Lupus and Pregnancy

Volume 66, Number 10
OBSTETRICAL AND GYNECOLOGICAL SURVEY
Copyright © 2011
by Lippincott Williams & Wilkins

CME REVIEWARTICLE

29

CHIEF EDITOR’S NOTE: This article is part of a series of continuing education activities in this Journal through which a total
of 36 AMA/PRA Category 1 CreditsTM can be earned in 2011. Instructions for how CME credits can be earned appear on the
last page of the Table of Contents.

Lupus and Pregnancy
Alan N. Baer, MD,* Frank R. Witter, MD,†
and Michelle Petri, MD, MPH‡
*Associate Professor, Division of Rheumatology, Department of Medicine, †Professor, Department of
Gynecology and Obstetrics, and ‡Professor, Division of Rheumatology, Department of Medicine,
Johns Hopkins University School of Medicine, Baltimore, MD
Systemic lupus erythematosus (SLE) disproportionately affects women in their reproductive age
years. Pregnancy in this systemic autoimmune disease has long been associated with poor
obstetric outcomes. However, the frequency of pregnancy loss in lupus has dropped to a level
commensurate with that of the general US population. The outcomes of lupus pregnancies are
better if conception is delayed until the disease has been inactive for at least 6 months, and the
medication regimen has been adjusted in advance. Pregnancy in lupus is prone to complications,
including flares of disease activity during pregnancy or in the postpartum period, preeclampsia,
miscarriage, stillbirth, intrauterine growth retardation, and preterm birth. Active lupus nephritis
poses the greatest risk. The recognition of a lupus flare during pregnancy may be difficult because
the signs and symptoms may mimic those of normal pregnancy. Monitoring should include baseline
and monthly laboratory tests, serial ultrasonography, fetal surveillance tests, and fetal m-mode
echocardiography for mothers with SS-A (Ro) or SS-B (La) antibodies. In the absence of any signs or
symptoms of active SLE, affected patients require no specific treatment during pregnancy. If hydroxychloroquine was in use before conception, it should be maintained throughout pregnancy. If a woman
with SLE has antiphospholipid antibodies, prophylactic treatment with aspirin and/or low-molecular
weight heparin is indicated to prevent fetal loss. Lupus flares during pregnancy are generally treated
with hydroxychloroquine, low-dose prednisone, pulse intravenous methylprednisolone, and azathioprine. High-dose prednisone and cyclophosphamide are reserved for severe lupus complications but
are associated with significant pregnancy-related complications and poor obstetrical outcomes.
Target Audience: Obstetricians and Gynecologists and Family Physicians
Learning Objectives: After completing the CME activity, physicians should be better able to provide
preconception counseling to a woman with lupus, differentiate signs of a lupus flare from symptoms of
pregnancy, differentiate preeclampsia from a flare of lupus nephritis, and differentiate the serious medical
complications of pregnancy in a lupus patient.

Systemic lupus erythematosus (SLE) is a multiorgan autoimmune disease, which disproportionately
Unless otherwise noted below, the authors, faculty and staff in
a position to control the content of this CME activity and their
spouses/life partners (if any) have disclosed that they have no
financial relationships with, or financial interest in, any commercial
organizations pertaining to this educational activity.
Supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (grant R01-AR43737) and National Institute of Dental and Craniofacial Research (contract NOI DE-32636),
Hopkins General Clinical Research Center (grant M01-RR-00052),
and the Jerome L. Greene Foundation.

affects women in their reproductive age years. The
disease is variable in its organ involvement, but is
characterized by the particular manner in which it
involves the skin, joints, serous membranes, kidneys,
and central nervous system (Table 1). It is associated
with the formation of high titers of autoantibodies to
Correspondence requests to: Alan N. Baer, MD, Associate Professor of Medicine, Johns Hopkins University, Clinical Director,
Division of Rheumatology, Good Samaritan Hospital, Suite 508,
Russell Morgan Building, 5601 Loch Raven Boulevard, Baltimore,
MD 21239. E-mail: [email protected].

www.obgynsurvey.com | 639

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Obstetrical and Gynecological Survey

TABLE 1
Major clinical and laboratory features of SLE
Criterion for Disease
Classification*
Cutaneous
Lupus-specific skin disease
Acute cutaneous lupus erythematosus
Malar “butterfly” rash
Subacute cutaneous lupus erythematosus
Discoid lupus
Nonspecific lupus skin lesions
Photosensitivity
Oral/nasopharyngeal ulceration
Livedo reticularis
Nonscarring alopecia
Vascular
Raynaud’s
Cutaneous vasculitis
Musculoskeletal
Arthralgia
Arthritis (ⱖ2 peripheral joints)
Myositis
Serositis
Pleuritis or pericarditis
Renal
Glomerulonephritis
Persistent proteinuria (⬎500 mg/d) or cellular casts
Nephrotic syndrome
Tubulointerstitial disease
Neuropsychiatric
Seizures or psychosis
Stroke
Cranial neuropathy
Transverse myelitis
Organic brain syndrome
Cognitive dysfunction
Pulmonary
Pulmonary fibrosis
Pulmonary hypertension
Cardiac
Endocarditis
Myocarditis
Hematologic
Hemolytic anemia or leucopenia or thrombocytopenia
Lymphadenopathy
Immunologic
Antinuclear antibodies
Lupus autoantibodies
dsDNA antibodies or Sm antibodies or antiphospholipid
antibodies (anticardiolipin antibodies, false-positive
test for syphilis, or lupus anticoagulant)
RNP antibodies
SS-A (Ro) antibodies
SS-B (La) antibodies
Hypocomplementemia

Frequency in Hopkins Lupus Cohort† (%)

X

53
51
21

X
X
X

55
51
21

52
15
93
74
8

X

X

X

Proteinuria: 41
18

X

Seizure: 10; psychosis: 4
4
2
1
5
6
8
8
1
2

X

X
X

Hemolytic anemia: 11; leucopenia: 44;
thrombocytopenia: 21
31
96
dsDNA (57); Sm (16); cardiolipin (48)

26
30
12
54

*To be classified as having systemic lupus erythematosus by the American College of Rheumatology Criteria, a patient must have any
4 or more of the 11 listed criteria, serially or simultaneously, during any interval of observation.1,2 Many other important features of lupus,
shown in the table, are not included in these criteria because they did not add to their ability to differentiate lupus from other systemic
rheumatic diseases.
†
Frequency of disease manifestations among 1827 consecutive patients in the Hopkins Lupus Cohort.

