrícia, Centro Hospitalar do Porto,
Hospital Santo António,
Porto, Portugal
F. Farinha : I. Almeida : A. Marinho : T. Mendonça : P. Barbosa :
J. Correia : C. Vasconcelos
Unidade de Imunologia Clínica, Centro Hospitalar do Porto,
Hospital Santo António,
ICBAS,
Porto, Portugal
G. Rocha
Serviço de Nefrologia, Centro Hospitalar do Porto,
Hospital Santo António,
Porto, Portugal
doses of prednisone (29), hydroxychloroquine (20), azathioprine (five), acetylsalicylic acid (51), and low molecular
weight heparin (13). Sixteen pregnancy-associated flares
were documented, mainly during the second trimester
(42%) and also in the following year after delivery (25%).
Renal involvement was found in 11 cases (68%). Spontaneous abortion occurred in 6%, 16% had premature
deliveries, and 74% were delivered at term. No cases of
maternal mortality occurred. No cases of fetal malformation
were recorded. There was one intrauterine fetal death and
one neonatal death at 24 gestational weeks. Pregnant
women with SLE are high risk patients, but we had a
90% success rate in our cohort. A control disease activity
strategy to target clinical remission is essential.
Keywords Systemic lupus erythematosus . Pregnancy .
Flare . Maternal outcome . Fetal outcome
Introduction
Systemic lupus erythematosus (SLE) is mainly a disease of
the fertile women and the coexistence of pregnancy is by no
means a rare event.
Women suffering from SLE appear not to have a reduced
fertility, which is generally only present due to the drugs, or
their dosing, especially cyclophosphamide, which can
induce ovarian failure [1, 2]. However, pregnancies occurring in patients with SLE are considered at high risk. The
management of pregnancy in SLE should start before
conception so as to optimize maternal health. The disease
is not itself a contraindication to pregnancy, with the
exception of organ-system complications such as pulmonary hypertension and renal failure [3].
Clinic Rev Allerg Immunol (2010) 38:302–306
The impact of pregnancy on SLE activity has been
debated in literature, but the majority of studies endorse an
increase in disease activity during pregnancy. In some
patients, this will mean a dramatic worsening of symptoms
that can be life threatening, and treatment itself is limited by
pregnancy. Most patients, however, will have a modest
increase in symptoms making pregnancy uncomfortable but
not affecting their long-term survival [4, 5].
Pregnancies for patients with lupus have a greater risk of
fetal loss, preterm delivery, pre-eclampsia, intrauterine
growth retardation, and neonatal lupus syndrome [6, 7].
Increased lupus activity, particularly before conception and
early in pregnancy, significantly increases the risks for
these complications. For this reason, timing pregnancy to
coincide with a period of SLE quiescence is a worthy goal
[4].
We conducted a retrospective review of all pregnant
women with SLE who were followed in our center from
1993 through 2007. The purpose of this study was to assess
the reciprocal clinical impact of SLE and pregnancy.
303
Internal medicine and obstetrics management protocol
General management guidelines for standard of care in
pregnant SLE patients are used in our institution and were
applied, as possible, to all patients in this study. Pregnancy
should be planned after at least 6 months remission of SLE.
A preconceptional consultation is mandatory. Frequent
consultation of obstetrics and internal medicine for precocious detection of SLE flares, pre-eclampsia, gestational
diabetes, intrauterine growth retardation (IUGR), congenital
heart block, and risk assessment for spontaneous preterm
delivery. Serial ultrasound with Doppler and fetal echocardiography were preformed weekly from 16 to 26 weeks of
gestation and biweekly from 26 to 32 weeks of gestation.
Serial monitoring of hematological and immunological parameters are frequent. Low dose acetylsalicylic acid was introduced as soon as pregnancy was documented if not already
prescribed. Anticoagulation with low molecular weight heparin used in all patients with antiphospholipid syndrome (APS).
There is a low threshold for admitting patients and
programmed delivery to take place at 37 to 38 weeks of
gestation as well as an early reevaluation in puerperium.