Lupus and Pregnancy Y CME Review Article

an array of ubiquitously expressed nuclear antigens
as well as to a limited number of cell- or tissuespecific antigens. The 1982 American College of
Rheumatology Criteria for Classification of SLE are
commonly used as guidelines for diagnosis (Table
1).1,2 However, they were intended for research classification and may not capture patients with early
disease or limited forms of lupus, such as patients
with isolated lupus nephritis.
The overall prevalence of SLE in the United States
is estimated to be in the range of 14.6 to 50.8 per
100,000 persons.3 It is 3 to 4 times higher in AfricanAmerican women compared with white women living in the United States. The 10-year survival of
patients with SLE has improved over the past 50
years and is now estimated to be 90%.3,4
Pregnancy in the setting of SLE has long been
associated with poor obstetric outcomes, prompting
physicians in the past to advise their lupus patients
not to consider childbirth. However, the frequency of
pregnancy loss in SLE has dropped over the last 40
years from levels as high as 43% in 1960–1965 to
17% in 2000–2003, a level now commensurate with
that of the general US population.5 The management
of maternal complications has also improved dramatically. Pregnancy is thus an option for many women
with lupus and can usually be managed successfully
in a high-risk clinic with the close collaboration of
the obstetrician and rheumatologist. At present, approximately 4500 pregnancies in the United States
each year are in women with SLE6,7 and thus an

641

understanding of the management of these patients is
essential for all obstetricians.
Pregnancy in the setting of SLE is prone to complications and must therefore be considered high-risk. In a
recent US study of 16.7 million pregnancies, 13,555
pregnancies occurred in lupus patients and were associated with a 20-fold increase in maternal mortality
and increased risks for cesarean deliveries (odds ratio: 1.7), preterm labor (odds ratio: 2.4), and preeclampsia (odds ratio: 3.0).6 In addition, there was a
higher rate of thrombotic, infectious, and hematologic complications.
Lupus disease activity may flare during pregnancy
or in the postpartum period. Reported rates of such
flares range from 13.5% to 65% of pregnancies in the
affected women.8 The extent to which this occurs has
been the subject of 7 prospective comparative studies
that have used nonpregnant lupus patients as controls. Of these studies, 4 did not identify an increased
rate of flares, while 3 did.9–16 This disparity reflects
variability in the severity of the lupus among the
patients in the study cohorts and in the criteria for
defining a lupus flare. Some symptoms and laboratory findings of a normal pregnancy can mimic those
of SLE, such as malar erythema, joint pain, anemia,
and mild thrombocytopenia, making it more difficult
to diagnose a lupus flare during pregnancy (Table 2).
Most of the manifestations of active lupus during
pregnancy are mild to moderate in severity and involve the skin and joints.20,21 Approximately 15% to
30% of patients who flare will have severe disease

TABLE 2
Assessment of lupus flares in pregnancy
Feature

Findings Indicative of a Lupus Flare

Findings of Normal Pregnancy That Can Mimic a Flare

Clinical

Active rash of lupus
Inflammatory arthritis
Lymphadenopathy
Fever ⬎38°C (not related to
infection or drug)
Pleuritis
Pericarditis

Erythrocycle sedimentation rate

Increased

Anemia

Hemoglobin ⬍10.5 gm/dL

Thrombocytopenia
Urinalysis
Proteinuria
dsDNA antibodies
Complement

Platelet count ⬍95,000
Hematuria or cellular casts
关ⱖ兴300 mg/d
Rising titers
关ⱖ兴25% drop

Fatigue
Arthralgias
Bland effusions of knees
Myalgias
Malar and palmar erythema
Postpartum hair loss
Carpal tunnel syndrome
Edema of hands, legs, and face
Mild resting dyspnea
18 – 46 mm/h ⬍20 weeks’ gestation
30 –70 mm/h 关ⱖ兴20 weeks’ gestation 17
Hemoglobin ⬎11 gm/dL during first 20 weeks’ gestation
Hemoglobin ⬎10.5 gm/dL h after 20 weeks’
gestation18
Mild in approximately 8%19
Rare hematuria from vaginal contamination
⬍300 mg/d
Negative or stable titers
Usually increased

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Obstetrical and Gynecological Survey

manifestations, with involvement of the kidney and
other internal organs.22 The presence of active SLE
within 6 months before conception is a risk factor for
a flare during pregnancy.
Preeclampsia complicates 13% to 35% of lupus
pregnancies compared with 5% to 8% of pregnancies
in the general US population.7,21,23 This occurs more
commonly in women with active lupus nephritis at
the time of conception.24 Other risk factors include
the sustained use of prednisone in doses of 20 mg
per day or greater during the pregnancy, obesity,
thrombocytopenia, and hypertension, and/or renal
disease.21,25,26
Approximately 19% of lupus pregnancies end with
a miscarriage or stillbirth.27 Up to 55% of these
pregnancy losses occur as stillbirths in the second
trimester, a rate much higher than that of the general
population. Clowse et al identified proteinuria (⬎500
mg/d), secondary antiphospholipid antibody syndrome, thrombocytopenia, and hypertension as 4
first-trimester risk factors for fetal loss.28
Preterm birth (delivery before 37 weeks) and intrauterine growth retardation (IUGR) are also more
common, with reported median prevalences of 33%
(range, 8%–63%) and 9% (range, 2%–40%), respectively.27 These outcomes are often associated with
active lupus nephritis with hypertension during the
first trimester and the subsequent development of
preeclampsia. Other risk factors include other forms
of increased lupus activity at the time of conception
and during the first trimester, a history of a previous
pregnancy loss, and the presence of antiphospholipid
antibodies. IUGR occurs even in those mothers with
mild disease.29 The neonates of lupus patients are
lower in birth weight at every gestational age than
normal controls even when controlling for hypertension and renal disease.30 Lupus may thus have an
effect on fetal growth irrespective of disease activity
or complications.
Active lupus nephritis poses the greatest risk to the
outcome of pregnancy in women with lupus.24 The
rates of pregnancy loss range from 8% to 36% among
patients with a history of lupus nephritis before pregnancy23,31,32 and may reach as high as 52% in women
with active lupus nephritis during pregnancy.31,33
Women with a serum creatinine of ⬎2.8 mg/dL at
the time of conception are at significant risk of preeclampsia and have only 20% to 30% pregnancy
success.34
Neonatal lupus occurs in 3.5% to 8% of lupus
pregnancies.20,35 This disease is associated with maternal anti-SS-A (Ro) (anti-52 kd and anti-60 kd) and
SS-B (La) (anti-48 kd) antibodies. The most serious

complication, in utero heart block (first-, second-, or
third-degree), occurs in 2% of the fetuses of women
with anti-SS-A (Ro) antibodies with a recurrence rate of
20% in subsequent pregnancies.36–39 The most common
manifestation is a rash that typically develops several
weeks into neonatal life. It is photosensitive, tends to
involve the face and scalp, and comprises annular or
elliptical erythematous plaques. It resolves within the
first 6 to 8 months of life, coincident with the clearance
of maternal autoantibodies from the infant’s circulation.
Other manifestations include thrombocytopenia, myocarditis, and hepatitis. Hydroxychloroquine use in pregnancy may reduce the risk of the cardiac manifestations
of neonatal lupus in mothers with anti-SS-A (Ro)
and/or SS-B (La) antibodies.40
Pathophysiology
The potential worsening of lupus during pregnancy
has generally been attributed to the associated alterations of sex hormone levels. Estrogen levels increase progressively in the maternal circulation
during pregnancy, especially in the third trimester.
Estrogens augment immunologic reactivity and have
been implicated as the cause of the increased risk of
autoimmune disease in women.41 Thus, increased
estrogen levels during pregnancy have been postulated to lead to an increased risk of lupus flare.
However, such an increase in estrogen levels was not
documented in a study of 17 pregnant lupus patients,
possibly as a result of placental compromise.42 Additionally, a recent study of transgenic SJL mice with
a common gonadal type showed that the XX sex
chromosome complement, when compared with that
of the XY chromosome, augments the expression of
SLE.43 Thus, there seems to be a direct role for the
sex chromosome complement, independent of the
sex hormone milieu, in the female bias noted in lupus
and other autoimmune diseases.
Placental pathology underlies the poor gestational
outcomes of lupus pregnancies. The primary lesions
relate to the placental vasculature and include decidual vasculopathy, decidual thrombi, and extensive
infarction.44,45 Placental weight is generally reduced.
These lesions are evident in lupus pregnancies
irrespective of the presence of antiphospholipid antibodies. The placental injury may stem from hypercoagulability, hypertension, and immune-mediated
vessel damage.
Complement activation may play a key role in the
genesis of preeclampsia, fetal loss, and intrauterine
growth restriction. The induction of fetal loss and
growth restriction requires complement activation in

Lupus and Pregnancy Y CME Review Article

a murine model of antiphospholipid antibody syndrome.46 Phosphatidylserine, externalized on the
outer leaflet of the trophoblast, serves as a target for
antiphospholipid antibodies. The binding of these
antibodies to the trophoblast, with subsequent activation of complement, is thought to promote an inflammatory response with placental injury and
adverse effects on the fetus. The complement activation product Bb, detected in the serum of pregnant
women (with or without lupus) in their first trimester,
was a strong predictor of the subsequent development of preeclampsia.47 Thus, complement activation
in early pregnancy of women not affected by lupus
may also play a role in the genesis of preeclampsia.
This complement activation may occur as part of a
maternal immune-mediated inflammatory response
to paternally derived fetal antigens on the surface of
trophoblasts. Its role in lupus pregnancies, independent of the presence of antiphospholipid antibodies,
is being explored in the PROMISSE study.48
Neonatal lupus results from the transplacental passage of maternal SS-A (Ro) and SS-B (La) antibodies
that bind to fetal tissue.49 In the heart, these antibodies trigger immune-mediated inflammation of the
atrioventricular nodal and myocardial tissues. Fibrosis then develops in the targeted tissues, resulting in
varying degrees of heart block and occasionally a
cardiomyopathy.
Fertility and Contraception in SLE Patients
Women with SLE have normal fertility, unless they
have advanced renal disease, are amenorrheic as a
result of very active disease, or have received cyclophosphamide therapy for more severe organ manifestations.50 Cyclophosphamide therapy, given either
as intravenous pulse therapy once a month or orally
on a daily basis, is associated with a high rate of
ovarian failure.51–53 The prevention of ovarian toxicity during intravenous cyclophosphamide therapy is
often attempted with the parallel administration of
gonadotropin-releasing hormone agonists (e.g., leuprolide, 3.75 mg, 2 weeks before each cyclophosphamide infusion).54 However, the efficacy of this
approach has not been established,55 and the initiation of these agonists in the follicular phase of the
menstrual cycle may increase estrogen levels and the
risk for thrombotic events. Egg, embryo, or ovarian
cryopreservation techniques are additional options
for fertility preservation before cytotoxic chemotherapy.56 Because the ovarian stimulation before oocyte
retrieval has the potential to increase the risk of
thrombotic events, alternative approaches should