Materials and methods
Assessment of SLE flare
Patients
We retrospectively reviewed the medical records of 51
consecutive pregnancies in 43 SLE patients from January
1993 to December 2007, regarding the clinical features,
treatment, and outcomes, in a tertiary university hospital
(Hospital Geral de Santo António, Porto, Portugal). These
patients belong to the Hospital Santo Antonio lupus cohort,
which includes more than 400 patients, and is one of the
largest in Portugal. All patients met at least four of the 1997
Revised American College of Rheumatology criteria for
SLE [25]. Each pregnancy was counted as a separate
observation. Baseline maternal information included age,
past obstetric history, duration of SLE, previous and current
manifestations of SLE, previous diagnosis of antiphospholipid syndrome, and medications. Active disease at conception was defined as the use of >10 mg of prednisone daily,
the use of any immunosuppressive agent, or an SLE
Disease Activity Index (SLEDAI) score ≥2 [26]. Baseline
laboratory data included: hematological parameters (hemoglobin, red and white cell and platelet counts, and
erythrocyte sedimentation rate), serum levels of creatinine,
urinalysis including microscopy, and 24-h urine collection
for measurement of total proteinuria. Immunological evaluation included: antinuclear antibodies, double-stranded
DNA antibodies, anti-Ro/SS-A and anti-La/SS-B antibodies, anti-cardiolipin (aCL) and anti-β2 glycoprotein antibodies, lupus anticoagulant test, and C3 and C4
complement components.
Patients were also assessed for disease flare, defined with
the use of criteria from the Safety of Estrogen in Lupus
Erythematosus National Assessment (SELENA) trial. Mild/
moderate flare included new or worsened cutaneous
disease, nasopharyngeal ulcers, pleuritis, pericarditis, arthritis, fever attributable to SLE, the addition of nonsteroidal
anti-inflammatory drug or hydroxychloroquine, an increase
in prednisone up to a dose of 0.5 mg/kg/day, or an increased
SLEDAI score ≥3. Severe flare was defined as new or
worse central nervous system disease, vasculitis, nephritis,
myositis, hemolytic anemia, platelet count <60,000/μL, the
addition of cyclophosphamide, azathioprine, or methotrexate, hospitalization for SLE-related manifestations, or an
increase prednisone to >0.5 mg/kg/day.
Obstetric assessment
Gestational age of pregnancy loss or delivery was recorded.
Fetal outcomes for live births included birth weight,
prematurity (<37 weeks of gestation), extreme prematurity
(<28 weeks of gestation), 1- and 5-min Apgar scores,
admission to the neonatal intensive care unit, neonatal
lupus rash, and congenital heart block.
Statistical analysis
Statistical analysis was performed using Statistical Package
for Social Sciences, version 16 of the SPSS, Inc. Compar-
304
Clinic Rev Allerg Immunol (2010) 38:302–306
ison of qualitative variables when applied was carried out
using binary and multinomial logistic regression. Statistical
significance was defined as p<0.05.
Results
Patient characteristics
The mean age of our patients was 28.7 ± 5.4 years,
minimum 17 and maximum 42. SLE was diagnosed at
age of 23.0±6.1 years. Previous manifestations of SLE
included: (1) cutaneous and articular in 67% (29 patients),
lupus nephritis in 33% (14 patients), and secondary
antiphospholipid syndrome in 26% (11 patients). Although
patients were advised according to the management
protocol to become pregnant only after at least 6 months
of SLE remission, 14 pregnancies (28%) occurred during
active disease or before completion of 6 months of SLE
remission.
Autoantibodies were positive as follows: antinuclear
antibodies in 48 cases (94%), anti-dsDNA in 22 (43%),
anti-cardiolipin (aCL) in 21 (41%), anti-SS-A in 12 (24%),
anti-beta2-glicoprotein in ten (20%), anti-SS-B in two
(4%), and anti-RNP in one (2%). Low complement was
found in 22 cases (43%).
Patients were being treated with low doses of prednisone
less that 10 mg/day (29), hydroxychloroquine (20), azathioprine (five), low dose acetylsalicylic acid (51), and low
molecular weight heparin twice a day (13).
SLE pregnancy-associated flares
Sixteen pregnancy-associated flares (31%) were documented and the systems involved are shown in Table 1.