643

be considered in lupus patients.57,58 Ovulation induction with or without in vitro fertilization is an
option for infertile women with SLE. However,
such treatment is only applicable to women with
intact ovarian function and must be approached
carefully because it has been associated with an
increased risk of maternal (lupus flare and thrombosis) and fetal complications.59–61
All women with lupus in their reproductive years
of life should be counseled by their gynecologists
and rheumatologists as to the potential risks of pregnancy, the need for pregnancy planning, and the
efficacy and safety of various modes of contraception. In a recent survey, 23% of women with lupus
reported engaging in frequent unprotected intercourse, emphasizing the need for women with lupus
to receive counseling about pregnancy planning and
appropriate contraception methods.62 Contraceptive
counseling is often not provided to lupus patients at
risk of pregnancy.63
Effective contraception is a key element of pregnancy planning. The safety of estrogen-containing
oral contraceptives in lupus has not been fully established.64 Two randomized placebo-controlled trials
did not show an increased rate of flares among
women with mild, stable lupus, who were receiving
oral contraceptives.65,66 Both studies excluded patients with active lupus, precluding the assessment of
the safety of these pills in patients with more active
disease. The study of Petri et al examined only combined oral contraceptives and precluded patients with
antiphospholipid antibodies or a history of thrombosis.66 The study of Sanchez-Guerero et al also examined progestogen-only pills and copper intrauterine
devices (IUDs) and included women with antiphospholipid antibodies, but not those with antiphospholipid syndrome.65 Alternative forms of contraception
are acceptable. The progesterone-only contraceptive,
Depo-Provera, is commonly used in lupus patients,
but its use for more than 2 years may increase the risk
of osteoporosis. Pregnane progestins may be an acceptable alternative, but are not available in the
United States and are not marketed as contraceptives.67 A levonorgestrel-containing IUD is appropriate for a woman in a monogamous relationship who
is not receiving potent immunosuppressive therapy
that might predispose to infection.68 For most lupus
patients, an IUD would be the optimal choice of
contraception, combining the greatest efficacy with
the least risk. However, IUDs were in use by only 3%
of the women in their reproductive age years, attending the lupus clinic at the University of Pittsburgh.62

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Obstetrical and Gynecological Survey

Preconception Counseling and Management
Pregnancy planning is essential for women with
SLE because the outcomes of such pregnancies are
far better if conception is delayed until the disease
has been inactive for at least 6 months, and the
patient’s medication regimen has been adjusted in
advance (later discussion). Before considering pregnancy, a woman with SLE should meet with both her
rheumatologist and a maternal-fetal medicine specialist to be apprised of the risk of both maternal and
fetal problems, to receive advise about the advisability and timing of pregnancy, and receive a specific
management plan concerning alterations in their medication regimen (if necessary) and monitoring. The steps
in monitoring and managing pregnancy in lupus patients are summarized in the algorithm (Fig. 1).
Conception should be delayed until the patient has
had quiescent SLE for at least 6 months. A small
minority of lupus patients should be advised not to

conceive; these include those with severe pulmonary
hypertension (estimated systolic pulmonary artery
pressure ⬎50 mm Hg), advanced renal insufficiency
(creatinine ⬎2.8 mg/dL), severe restrictive lung disease (forced vital capacity ⬍1 L), heart failure, a
history of severe preeclampsia, or a history within
the past 6 months of a severe lupus flare, active lupus
nephritis, or stroke.26 In the absence of any signs or
symptoms of active SLE, affected patients require no
specific treatment during pregnancy.69 Drug use during
pregnancy is summarized in Table 3. Immunosuppressive medications with potential teratogenicity, including methotrexate, leflunomide, mycophenolate, and
cyclophosphamide, should be stopped at least 3 months
before conception. A more rigorous protocol is required
for the elimination of leflunomide from the patient
before attempted conception. This uses oral cholestyramine for a period of 11 days, followed by a measurement of the blood level. Hydroxychloroquine is safe

Fig. 1. Steps in managing and monitoring a lupus pregnancy.

Lupus and Pregnancy Y CME Review Article

645

TABLE 3
Use of drugs in lupus pregnancy
Drug

FDA Pregnancy-Risk
Category

Nonsteroidal anti-inflammatory
drugs (NSAIDs)
Hydroxychloroquine

C

Nonfluorinated corticosteroids
(e.g., prednisone,
methylprednisolone)
Fluorinated corticosteroids (e.g.,
betamethasone and
dexamethasone)
Intravenous pulse
methylprednisolone
Leflunomide

B

C

Maternal and Fetal Outcomes
Related to Use During Pregnancy
May lead to constriction of fetal
ductus arteriosus.
Considered safe in doses used to
treat lupus
Associated with a small risk of orofacial clefts

Recommendation for Use During
Pregnancy
Avoid, especially in third
trimester
Continue to prevent lupus flares
Treatment of severe flares

C

Cross the placenta

Use only if intent is to treat fetus

B

May reach the fetus

Treatment of severe flares

X

High rate of fetal anomalies in rodent studies but 9.3% in registry
of rheumatoid arthritis patients (compared with 13% for
control RA group and 3.5% for
healthy women)70
Estimated congenital anomaly rate
of 10%–15% with doses used for
rheumatic disease.71 Discontinue
at least 3 menstrual cycles before
attempting to conceive
Use in first trimester associated with
malformations and miscarriage
Use in second and third trimesters associated with growth
retardation, suppression of fetal
hematopoiesis, impaired neurological development.
No increased risk of congenital
anomalies. May be associated
with increased rates of prematurity. Often used during pregnancy
by women with organ transplants
May be associated with IUGR

Contraindicated

Methotrexate

X

Cyclophosphamide

D

Cyclosporine

C

Azathioprine

D

Intravenous immunoglobulin

C

Mycophenolate mofetil

D

Bisphosphonates

C

Warfarin

X

Rituximab

C

Studies in women with multiple
sclerosis and antiphospholipid
antibody syndrome have not revealed any fetal risk.
Increased risk for congenital anomalies, including facial dysmorphia
and malformation of the ears
Cross the placenta; effects on neonatal bone metabolism are
unknown.
Teratogenic in the first trimester
Associated with transient B-cell depletion in fetus if administered to
mother in second or third trimester

Contraindicated

Use only when mother’s life is at
risk and other options
exhausted.

May be used for treatment of
lupus

Long track record of use in lupus pregnancies
May be used for certain lupus
manifestations

Contraindicated

Discontinue before conception

Switch to heparin before
attempting to conceive
May be used for certain lupus
manifestations

FDA pregnancy-risk categories: A, no risk in adequate controlled trials of pregnant women; B, no risk to fetus demonstrated in animal
reproduction studies or adverse effect noted in animal studies but no risk evident in controlled trials of pregnant women; C, no data in
humans are available and animal studies either positive for fetal risk or have not been conducted; D, evidence of human fetal risk exists,
but the potential benefit outweighs the potential risk to the fetus; X, risk associated with the use of the drug clearly outweighs any
positive benefit.72,73
IUGR indicates intrauterine growth retardation.

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Obstetrical and Gynecological Survey

and should be continued during pregnancy. In fact, its
discontinuation may place the patient at greater risk of
increased lupus disease activity during her pregnancy.74,75 If there is a need for continued therapy with
a nonsteroidal immunosuppressive agent, azathioprine
is considered the safest to use because the fetal liver
cannot metabolize azathioprine into its active form.76,77
Low-dose maintenance therapy with corticosteroids can
be maintained if needed for disease control, but the dose
should be kept at levels equivalent to prednisone 10 mg
daily or less. Higher corticosteroid doses have been
reported to increase the risk of hypertension, preeclampsia, preterm birth, premature rupture of
membranes, IUGR, and gestational diabetes in lupus patients. However, this has not been evident in
the therapy of other conditions and has been assessed
to cause a small risk to the developing fetus.72
If a woman with SLE has antiphospholipid antibodies, prophylactic treatment is prescribed to prevent fetal loss. In a first pregnancy, a woman with
antiphospholipid antibodies and with no history of
thrombosis should be treated with low-dose (81 mg)
aspirin alone. A woman with antiphospholipid antibodies and a history of obstetric complications, such
as late (⬎10 weeks) fetal death, IUGR, or preeclampsia should be treated with low-dose aspirin plus lowmolecular weight heparin as soon as the pregnancy is
diagnosed. Enoxaparin 30 mg every 12 hours or
dalteparin 2500 units every 12 hours is used most
commonly. Unfractionated heparin (5000 units every
12 hours) is an acceptable alternative. Low-molecular
weight heparin should be switched to unfractionated heparin 4 weeks before the anticipated delivery date. Unfractionated heparin is discontinued at
the onset of labor or 8 hours before planned cesarean delivery. Heparin is continued for 6 weeks
postpartum. Low-dose aspirin alone may be an
option for a woman with antiphospholipid antibodies and recurrent early (⬍10 weeks gestation) miscarriages,78,79 but many clinicians would prescribe
concomitant heparin.
Diagnostic Testing During Pregnancy
The prenatal care of the pregnant woman with SLE
requires close collaboration between the obstetrician
and the rheumatologist, and management in a highrisk clinic. Recommendations for monitoring the patient during pregnancy are detailed in Table 4 and
Figure 1. The rheumatologist should evaluate the
patient every 4–6 weeks,25 while the obstetrician
should evaluate her every 4 weeks until 20 weeks of
gestation, then every 2 weeks until 28 weeks, and

then weekly until the time of delivery.80 A lower
frequency of obstetrical visits is appropriate if
there are few risk factors for poor obstetrical outcomes.81 The obstetrical visits should include measurement of the woman’s blood pressure, weight
gain, uterine size, fetal heart rate, urinalysis, and
urine protein-to-creatinine ratio. Additionally, the
obstetrician should ask about symptoms of lupus
flares at every visit.
At the onset of pregnancy, baseline laboratory tests
should include, in addition to the standard registration labs, a complete blood count and chemistry
panel as well as measures of lupus activity (C3, C4,
CH50, anti-dsDNA antibodies), risk for neonatal lupus (anti-SS-A (Ro), anti-SS-B (La)), risk for fetal
loss (anticardiolipin antibodies, lupus anticoagulant
[e.g., Russell Viper Venom Test]), and measures of
renal function (urinalysis and spot urine protein-tocreatinine ratio). Because an elevation in the serum
urate level can be a marker of preeclampsia, a baseline level should be obtained. On a monthly basis
throughout the pregnancy, laboratory studies should
include a complete blood count, chemistry panel with
serum urate level, urinalysis, spot urine protein/creatinine ratio, C3, C4, CH50, and dsDNA antibodies.
If there is protein by urine dipstick and/or an elevated
spot urine protein-to-creatinine ratio, then a 24-hour
urine protein-to-creatinine ratio should be measured.82 Additionally, first and/or second trimester
aneuploidy screening should be offered and routine
28-week laboratory tests should be drawn.
A sonogram with measurement of crown-rump distance should be performed early in pregnancy to confirm gestational dating. First trimester nuchal translucency screening should be offered. Another sonogram
should be performed at 16–20 weeks of gestation to
survey for fetal anomalies and to monitor fetal growth.
Subsequent sonograms should be done at 4 week intervals or every 3 weeks in the setting of preeclampsia or
suspected IUGR to monitor fetal growth and measure
amniotic fluid volume. The combination of abdominal
circumference ⬍10th percentile and an estimated fetal
weight ⬍50th percentile is predictive of IUGR when
detected by an ultrasound examination within 5 weeks
of delivery.83 Uterine artery Doppler studies serve to
define the adequacy of uteroplacental blood flow and
may have utility as a predictor of preeclampsia.84 The
first such study may be done around the 20th week of
gestation, and if abnormal, repeated 4 weeks later.85
Fetal surveillance tests should be started at 26–28
weeks and continued weekly until birth. These include the nonstress test (NST), which can begin at 28
weeks, the biophysical profile, which can begin at 26

Lupus and Pregnancy Y CME Review Article

647

TABLE 4
Monitoring of the pregnant lupus patient
Type of Monitoring

Timing During Gestation

Testing

Clinic visit: obstetrician

Conception to 20 weeks: monthly
20 –28 weeks: every 2 weeks
28 weeks to delivery: every week