There were no significant associations with flare severity:
four (25%) were mild, five (31%) were moderate, and
seven (44%) were severe. Flares occurred mainly during the
second trimester (42%) and also in the following year after
delivery (25%), as shown in Table 2.
Renal involvement was the most frequently found, being
reported in 11 cases (68%). Previous renal involvement was
present in six of these cases and seems to increase the risk of
Table 1 Systems involved in SLE flare
Manifestations
Pregnancies
Percent of flares
Renal
Severe thrombocytopenia
Catastrophic APS
Neurologic (convulsions)
Cutaneous
11
2
1
1
1
69%
13%
6%
6%
6%
Table 2 Distribution of the 16 flares during and after pregnancy
Period
No. of flares
Percent
1st trimester
2nd trimester
3rd trimester
Puerperium
Until 1 year after childbirth
1
7
3
1
4
8%
42%
17%
8%
25%
renal flare (3.8 times), although not significant (p=0.069)
due to the reduced sample size.
We found as possible flare-associated predictors the
treatment with azathioprine (hazard ratio of 9.1, p=0.010)
and prednisolone (hazard ratio of 7.3, p=0.018).
Pregnancy outcome
No cases of maternal mortality were recorded. Spontaneous
abortion occurred in 6%, 16% had premature deliveries,
and 74% were delivered at term (Table 3). There was one
intrauterine fetal death and one neonatal death due to
prematurity; both at 24 gestational weeks, but no cases of
fetal malformation were recorded. No significant associations
between SLE manifestations and pregnancy outcome or
between autoantibodies and pregnancy outcome were found.
Neonatal lupus syndrome
Two cases of neonatal lupus syndrome occurred. One case
of first degree heart block in a newborn whose mother was
anti-SS-B positive and one case of photosensitive rash
interpreted as cutaneous manifestation of lupus.
Discussion
The hormonal and physiologic changes that occur in
pregnancy can induce lupus activity. Likewise, the increased inflammatory response during a lupus flare can
cause significant pregnancy complications. Many of the
signs and symptoms that occur during pregnancy can be
easily mistaken for signs of active SLE. Symptoms such as
severe fatigue, melasma, post-partum hair loss, increased
shortness of breath, arthralgias, and headaches frequently
accompany normal pregnancy, and could be difficult to
distinguish from SLE flare [4, 5].
Recent prospective studies showed a favorable outcome
in SLE pregnant women [8–10]. They include a different
selection of patients with SLE than those included in
retrospective studies, mainly those with less severe disease.
In most of our patients, the disease was clinically
inactive at conception and this fact may explain the
Clinic Rev Allerg Immunol (2010) 38:302–306
Table 3 Pregnancy outcomes
305
Outcome
No. of pregnancies
Percent
Spontaneous abortion (1st trimester)
Medical interruption
Intrauterine fetal death
Premature deliveries
Medical indication
Spontaneous
Delivered at term
3
1
1
6%
2%
2%
6
2
38
12%
4%
74%
discrepancy with studies including a predominance of
patients with more severe and chronic manifestations of
SLE and showing flare rates as high as 60% [11, 12].
To minimize the risk of flare during pregnancy, the
disease should be inactive for at least 6 months prior to
conception [3].
The mother needs to be followed up regularly after
delivery because of the high risk of post-partum flare [5].
Renal flares are more common in those who had active
disease at conception than those in remission [3, 13]. The
pre-existence of lupus nephritis is an important risk factor.
Pregnancy outcome is especially affected by renal disease,
and even inactive renal lupus is associated with increased
risk of fetal loss, pre-eclampsia, and intrauterine growth
restriction [1, 14, 15]. Differentiating lupus flares from
pregnancy-related physiological changes or active lupus
nephritis from pre-eclampsia often poses a challenge to the
physician, although it should be noted that the two may
coexist. Features that suggest a renal flare include a rise in
anti-dsDNA antibodies, low or dropping complement
levels, clinical evidence of a lupus flare in other organs,
and active urinary sediment. Pre-eclampsia is suggested by
rising uric acid and liver enzyme levels in the presence of
inactive urinary sediment. Despite these indicators, it is not
always possible to differentiate between a lupus nephritis
flare and pre-eclampsia. The treatment of these two
conditions is different: pre-eclampsia will remit with
delivery of the fetus, but active SLE will require immunosupression [3–5].