Clinic visit: rheumatologist
Laboratory

Monthly
Initial assessment

Standard prenatal visit
Standard registration and 28 week labs
Assessment at each visit for signs and symptoms
of lupus
Clinical assessment
Complete blood count
Chemistry panel
Serum urate level
Urinalysis
Spot or 24-h urine protein-to-creatinine ratio
C3, C4, CH50
dsDNA antibodies
SS-A and SS-B antibodies
Cardiolipin antibodies
Lupus anticoagulant assay (e.g., Russell viper
venom test)
Complete blood count
Chemistry panel
Serum urate level
Urinalysis
C3, C4, CH50
dsDNA antibodies
24-h or spot urine protein to creatinine ratio if urine
dipstick positive
Assessment of crown-rump length
Fetal anatomy scan
Monitoring for fetal growth disturbances and
oligohydramnios

Monthly

Sonography

Fetal surveillance

Fetal m-mode echocardiography
(in setting of maternal SS-A
(Ro) and/or SS-B (La)
antibodies)

7–13 wk
16 –20 wk
Then every 4 weeks (or every 3
weeks in setting of preeclampsia or suspected IUGR)
At 26 –28 weeks, and then weekly
until birth

Weekly beginning at 16 weeks
and continuing till delivery

Nonstress test to start at 28 weeks
Biophysical profile to start at 26 weeks
Fetal umbilical artery Doppler velocimetry to start at
26 weeks
Assessment for heart block

IUGR indicates intrauterine growth retardation.

weeks without the NST, and fetal umbilical artery
Doppler velocimetry, which can begin at 26 weeks.
The NST evaluates the fetal heart rate response to
fetal motion. The criteria for an acceleration vary by
gestational age. Between 28 and 32 weeks, it is 10
beats per minute lasting 10 seconds. After 32 weeks,
it is 15 beats per minute lasting 15 seconds. The
biophysical profile provides a score of fetal well
being and includes a NST as well as ultrasound
assessments of fetal breathing motion, fetal body or
limb movement, fetal tone and posture, and determination of an amniotic fluid pocket free of umbilical
cord that is greater than 2 cm in depth. It requires up
to a 30-minute real-time 2-dimensional ultrasound examination of the fetus. Abnormal umbilical and uterine
arterial blood flow assessed with Doppler velocimetry
during the second trimester may be predictive of pre-

eclampsia and IUGR.81,86,87 Detection of IUGR with
these fetal surveillance tests should prompt closer monitoring and consideration of early delivery.
In utero heart block develops as a manifestation of
neonatal lupus after 16 weeks of gestation. Most cases
occur between 16 and 24 weeks, but some occur as late
as 38–40 weeks. Because the early recognition of heart
block in the fetus may allow for therapeutic intervention, close monitoring of at-risk fetuses is mandatory.
The fetal heart rhythm should be monitored by m-mode
echocardiography weekly from 16 weeks onward.80
Differential Diagnosis of Medical Complications
During a Lupus Pregnancy
The close collaboration of a maternal-fetal medicine specialist and a rheumatologist is a key to the

648

Obstetrical and Gynecological Survey

differential diagnosis of medical complications that
may arise in the course of a lupus pregnancy. These
include lupus flares with or without glomerulonephritis, hypertension, preeclampsia, and the HELLP
(hemolysis, elevated liver enzymes, and low platelet
counts) syndrome. The availability of serial laboratory tests (such as serum urate, complement and
dsDNA antibody levels, obtained at booking and
monthly during the pregnancy) greatly facilitates this
diagnostic process.
The recognition of a lupus flare during pregnancy
may be difficult because the signs and symptoms may mimic those of normal pregnancy. Such
flares may occur at any time during pregnancy or in
the immediate postpartum period. However, several
prospective studies have suggested that the frequency
of these flares may be lowest in the third trimester.11,12,88 Severe fatigue, facial and palmar erythema, melasma, postpartum hair loss, dyspnea,
arthralgias, and headaches frequently accompany
normal pregnancy (Table 2).89 Bland joint effusions
occur in late pregnancy.90 In a normal pregnancy, the
maternal blood volume increases by 50%, and the red
cell mass increases by 35%.91 As a result of the
hemodilution, a mild anemia is present in up to 50%
and mild thrombocytopenia is present in up to 8%.19
Renal blood flow and the glomerular filtration rate
increase by more than 50% to accommodate the
increased blood volume, resulting in a decreased
serum creatinine level.34 A serum creatinine level of
⬎0.8 mg/dL and blood urea nitrogen (BUN) level of
⬎13 mg/dL are considered indicative of renal impairment in pregnancy.91 A creatinine level that remains stable throughout pregnancy and does not decrease can also be a sign of renal insufficiency. The
increased renal blood flow results in increased tubular flow and may increase urine protein spillage.
Levels of proteinuria up to 300 mg/d are considered
normal in pregnancy. In women with prior renal
damage from lupus nephritis, the degree of urine
protein loss may increase. However, a doubling in
the amount of the baseline urine protein should be a
cause for concern. Hepatic protein synthesis also
increases in pregnancy, and this can result in higher
levels of the serum complement components as well
as fibrinogen.92,93 The latter may lead to a substantial
increase in the erythrocyte sedimentation rate in a
normal pregnancy.
The differentiation of preeclampsia from lupus glomerulonephritis is notoriously difficult. Both may
present with increasing proteinuria, hypertension,
lower extremity edema, deterioration in renal function, and thrombocytopenia. In addition, the 2 con-