It is now well established that the presence of antiphospholipid antibodies (aPL), namely the lupus anticoagulant (LA) and anti-cardiolipin antibodies (aCL), are
important risk factors for abortion in both SLE and nonSLE patients [16, 17]. However, if appropriately managed,
the antiphospholipid syndrome is “one of the few tractable
causes of pregnancy losses” [18]. Clinical evidence clearly
favors the use of antiaggregant/anticoagulant agents, mainly
aspirin and heparin, to prevent aPL-associated miscarriages
[19].
There are very few data about the long-term outcome of
children born to patients with aPL. An increased occurrence
of learning disabilities was already reported in children
born from SLE patients, and aPL might be considered at
least part of the pathogenic factors responsible for them
[18].
Concerning medical therapy, only cyclophosphamide,
mycophenolate mofetil, methotrexate, and leflunomide are
totally contraindicated drugs both in pregnancy and
lactation because of their teratogenicity and embryotoxicity.
Minimal data on cyclosporine and TNF alpha inhibitors
during pregnancy limit their use during pregnancy, whereas
azathioprine may be continued in pregnant patients on the
basis of recent data. Hydroxychloroquine should not be
stopped in early pregnancy, because this could precipitate a
flare, and its long half-life means the fetus would continue
to be safely exposed to the drug for several weeks, even
after discontinuation. Only one of 20 patients in our study
on hydroxychloroquine stopped taking the drug. That
patient had an intrauterine fetal death at 24 gestational
weeks. The dose of prednisolone should ideally be kept at
10 mg daily or less because of increased risk of maternal
hypertension, pre-eclampsia, gestational diabetes, and infection [4–6, 18, 20, 21]. There is no evidence that flares,
which generally respond to prednisone therapies, could be
prevented by a steroid prophylaxis. Some authors
recommend the use of prednisone throughout pregnancy
for all pregnant lupus patients [22, 23], but others disagree
[3, 14, 21].
Neonatal lupus syndrome is associated with maternal
anti-Ro/SS-A and anti-La/SS-B antibodies. It may occur in
the offspring of women with these conditions, regardless of
their clinical diagnosis and even if the mother is asymptomatic. Congenital heart block occurs between 18 and
30 weeks, and fetal echocardiography should be performed
over this period to enable early detection. This irreversible
complication occurs in 2% of fetuses of women with the
anti-Ro antibody, with a recurrence rate of 16% in
subsequent pregnancies [24]. Also, cholestatic hepatitis,
cytopenias, and photosensitive rash are grouped under the
heading of “neonatal lupus syndrome”. Those aspects are
usually transient, and are also linked to anti-Ro antibodies
[5, 18, 21]. Two cases of neonatal lupus were registered:
one with congenital heart block and the other with
photosensitive rash.
306
Conclusion
With improvements in diagnosis and treatment, the prognosis of patients with SLE has generally improved in recent
years. Similarly, the outlook for women who become
pregnant in the setting of this disorder is far more optimistic
than it was in the past. However, the risk of significant
morbidity to both the mother and the fetus still exists.
Management of SLE in pregnancy is a multidisciplinary
effort including an internist, an obstetrician with experience
in management of patients with SLE, and, if indicated by
the patient’s renal status, a nephrologist. It is essential that
the maternal disease is well controlled prior to, during, and
after pregnancy to ensure the best possible outcome for the
mother and child.