ditions may coexist. Preeclampsia is defined by the
presence of a blood pressure ⬎140/90 and proteinuria ⬎0.3 g in a 24-hour urine specimen detected for
the first time after 20 weeks of gestation. However, a
pregnant woman with more severe lupus may have
hypertension and/or proteinuria in the first half of
pregnancy, thereby obscuring early recognition of
this complication. The risk of preeclampsia is higher
in any woman with a prior or family history of
preeclampsia, body mass index of 35 kg/m2 or
higher, antiphospholipid antibodies, and/or preexisting diabetes, renal disease, or hypertension.94 Elevated serum levels of soluble FMS-like tyrosine
kinase 1 (FLT-1, also known as vascular endothelial
growth factor receptor-1) at 22–32 weeks of gestation are associated with the subsequent development
of preeclampsia in SLE.95 Features of preeclampsia,
which serve to distinguish it from active lupus nephritis are summarized in Table 5 and include a
serum uric acid ⬎5.5 mg/dL, a urine calcium level of
⬍195 mg/d,96 and rising liver enzyme levels. Uterine
artery Doppler ultrasonography may help define inadequate uteroplacental blood flow in preeclampsia.
An increased pulsatility index with notching predicts
preeclampsia in high-risk patients with a positive
likelihood ratio of 21, but is less accurate in cases of
severe preeclampsia.84
Findings indicative of active lupus nephritis include a rise in dsDNA antibody titer, low or dropping
complement levels, clinical evidence of lupus flare in
other organs, and an active urinary sediment. During
normal pregnancy, there is a 10% to 50% increase in
the level of the complement components, probably as
a result of increased hepatic synthesis. Thus, a lupus
flare during pregnancy may be associated with complement levels that have dropped, but still remain in
the “normal” range. Accordingly, a 25% or more
drop in serum complement levels during pregnancy
can be considered indicative of a lupus flare.89 An
TABLE 5
Differentiation of active lupus nephritis from preeclampsia
Active Lupus Nephritis
Hypertension
Proteinuria
Urinary sediment
Uric acid
DNA antibody levels
24-h urine calcium
Complement levels
Soluble FMS-like
tyrosine kinase 1

Preeclampsia

Onset before 20 weeks Onset after 20
weeks
ⱖ300 mg/d
ⱖ300 mg/dL
Active
Inactive
ⱕ5.5 mg/dL
⬎5.5 mg/dL
Rising
Stable or
negative
ⱖ195 mg/d
⬍195 mg/d
ⱖ25% drop
Normal
Normal
Elevated

Lupus and Pregnancy Y CME Review Article

increased level of complement split products, such as
C3a, may also indicate a flare, but measurement of
such split products is not routinely available. A renal
biopsy may be needed to assist in the differentiation,97 although the risk of bleeding after the biopsy
is higher in pregnancy. On occasion, delivery or a
trial of empiric therapy is needed to resolve this
diagnostic challenge.
Several forms of microangiopathy may complicate
pregnancy in lupus, and their differentiation may be
difficult (Table 6), in part because of the potential
overlap of these conditions. However, such differentiation of these microangiopathies is critical because
the management will vary depending on the type
(vide infra). The HELLP syndrome is a complication
of pregnancy, characterized by microangiopathic hemolytic anemia, thrombocytopenia, and liver injury.
It occurs in 0.5% to 0.9% of all pregnancies and in
10% to 20% of cases of severe preeclampsia,102 with
a peak frequency between the 27th and 37th weeks of
gestation. It may develop postpartum in 30% of
cases. Acute fatty liver of pregnancy is a rare complication of pregnancy, which occurs in the third
trimester and is characterized by a conjugated hyperbilirubinemia, elevated hepatic transaminases, and
evidence of disseminated intravascular coagulation.

649

The occasional presence of hypertension, proteinuria,
and thrombocytopenia may lead to confusion with
preeclampsia and/or the HELLP syndrome. However, the presence of hypoglycemia would favor
acute fatty liver. Thrombotic thrombocytopenic
purpura is characterized by microangiopathic hemolytic anemia, severe thrombocytopenia, fever, and
central nervous system and renal disease. It may
occur rarely in conjunction with systemic lupus.103
Lupus patients with high titers of antiphospholipid
antibodies are at risk of thrombotic disease, including
thrombotic microangiopathies affecting the kidneys,
hearts, and lung.104 Pregnant lupus patients with antiphospholipid antibodies may also develop hepatic
infarcts, often in association with the HELLP syndrome.104 Catastrophic antiphospholipid antibody
syndrome (CAPS) is a rare entity, characterized by
an acute thrombotic microangiopathy affecting the
small vessels of at least 3 organ systems. In a series
of 15 patients who developed CAPS in association
with pregnancy, 7 had systemic lupus. The CAPS
occurred during pregnancy in 7 patients, during the
puerperium in 6 patients, and 2 days after a dilatation
and curettage for fetal death at 18 weeks of gestation
in 1 patient.98 The kidneys, lungs, and brain were the

TABLE 6
Differentiation of microangiopathies in lupus pregnancy
HELLP†

Features*
Usual time of onset
Fever
Abdominal pain and other
symptoms
Jaundice
Central nervous system
involvement
Lung involvement
Elevated liver enzymes
Elevated bilirubin
Hepatic infarcts
Hypertension
Proteinuria
DIC
Microangiopathic hemolytic
anemia
Thrombocytopenia
Hypoglycemia
ADAMTS-13 ⬍5%

⬎34 weeks, including postpartum
Absent
60%– 80%
5%–10%
40%– 60%
Rare
100%
50%– 60%
With antiphospholipid
antibodies
80%
90%–95%
5%–56%
50 –100%
Usually ⬎20,000
Absent
Absent

Adapted from references.98–101
†
Hemolysis, elevated liver enzymes, and low platelets.
‡
Acute fatty liver of pregnancy.
§
Thrombotic thrombocytopenic purpura.
¶
Catastrophic antiphospholipid antibody syndrome.

AFLP‡
⬎27 weeks
25%–32%
35%–50%
40%–90%
30%– 40%
Rare
100%
100%

50%
30%–50%
73%
15–20%
None initially
Common
Absent

TTP§

CAPS¶

Late second to early
third trimester
20%–50%
Common

Second or third trimester
or postpartum
10%
Common

Rare

Not reported
60%

66%
Rare
Usually mild
100%

73%
Not reported
Not reported
Not reported

20%–75%
Common
Rare
100%

Not reported
Common
20%
With concomitant HELLP

Usually ⬍20,000
Absent
33%–100%

60%
Absent
Not reported

650

Obstetrical and Gynecological Survey

most commonly affected organs. The HELLP syndrome occurred in 8 of these patients.
Therapy of Lupus Flares During Pregnancy
The management of lupus flares during pregnancy
depends on the severity and type of organ involvement. Joint pain can be managed with acetaminophen. NSAIDs should be avoided during pregnancy.
Their use has been reported to cause reversible oligohydramnios as a result of decreased fetal renal
excretion, prolongation of labor, and premature closure of the patent ductus arteriosus.77 Hydroxychloroquine is generally effective for arthritis and skin
manifestations of lupus. As noted earlier, this drug
decreases the incidence of flares and should be maintained throughout pregnancy, particularly if it was
being used before conception.75
Lupus manifestations that are not adequately controlled with acetaminophen and hydroxychloroquine require corticosteroids. Anemia (hemoglobin ⬍8 g/dL),
sustained fever (⬎38.5°C), and low serum albumin
levels (⬍3 g/dL) threaten the developing fetus and
demand more aggressive therapy.105 Prednisone is the
preferred corticosteroid because it is largely inactivated
by the placenta. The fluorinated glucocorticoids, dexamethasone, and betamethasone, easily cross the placenta, and therefore should only be used if there is
intent to treat the fetus, such as treating in utero heart
block or inducing fetal lung maturation before preterm
delivery. Low-dose prednisone (⬍20 mg/d) can be used
to treat mild lupus activity, and higher doses, including
pulse intravenous methylprednisolone, can be used to
treat more severe lupus activity.106 There may be a
2-fold increased risk for cleft lip or palate with systemic
corticosteroid use in the first trimester, although the
absolute risk remains low (approximately 2/1000 babies
with corticosteroid exposure).107,108
Moderate to severe lupus activity may require
long-term management with a second-line agent in
addition to prednisone. This often facilitates tapering
the prednisone to a lower dose and is thus “steroidsparing.” Azathioprine is the preferred drug in this
category, although its use during pregnancy has been
associated with IUGR and an increased rate of pregnancy loss.76,109 Cyclosporine is safe for the fetus and
can be used to treat renal disease during pregnancy,
but poses risks of maternal nephrotoxicity. Intravenous immunoglobulin has an accepted indication for
the treatment of thrombocytopenia during pregnancy.
Mycophenolate is teratogenic and should be avoided
during pregnancy.110,111 Cyclophosphamide is occasionally used for severe manifestations of lupus that

have not responded to other therapies, with the understanding that the fetus may not survive without
treatment of the mother. Its use in the first trimester
is associated with fetal malformation and in the second and third trimesters with growth retardation and
suppression of fetal hematopoiesis.110
The treatment of chronic hypertension in pregnancy is reserved for patients with diastolic blood
pressures greater than 90 mm Hg. Methyldopa and
labetalol are the preferred agents, but nifedipine can
also be used. Angiotensin-converting enzyme (ACE)
inhibitors and angiotensin receptor blockers are contraindicated in pregnancy because of their association
with irreversible renal damage in the fetus and fetal
loss. Diuretics are usually avoided because they can
decrease intravascular volume. Furosemide is the
loop diuretic with the best track record in the management of chronic renal failure in pregnancy.
The management of microangiopathy in a lupus
pregnancy varies by diagnosis and gestational age.
The HELLP syndrome should be managed with immediate delivery at 34 weeks of gestation or later.112
At 27 to 34 weeks of gestation, delivery should be
within 48 hours, but an initial attempt should be
made to stabilize the patient in a tertiary care unit,
with close maternal and fetal surveillance, and to
administer corticosteroids (e.g., 2 doses of 12 mg
betamethasone 24 hours apart or 6 mg of dexamethasone 12 hours apart) to promote fetal lung maturation. Before 27 weeks of gestation, an attempt to
manage the patient expectantly for more than 48–72
hours may be considered, but immediate delivery is
indicated if the condition of the mother or fetus
deteriorates. Corticosteroids do not seem to reduce
maternal morbidity in the HELLP syndrome, but
may serve to increase the platelet count and allow
vaginal delivery. Women with acute fatty liver of
pregnancy require delivery after stabilization, with
administration of fresh frozen plasma and other
blood products for those with bleeding and/or severe
coagulopathies.99 Thrombotic thrombocytopenic
purpura is treated with plasma exchange or plasmapheresis.113 Catastrophic antiphospholipid syndrome that develops during pregnancy is managed
with prompt delivery. Before delivery, heparin anticoagulation should be maintained and fetal lung maturation should be promoted, if necessary. High-dose
corticosteroids, intravenous immunoglobulin therapy, and plasma exchange were commonly administered in the reported cases of this rare entity.98
The optimal treatment for in utero heart block in a
mother with anti-SS-A (Ro) or SS-B (La) antibodies
has not been established. A retrospective case-control

Lupus and Pregnancy Y CME Review Article

study has suggested that hydroxychloroquine may reduce the risk of its occurrence.40 In 2 recent trials,
intravenous immunoglobulin therapy did not reduce the
expected 20% incidence of fetal heart block in high-risk
pregnant women with a previous pregnancy complicated by this disease.114,115 The initiation of maternal
oral dexamethasone therapy at the first indication of
heart block is recommended. In a recent retrospective
review of 37 consecutive cases of fetal complete atrioventricular heart block observed between 1990 and
2003, Jaeggi et al noted a significant reduction in morbidity and improved outcome for those fetuses and
neonates treated routinely after 1996 with maternal
dexamethasone (4–8 mg/d for 2 weeks, followed
by 4 mg/d) and a beta- sympathomimetic agent (if
the average heart rate declined below 55 bpm)
compared with those who did not routinely receive
transplacental therapy between 1990 and 1996.116 However long-term use of a beta-sympathomimetic agent at the
level that increases fetal heart rate may be associated with
adverse neurobehavioral outcomes in the infant and is
contraindicated.117
Summary
The majority of lupus pregnancies have good outcomes for both the mother and the fetus, but these
outcomes can only be achieved with careful preconception planning, assessment of risk factors, and close
management and monitoring of both the disease and the
health of the fetus. Women with quiescent lupus should
not be discouraged from becoming pregnant, but will
still need to be monitored closely during pregnancy.
The optimal management of the pregnant woman with
lupus should be in a high-risk clinic and involve the
close collaboration of the obstetrician or maternal-fetal
medicine specialist with a rheumatologist.
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