References
1. Mecacci F, Pieralli A, Bianchi B, Paidas MJ (2007) The impact of
autoimmune disorders and adverse pregnancy outcome. Semin
Perinatol 31:223–226
2. Chakravarty EF, Colón I, Langen ES, Nix DA et al (1982) Factors
that predict prematurity and preeclampsia in pregnancies that are
complicated by systemic lupus erythematosus. Am J Obstet
Gynecol 142:159–164
3. Khamashta MA (2006) Systemic lupus erythematosus and
pregnancy. Best Pract Res Clin Rheumatol 20(4):685–694
4. Clowse MEB (2007) Lupus activity in pregnancy. Rheum Dis
Clin N Am 33:237–252
5. Gordon C (2004) Pregnancy and autoimmune diseases. Best Pract
Res Clin Rheumatol 18(3):359–379
6. D’Cruz DP, Khamashta MA, Hughes GRV (2007) Systemic lupus
erythematosus. Lancet 369:587–596
7. Ruiz-Irastorza G, Khamashta MA (2004) Evalution of systemic
lupus erythematosus activity during pregnancy. Lupus 13:679–682
8. Tincani A, Faden D, Tarantini M et al (1992) Systemic lupus
erythematosus and pregnancy: a prospective study. Clin Exp
Rheumatol 10:439–446
9. Lima F, Buchanam NM, Khamashta MA, Kerslake S, Hughes
GRV (1995) Obstetric outcome in systemic lupus erythematosus.
Semin Arthritis Rheum 25:184–192
10. Laskin CA, Clark C, Sptitzer KA. Decrease in pregnancy loss
rates in systemic lupus erythematosus over a 40-year period. Fertil
Steril—Abstracts 2005;84(1):S445–S446.
Clinic Rev Allerg Immunol (2010) 38:302–306
11. Nossent HC, Swaak TJG (1990) Systemic lupus erythematosus
VI. Analysis of the interrelationship with pregnancy. J Rheumatol
17:771–776
12. Petri M, Howard D, Repke J (1991) Frequency of lupus flare in
pregnancy. The Hopkins Lupus Pregnancy Center experience.
Arthritis Rheum 34:1538–1545
13. Moroni G, Quaglini S, Banfi G et al (2002) Pregnancy in lupus
nephritis. Am J Kidney Dis 40:713–720
14. Cervera R, Font J, Carmona F, Balasch J (2002) Pregnancy
outcome in systemic lupus erythematosus: good news for the new
millennium. Autoimmunity Reviews 1:354–359
15. Tandon A, Ibanez D, Gladman DD, Urowitz MB (2004) The
effect of pregnancy on lupus nephritis. Arthritis Rheum 50:3941–
3946
16. Cervera R, Font J, López-Soto A, Casals F et al (1990) Isotype
distribution of anticardiolipin antibodies in systemic lupus
erythematosus. Prospective analysis of a series of 100 patients.
Ann Rheum Dis 49:109–113
17. Cervera R, Piette JC, Font J et al (2002) Antiphospholipid
syndrome: clinical and immunologic manifestations and patterns
of disease expression in a cohort of 1000 patients. Arthritis
Rheum 46:1019–1027
18. Ticani A, Rebaioli CB, Frassi M et al (2005) Pregnancy and
autoimmunity: maternal treatment and maternal disease influence
on pregnancy outcome. Autoimmunity Reviews 4:423–428
19. Silveira LH, Hubble CL, Jara LJ et al (1992) Prevention of
anticardiolipin antibody-related pregnancy losses with prednisone
and aspirin. Am J Med 93:403–411
20. Khanna D, McMahon M, Furst DE (2004) Safety of tumor
necrosis factor-alpha antagonists. Drug Saf 27:307–324
21. Meyer O (2004) Making pregnancy safer for patients with lupus.
Jt Bone Spine 71:178–182
22. Petri M, Howard D, Repke J et al (1992) The Hopkins Lupus
Pregnancy Center: 1987–1991 update. Am J Reprod Immunol
28:188–191
23. Lockshin M, Reinitz E, Druzin ML et al (1984) Lupus pregnancy:
a case–control prospective study demonstrating absence of lupus
exacerbations during or after pregnancy. Am J Med 77: 893–889
24. Brucato A, Frassi M, Franceschini F et al (2001) Risk of
congenital complete heart block in newborns of mothers with
anti-Ro/SSA antibodies detected by counterimmunoelectophoresis: a prospective study of 100 women. Arthritis Rheum 44:1832–
1835
25. Hochberg MC (1997) Updating the American College of
Rheumatology revised criteria for the classification of systemic
lupus erythematosus. Arthritis Rheum 40:1725
26. Bombardier C, Gladman DD, Urowitz MB et al (1992)
Derivation of the SLEDAI. A disease activity index for lupus
patients. The Committee on Prognosis Studies in SLE. Arthritis
Rheum 35:630–40